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WO2025054311A1 - Formulation containing taurursodiol and sodium phenylbutyrate - Google Patents

Formulation containing taurursodiol and sodium phenylbutyrate Download PDF

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Publication number
WO2025054311A1
WO2025054311A1 PCT/US2024/045366 US2024045366W WO2025054311A1 WO 2025054311 A1 WO2025054311 A1 WO 2025054311A1 US 2024045366 W US2024045366 W US 2024045366W WO 2025054311 A1 WO2025054311 A1 WO 2025054311A1
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Prior art keywords
composition
impurity
rrt
months
storage
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French (fr)
Inventor
Joshua Barry COHEN
Justin Bernard KLEE
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Amylyx Pharmaceuticals Inc
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Amylyx Pharmaceuticals Inc
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Publication of WO2025054311A1 publication Critical patent/WO2025054311A1/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin

Definitions

  • impurities are classified as organic impurities, inorganic impurities, or residual solvents. Of these three types, inorganic impurities and residual solvents are typically fewer in number and more straightforward to address.
  • Organic impurities may be present in a pharmaceutical composition as a result of synthetic processes or as an unintended by-product from purification or isolation methods.
  • Organic impurities can also arise from handling the active pharmaceutical ingredient (API), during formulation, and/or storage and transport of the final dosage form. These impurities can also arise from other sources including raw materials, side-reactions, reagents, methods or processes, atmospheric contamination during manufacturing, cross-contamination, and the like. Of particular importance are degradation-related impurities, that may occur during storage and handling, i.e., after the dosage form has left its place of manufacture. These types of impurities typically result from various breakdown mechanisms such as Attorney Docket No.38709-0035WO1 hydrolysis, oxidation, ultraviolet light, heat, or from the API interacting with excipients or storage containers.
  • API active pharmaceutical ingredient
  • TURSO sodium phenylbutyrate and taurursodiol
  • ALS amyotrophic lateral sclerosis
  • Certain impurities may be present in a pharmaceutical composition comprising sodium phenylbutyrate and taurursodiol. Detection of these and other impurities is needed to provide a pharmaceutical composition comprising sodium phenylbutyrate and taurursodiol of suitable quality, purity, and strength for use in further clinical studies and in treatments.
  • composition comprising about 8% to about 12% w/w of taurursodiol (TURSO); about 27% to about 32% w/w of sodium phenylbutyrate; wherein the composition comprises not more than (i) 0.2% of an impurity having a relative retention time (RRT) of about 0.18; (ii) 0.4% of an impurity having a RRT of about 0.31; and (iii) 0.4% of an impurity having a RRT of about 0.37; and wherein each RRT is determined relative to sodium phenylbutyrate.
  • RRT relative retention time
  • a method of detecting one or more impurities in a composition comprising about 8% to about 12% w/w of taurursodiol (TURSO); about 27% to about 32% w/w of sodium phenylbutyrate; and one or more impurities, the method comprising: (a) dissolving the composition in a solvent comprising about 5% (v/v) acetonitrile in deionized water to form a mixture; (b) contacting a stationary phase of a C-18 reverse phase chromatography column with the mixture; (c) eluting the mixture with a mobile phase to separate out one or more of the one or more impurities, wherein the mobile phase comprises about 5% to about 95% of 0.5% (v/v) aqueous phosphoric acid and about 5% to about 95% of acetonitrile; and (d) optionally quantifying the amount of the one or more impurities in the composition.
  • TURSO taurursodiol
  • the present disclosure relates to a pharmaceutical composition
  • a pharmaceutical composition comprising sodium phenylbutyrate and taurursodiol (TURSO), with levels of particular impurities specified by their HPLC relative retention time (RRT, relative to TURSO), a dosage form thereof, and methods for detecting one or more impurities within the above described pharmaceutical composition and/or dosage form.
  • RRT HPLC relative retention time
  • the term “approximately” refers to the exact number that it precedes, as well to as modify a number to encompass a range of uncertainty of the number of from 0% to 5% of the numerical value.
  • a composition comprises “not more than” a specified amount of a component (e.g., an impurity)
  • the composition includes the component in an amount of greater than 0% and equal to or lesser than the specified amount.
  • measuring and/or determining that the composition comprises greater than 0% of the component and equal to or lesser than the specified amount is or was performed by high-performance liquid chromatography (HPLC).
  • the composition includes not more than 0.2% of an impurity having a relative retention time (RRT) of about 0.18
  • the composition (i) includes the impurity having the RRT of about 0.18 as measured and/or determined by HPLC; and (ii) includes 0.2% or less of the impurity.
  • unit dosage form(s) includes sachets; tablets; caplets; capsules, such as soft elastic gelatin capsules; cachets; troches; lozenges; dispersions; powders; solutions; gels; liquid dosage forms suitable for oral or mucosal administration to a patient, including suspensions (e.g., aqueous or non-aqueous liquid suspensions), emulsions (e.g., oil-in-water emulsions, or a water-in-oil liquid emulsion), solutions, and elixirs; and sterile solids (e.g., crystalline or amorphous solids) that can be reconstituted to provide liquid dosage forms suitable for oral or parenteral administration to a patient.
  • suspensions e.g., aqueous or non-aqueous liquid suspensions
  • emulsions e.g., oil-in-water emulsions, or a water-in-oil liquid emulsion
  • solutions elixi
  • the unit dosage form does not necessarily have to be administered as a single dose.
  • the term “sachet” refers to a bag or pouch that contains a composition described herein.
  • the composition is vacuum- Attorney Docket No.38709-0035WO1 packed in the sachet, or alternatively or in addition, packaged under an inert atmosphere such as nitrogen or argon.
  • the sachet comprises two or more (e.g., 2, 3, 4, or 5) layers.
  • the layers are selected from, for example, paper, aluminum foil, or plastic.
  • the inner layer of the sachet comprises aluminum.
  • Treating” or “treatment” refers to reducing the symptoms or arresting or inhibiting further development of the disease (in whole or in part). “Treating” or “treatment” includes any effect, e.g., lessening, reducing, modulating, or eliminating, that results in the improvement of the disease and the like.
  • the term “therapeutically effective amount,” as used herein, refers to the amount of one or more active chemical entities or pharmaceutical agent (e.g., TURSO and PB) being administered which elicits the biological or medicinal response in a tissue, system, animal, individual, or human that is being sought. In some embodiments, the response includes reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system.
  • an appropriate “therapeutically effective amount” in any individual case is determined, e.g., using any suitable technique, such as a dose escalation study.
  • the terms "subject” and “patient” are used interchangeably, and refer to any animal, including mammals such as mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, primates, and humans.
  • the subject is a human (e.g., a man, a woman, or a child).
  • the subject has experienced and/or exhibited at least one symptom of the disease or disorder to be treated and/or prevented.
  • FIGS. 1A-1B show a representative chromatogram of diluent at (FIG. 1A) 260 nM and (FIG.
  • FIGS. 2A-2B show a representative chromatogram of working standard solution at (FIG. 2A) 260 nM and (FIG. 2B) 203 nm.
  • FIGS.3A-3B show a representative chromatogram of QL solution at (FIG.3A) 260 nM and (FIG. 3B) 203 nm.
  • FIG. 4 shows a representative chromatogram of resolution solution at 260 nM, observed during validation of HPLC method; shows all impurities.
  • FIG. 5 shows a representative chromatogram of resolution solution at 260 nM, observed with validated HPLC method.
  • FIG.6 shows a representative chromatogram (expanded) of resolution solution at 260 nM, observed with validated HPLC method.
  • FIG. 7 shows a representative chromatogram of resolution solution at 203 nM, observed with validated HPLC method.
  • FIG.8 shows a representative chromatogram (expanded) of resolution solution at 203 nM, observed with validated HPLC method.
  • FIG. 9 shows a representative chromatogram of marker solution at 203 nM.
  • FIG. 10 shows a representative chromatogram of marker solution at 203 nM, expanded scale.
  • FIG. 11 shows a representative chromatogram of flavor masking sample solution spiked with 1% TCDC at 203 nM.
  • FIGS. 17A-17C show a representative UV spectrum of PB and related impurities: FIG 17A is glucosylmaltol, FIG. 17B is impurity A, FIG 17C is PB. FIGS.
  • FIG. 18A-18B shows a representative UV spectrum of PB and related impurities: FIG 18A is impurity B, FIG. 18B is PB at QL level.
  • FIG. 19 shows a representative UV spectrum of impurity RRT 0.18/0.19 at retention time 1.2/2.2 min.
  • FIG.20 shows a representative expanded chromatogram of AMX-0035 sample solution at 260 nM, with peaks 1-4 tabulated.
  • FIGS. 21A-21B show a representative UV spectrum of impurities observed in AMX-0035 sample solution between 3.4 – 3.8 minutes: FIG. 21A is peak 1 and FIG. 21B is peak 2.
  • FIGS. 22A-22B show a representative UV spectrum of impurities observed in AMX-0035 sample solution between 3.4 – 3.8 minutes: FIG.
  • FIGS. 22A is peak 3 and FIG. 22B is peak 4.
  • FIGS. 23A-23B show a representative UV spectrum of impurities observed in AMX-0035 sample solution: FIG.23A is impurity RRT 0.37 and FIG.23B is impurity RRT 0.76.
  • FIGS. 24A-24B show a representative UV spectrum of impurities observed in AMX-0035 sample solution: FIG.24A is impurity RRT 0.83 and FIG.24B is impurity RRT 0.85.
  • FIGS. 25A-25B show a representative UV spectrum of impurities observed in AMX-0035 sample solution: FIG.25A is impurity RRT 0.90 and FIG.25B is impurity RRT 0.92.
  • FIG. 25A-25B show a representative UV spectrum of impurities observed in AMX-0035 sample solution: FIG.25A is impurity RRT 0.90 and FIG.25B is impurity RRT 0.92.
  • FIG. 25A-25B show a representative UV spectrum of impurities
  • FIG. 26 shows a representative UV spectrum of impurity RTT 0.96 observed in AMX-0035 sample solution.
  • FIGS. 27A-27C show a representative UV spectrum of TUDCA and related impurities observed in AMX-0035 sample solution: FIG.27A is TUDCA, FIG.27B is TCDC, and FIG. 27C is UDCA.
  • FIG. 28 shows a representative UV spectrum of TUDCA observed in AMX- 0035 sample solution at QL level.
  • FIG. 29 shows PB assay results for AMX-0035 batches under the proposed storage condition (25°C ⁇ 2°C/ 60% RH ⁇ 5%).
  • Attorney Docket No.38709-0035WO1 FIG.
  • FIG. 30 shows taurursodiol assay results for AMX-0035 batches under the proposed storage condition (25°C ⁇ 2°C/ 60% RH ⁇ 5%).
  • FIG. 31 shows RRT 0.18/0.19 degradation products observed at 260 nm for AMX-0035 batches under the proposed storage condition (25°C ⁇ 2°C/ 60% RH ⁇ 5%).
  • FIG. 32 shows RRT 0.31/0.32 degradation products observed at 260 nm for AMX-0035 batches under the proposed storage condition (25°C ⁇ 2°C/ 60% RH ⁇ 5%).
  • FIG. 33 shows RRT 0.37 degradation product observed at 260 nm for AMX- 0035 batches under the proposed storage condition (25°C ⁇ 2°C/ 60% RH ⁇ 5%).
  • FIG. 34 shows total degradation products observed at 260 nm for AMX-0035 batches under the proposed storage condition (25°C ⁇ 2°C/ 60% RH ⁇ 5%).
  • FIG.35 shows TCDC results observed at 203 nm for AMX-0035 batches under the proposed storage condition (25°C ⁇ 2°C/ 60% RH ⁇ 5%).
  • FIG. 36 shows total degradation products observed at 203 nm for AMX-0035 batches under the proposed storage condition (25°C ⁇ 2°C/ 60% RH ⁇ 5%).
  • FIG. 37 shows pH of reconstituted AMX-0035 batches stored under the proposed storage condition (25°C ⁇ 2°C/ 60% RH ⁇ 5%).
  • a composition comprising taurursodiol (TURSO, also referred to herein as “TUDCA”) and sodium phenylbutyrate.
  • the composition comprises about 8% to about 12% w/w of taurursodiol (TURSO).
  • the composition comprises about 27% to about 32% w/w of sodium phenylbutyrate (“NaPB”, also referred to herein as “PB”).
  • the composition comprises not more than 0.2% of an impurity having a relative retention time (RRT) of about 0.18. In some embodiments, the composition comprises not more than 0.2% of an impurity having a relative retention time (RRT) of about 0.19. In some embodiments, the composition comprises not more than 0.2% of an impurity having a relative retention time (RRT) of about 0.18 or 0.19. In some embodiments, the composition comprises not more than 0.5% of an impurity having a RRT of about 0.30. In some embodiments, the composition comprises not more than 0.4% of an impurity having a RRT of about 0.31.
  • the Attorney Docket No.38709-0035WO1 composition comprises not more than 0.3% of an impurity having a RRT of about 0.31. In some embodiments, the composition comprises not more than 0.4% of an impurity having a RRT of about 0.32. In some embodiments, the composition comprises not more than 0.4% of an impurity having a RRT of about 0.31 or 0.32. In some embodiments, the composition comprises not more than 0.4% of an impurity having a RRT of about 0.37.
  • the composition comprises not more than (i) 0.2% of an impurity having a relative retention time (RRT) of about 0.18; (ii) 0.4% of an impurity having a RRT of about 0.31; and (iii) 0.4% of an impurity having a RRT of about 0.37.
  • each RRT is determined relative to sodium phenylbutyrate.
  • the RRT is determined relative to sodium phenylbutyrate in a high- performance liquid chromatography (HPLC) method.
  • the HPLC method is an HPLC method disclosed herein.
  • the HPLC method is a method delineated under “Methods of Detecting Impurities” or disclosed in Example 1.
  • a composition comprising taurursodiol (TURSO) and sodium phenylbutyrate.
  • the composition comprises approximately 8% to approximately 12% w/w of taurursodiol (TURSO).
  • the composition comprises approximately 27% to approximately 32% w/w of sodium phenylbutyrate.
  • the composition comprises not more than 0.2% of an impurity having a relative retention time (RRT) of approximately 0.18.
  • the composition comprises not more than 0.2% of an impurity having a relative retention time (RRT) of approximately 0.19. In some embodiments, the composition comprises not more than 0.2% of an impurity having a relative retention time (RRT) of approximately 0.18 or 0.19. In some embodiments, the composition comprises not more than 0.5% of an impurity having a RRT of approximately 0.30. In some embodiments, the composition comprises not more than 0.4% of an impurity having a RRT of approximately 0.31. In some embodiments, the composition comprises not more than 0.3% of an impurity having a RRT of approximately 0.31. In some embodiments, the composition comprises not more than 0.4% of an impurity having a RRT of approximately 0.32.
  • the composition comprises not more than 0.4% of an impurity having a RRT of approximately 0.31 or 0.32. In some embodiments, the composition comprises Attorney Docket No.38709-0035WO1 not more than 0.4% of an impurity having a RRT of approximately 0.37. In some embodiments, the composition comprises not more than (i) 0.2% of an impurity having a relative retention time (RRT) of approximately 0.18; (ii) 0.4% of an impurity having a RRT of approximately 0.31; and (iii) 0.4% of an impurity having a RRT of approximately 0.37. In some embodiments, each RRT is determined relative to sodium phenylbutyrate.
  • a composition comprising taurursodiol (TURSO) and sodium phenylbutyrate.
  • the composition comprises 8% to 12% w/w of taurursodiol (TURSO).
  • the composition comprises 27% to 32% w/w of sodium phenylbutyrate.
  • the composition comprises not more than 0.2% of an impurity having a relative retention time (RRT) of 0.18.
  • the composition comprises not more than 0.2% of an impurity having a relative retention time (RRT) of 0.19.
  • the composition comprises not more than 0.2% of an impurity having a relative retention time (RRT) of 0.18 or 0.19.
  • the composition comprises not more than 0.5% of an impurity having a RRT of 0.30. In some embodiments, the composition comprises not more than 0.4% of an impurity having a RRT of 0.31. In some embodiments, the composition comprises not more than 0.3% of an impurity having a RRT of 0.31. In some embodiments, the composition comprises not more than 0.4% of an impurity having a RRT of 0.32. In some embodiments, the composition comprises not more than 0.4% of an impurity having a RRT of 0.31 or 0.32. In some embodiments, the composition comprises not more than 0.4% of an impurity having a RRT of 0.37.
  • the composition comprises not more than (i) 0.2% of an impurity having a relative retention time (RRT) of 0.18; (ii) 0.4% of an impurity having a RRT of 0.31; and (iii) 0.4% of an impurity having a RRT of 0.37.
  • RRT relative retention time
  • each RRT is determined relative to sodium phenylbutyrate.
  • Some embodiments provide a composition comprising about 8% to about 12% w/w of taurursodiol (TURSO); about 27% to about 32% w/w of sodium phenylbutyrate; wherein the composition comprises not more than (i) 0.2% of an impurity having a relative retention time (RRT) of about 0.18; (ii) 0.4% of an impurity having a RRT of about 0.31; and (iii) 0.4% of an impurity having a RRT of about 0.37; and Attorney Docket No.38709-0035WO1 wherein each RRT is determined relative to sodium phenylbutyrate using the HPLC method disclosed in Example 1.
  • RRT relative retention time
  • Some embodiments provide a composition comprising about 8% to about 12% w/w of taurursodiol (TURSO); about 27% to about 32% w/w of sodium phenylbutyrate; wherein the composition comprises not more than (i) 0.2% of an impurity having a relative retention time (RRT) of about 0.18; (ii) 0.4% of an impurity having a RRT of about 0.31; and (iii) 0.4% of an impurity having a RRT of about 0.37; and wherein each RRT is determined relative to sodium phenylbutyrate.
  • RRT relative retention time
  • Some embodiments provide a composition comprising approximately 8% to approximately 12% w/w of taurursodiol (TURSO); approximately 27% to approximately 32% w/w of sodium phenylbutyrate; wherein the composition comprises not more than (i) 0.2% of an impurity having a relative retention time (RRT) of approximately 0.18; (ii) 0.4% of an impurity having a RRT of approximately 0.31; and (iii) 0.4% of an impurity having a RRT of approximately 0.37; and wherein each RRT is determined relative to sodium phenylbutyrate.
  • RRT relative retention time
  • Some embodiments provide a composition comprising 8% to 12% w/w of taurursodiol (TURSO); 27% to 32% w/w of sodium phenylbutyrate; wherein the composition comprises not more than (i) 0.2% of an impurity having a relative retention time (RRT) of 0.18; (ii) 0.4% of an impurity having a RRT of 0.31; and (iii) 0.4% of an impurity having a RRT of 0.37; and wherein each RRT is determined relative to sodium phenylbutyrate.
  • RRT relative retention time
  • Some embodiments provide a composition comprising about 8% to about 12% w/w of taurursodiol (TURSO); about 27% to about 32% w/w of sodium phenylbutyrate; wherein the composition comprises not more than (i) 0.2% of an impurity having a relative retention time (RRT) of about 0.18; (ii) 0.5% of an impurity having a RRT of about 0.30; (iii) 0.4% of an impurity having a RRT of about 0.31; and (iv) 0.4% of an impurity having a RRT of about 0.37; and wherein each RRT is determined relative to sodium phenylbutyrate.
  • RRT relative retention time
  • compositions comprising approximately 8% to approximately 12% w/w of taurursodiol (TURSO); approximately 27% to approximately 32% w/w of sodium phenylbutyrate; Attorney Docket No.38709-0035WO1 wherein the composition comprises not more than (i) 0.2% of an impurity having a relative retention time (RRT) of approximately 0.18; (ii) 0.5% of an impurity having a RRT of approximately 0.30; (iii) 0.4% of an impurity having a RRT of approximately 0.31; and (iv) 0.4% of an impurity having a RRT of approximately 0.37; and wherein each RRT is determined relative to sodium phenylbutyrate.
  • RRT relative retention time
  • Some embodiments provide a composition comprising 8% to 12% w/w of taurursodiol (TURSO); 27% to 32% w/w of sodium phenylbutyrate; wherein the composition comprises not more than (i) 0.2% of an impurity having a relative retention time (RRT) of 0.18; (ii) 0.5% of an impurity having a RRT of 0.30; (iii) 0.4% of an impurity having a RRT of 0.31; and (iv) 0.4% of an impurity having a RRT of 0.37; and wherein each RRT is determined relative to sodium phenylbutyrate.
  • RRT relative retention time
  • Some embodiments provide a composition comprising about 8% to about 12% w/w of taurursodiol (TURSO); about 27% to about 32% w/w of sodium phenylbutyrate; wherein the composition comprises not more than (i) 0.2% of an impurity having a relative retention time (RRT) of about 0.18 or 0.19; (ii) 0.5% of an impurity having a RRT of about 0.30; (iii) 0.4% of an impurity having a RRT of about 0.31 or 0.32; and (iv) 0.4% of an impurity having a RRT of about 0.37; and wherein each RRT is determined relative to sodium phenylbutyrate.
  • RRT relative retention time
  • Some embodiments provide a composition comprising approximately 8% to approximately 12% w/w of taurursodiol (TURSO); approximately 27% to approximately 32% w/w of sodium phenylbutyrate; wherein the composition comprises not more than (i) 0.2% of an impurity having a relative retention time (RRT) of approximately 0.18 or 0.19; (ii) 0.5% of an impurity having a RRT of approximately 0.30; (iii) 0.4% of an impurity having a RRT of approximately 0.31 or 0.32; and (iv) 0.4% of an impurity having a RRT of approximately 0.37; and wherein each RRT is determined relative to sodium phenylbutyrate.
  • RRT relative retention time
  • Some embodiments provide a composition comprising 8% to 12% w/w of taurursodiol (TURSO); 27% to 32% w/w of sodium phenylbutyrate; wherein the composition comprises not more than (i) 0.2% of an impurity having a relative retention time (RRT) of 0.18 or 0.19; (ii) 0.5% of an impurity having Attorney Docket No.38709-0035WO1 a RRT of 0.30; (iii) 0.4% of an impurity having a RRT of 0.31 or 0.32; and (iv) 0.4% of an impurity having a RRT of 0.37; and wherein each RRT is determined relative to sodium phenylbutyrate.
  • RRT relative retention time
  • the composition comprises not more than 0.2% of an impurity having a relative retention time (RRT) of about 0.18. In some embodiments, the composition comprises not more than 0.1% of an impurity having a relative retention time (RRT) of about 0.18. In some embodiments, the composition comprises not more than 0.2% of an impurity having a relative retention time (RRT) of approximately 0.18. In some embodiments, the composition comprises not more than 0.1% of an impurity having a relative retention time (RRT) of approximately 0.18. In some embodiments, the composition comprises not more than 0.2% of an impurity having a relative retention time (RRT) of 0.18.
  • the composition comprises not more than 0.1% of an impurity having a relative retention time (RRT) of 0.18. In some embodiments, the composition comprises not more than 0.2% of an impurity having a relative retention time (RRT) of about 0.19. In some embodiments, the composition comprises not more than 0.1% of an impurity having a relative retention time (RRT) of about 0.19. In some embodiments, the composition comprises not more than 0.2% of an impurity having a relative retention time (RRT) of approximately 0.19. In some embodiments, the composition comprises not more than 0.1% of an impurity having a relative retention time (RRT) of approximately 0.19.
  • the composition comprises not more than 0.2% of an impurity having a relative retention time (RRT) of 0.19. In some embodiments, the composition comprises not more than 0.1% of an impurity having a relative retention time (RRT) of 0.19. In some embodiments, the composition comprises not more than 0.2% of an impurity having a relative retention time (RRT) of about 0.18 or 0.19. In some embodiments, the composition comprises not more than 0.1% of an impurity having a relative retention time (RRT) of about 0.18 or 0.19. In some embodiments, the composition comprises not more than 0.2% of an impurity having a relative retention time (RRT) of approximately 0.18 or 0.19.
  • the composition comprises not more than 0.1% of an impurity having a relative retention time (RRT) of approximately 0.18 or 0.19. In some embodiments, the composition comprises not Attorney Docket No.38709-0035WO1 more than 0.2% of an impurity having a relative retention time (RRT) of 0.18 or 0.19. In some embodiments, the composition comprises not more than 0.1% of an impurity having a relative retention time (RRT) of 0.18 or 0.19. In some embodiments, the composition comprises not more than 0.5% of an impurity having a RRT of about 0.30. In some embodiments, the composition comprises not more than 0.4% of an impurity having a RRT of about 0.30.
  • the composition comprises not more than 0.3% of an impurity having a RRT of about 0.30. In some embodiments, the composition comprises not more than 0.2% of an impurity having a RRT of about 0.30. In some embodiments, the composition comprises not more than 0.1% of an impurity having a RRT of about 0.30. In some embodiments, the composition comprises not more than 0.5% of an impurity having a RRT of approximately 0.30. In some embodiments, the composition comprises not more than 0.4% of an impurity having a RRT of approximately 0.30. In some embodiments, the composition comprises not more than 0.3% of an impurity having a RRT of approximately 0.30.
  • the composition comprises not more than 0.2% of an impurity having a RRT of approximately 0.30. In some embodiments, the composition comprises not more than 0.1% of an impurity having a RRT of approximately 0.30. In some embodiments, the composition comprises not more than 0.5% of an impurity having a RRT of 0.30. In some embodiments, the composition comprises not more than 0.4% of an impurity having a RRT of 0.30. In some embodiments, the composition comprises not more than 0.3% of an impurity having a RRT of 0.30. In some embodiments, the composition comprises not more than 0.2% of an impurity having a RRT of 0.30. In some embodiments, the composition comprises not more than 0.1% of an impurity having a RRT of 0.30.
  • the composition comprises not more than 0.4% of an impurity having a RRT of about 0.31. In some embodiments, the composition comprises not more than 0.3% of an impurity having a RRT of about 0.31. In some embodiments, the composition comprises not more than 0.2% of an impurity having a RRT of about 0.31. In some embodiments, the composition comprises not more than 0.1% of an impurity having a RRT of about 0.31. In some embodiments, the composition comprises not more than 0.4% of an impurity having a RRT of approximately 0.31. In some embodiments, the composition comprises not more than 0.3% of an impurity having a RRT of approximately 0.31.
  • the Attorney Docket No.38709-0035WO1 composition comprises not more than 0.2% of an impurity having a RRT of approximately 0.31. In some embodiments, the composition comprises not more than 0.1% of an impurity having a RRT of approximately 0.31. In some embodiments, the composition comprises not more than 0.4% of an impurity having a RRT of 0.31. In some embodiments, the composition comprises not more than 0.3% of an impurity having a RRT of 0.31. In some embodiments, the composition comprises not more than 0.2% of an impurity having a RRT of 0.31. In some embodiments, the composition comprises not more than 0.1% of an impurity having a RRT of 0.31.
  • the composition comprises not more than 0.4% of an impurity having a RRT of about 0.32. In some embodiments, the composition comprises not more than 0.3% of an impurity having a RRT of about 0.32. In some embodiments, the composition comprises not more than 0.2% of an impurity having a RRT of about 0.32. In some embodiments, the composition comprises not more than 0.1% of an impurity having a RRT of about 0.32. In some embodiments, the composition comprises not more than 0.4% of an impurity having a RRT of approximately 0.32. In some embodiments, the composition comprises not more than 0.3% of an impurity having a RRT of approximately 0.32.
  • the composition comprises not more than 0.2% of an impurity having a RRT of approximately 0.32. In some embodiments, the composition comprises not more than 0.1% of an impurity having a RRT of approximately 0.32. In some embodiments, the composition comprises not more than 0.4% of an impurity having a RRT of 0.32. In some embodiments, the composition comprises not more than 0.3% of an impurity having a RRT of 0.32. In some embodiments, the composition comprises not more than 0.2% of an impurity having a RRT of 0.32. In some embodiments, the composition comprises not more than 0.1% of an impurity having a RRT of 0.32.
  • the composition comprises not more than 0.4% of an impurity having a RRT of about 0.31 or 0.32. In some embodiments, the composition comprises not more than 0.3% of an impurity having a RRT of about 0.31 or 0.32. In some embodiments, the composition comprises not more than 0.2% of an impurity having a RRT of about 0.31 or 0.32. In some embodiments, the composition comprises not more than 0.1% of an impurity having a RRT of about 0.31 or 0.32. In some embodiments, the composition comprises not more than 0.4% of an impurity having a RRT of approximately 0.31 or 0.32.
  • the composition comprises Attorney Docket No.38709-0035WO1 not more than 0.3% of an impurity having a RRT of approximately 0.31 or 0.32. In some embodiments, the composition comprises not more than 0.2% of an impurity having a RRT of approximately 0.31 or 0.32. In some embodiments, the composition comprises not more than 0.1% of an impurity having a RRT of approximately 0.31 or 0.32. In some embodiments, the composition comprises not more than 0.4% of an impurity having a RRT of 0.31 or 0.32. In some embodiments, the composition comprises not more than 0.3% of an impurity having a RRT of 0.31 or 0.32.
  • the composition comprises not more than 0.2% of an impurity having a RRT of 0.31 or 0.32. In some embodiments, the composition comprises not more than 0.1% of an impurity having a RRT of 0.31 or 0.32. In some embodiments, the composition comprises not more than 0.4% of an impurity having a RRT of about 0.37. In some embodiments, the composition comprises not more than 0.3% of an impurity having a RRT of about 0.37. In some embodiments, the composition comprises not more than 0.2% of an impurity having a RRT of about 0.37. In some embodiments, the composition comprises not more than 0.1% of an impurity having a RRT of about 0.37.
  • the composition comprises not more than 0.4% of an impurity having a RRT of approximately 0.37. In some embodiments, the composition comprises not more than 0.3% of an impurity having a RRT of approximately 0.37. In some embodiments, the composition comprises not more than 0.2% of an impurity having a RRT of approximately 0.37. In some embodiments, the composition comprises not more than 0.1% of an impurity having a RRT of approximately 0.37. In some embodiments, the composition comprises not more than 0.4% of an impurity having a RRT of 0.37. In some embodiments, the composition comprises not more than 0.3% of an impurity having a RRT of 0.37.
  • the composition comprises not more than 0.2% of an impurity having a RRT of 0.37. In some embodiments, the composition comprises not more than 0.1% of an impurity having a RRT of 0.37. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of about 0.38. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of approximately 0.38. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of 0.38. Attorney Docket No.38709-0035WO1 In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of about 0.62.
  • the composition further comprises not more than 0.1% of an impurity having a RRT of approximately 0.62. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of 0.62. In some embodiments, the composition further comprises not more than 0.15% of an impurity having a RRT of about 0.63. In some embodiments, the composition further comprises not more than 0.15% of an impurity having a RRT of approximately 0.63. In some embodiments, the composition further comprises not more than 0.15% of an impurity having a RRT of 0.63. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of about 0.63.
  • the composition further comprises not more than 0.1% of an impurity having a RRT of approximately 0.63. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of 0.63. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of about 0.64. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of approximately 0.64. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of 0.64. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of about 0.67.
  • the composition further comprises not more than 0.1% of an impurity having a RRT of approximately 0.67. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of 0.67. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of about 0.68. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of approximately 0.68. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of 0.68. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of about 0.70.
  • the composition further comprises not more than 0.1% of an impurity having a RRT of approximately Attorney Docket No.38709-0035WO1 0.70. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of 0.70. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of about 0.71. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of approximately 0.71. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of 0.71. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of about 0.73.
  • the composition further comprises not more than 0.1% of an impurity having a RRT of approximately 0.73. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of 0.73. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of about 0.74. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of approximately 0.74. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of 0.74. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of about 0.76.
  • the impurity having a RRT of about 0.76 is 4-[4-(3-carboxypropyl)phenyl]-4-oxobutanoic acid. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of approximately 0.76. In some embodiments, the impurity having a RRT of approximately 0.76 is 4-[4-(3-carboxypropyl)phenyl]-4-oxobutanoic acid. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of 0.76.
  • the impurity having a RRT of 0.76 is 4-[4-(3-carboxypropyl)phenyl]-4-oxobutanoic acid.
  • the composition further comprises not more than 0.2% of an impurity having a RRT of about 0.79. In some embodiments, the composition further comprises not more than 0.2% of an impurity having a RRT of approximately 0.79. In some embodiments, the composition further comprises not more than 0.2% of an impurity having a RRT of 0.79. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of about 0.79.
  • the composition further comprises not more than 0.1% of an impurity Attorney Docket No.38709-0035WO1 having a RRT of approximately 0.79. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of 0.79. In some embodiments, the impurity having a RRT of 0.79 is 4-oxo-4-phenylbutanoic acid. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of about 0.80. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of approximately 0.80. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of 0.80.
  • the composition further comprises not more than 0.1% of an impurity having a RRT of about 0.83. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of approximately 0.83. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of 0.83. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of about 0.85. In some embodiments, the impurity having an RRT of about 0.85 is 4-(3-formylphenyl)butanoic acid. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of approximately 0.85.
  • the impurity having an RRT of approximately 0.85 is 4-(3-formylphenyl)butanoic acid. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of 0.85. In some embodiments, the impurity having an RRT of 0.85 is 4-(3- formylphenyl)butanoic acid. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of about 0.86. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of approximately 0.86. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of 0.86.
  • the composition further comprises not more than 0.1% of an impurity having a RRT of about 0.90.
  • the impurity having an RRT of about 0.90 is 4,4’-1,4-phenylene dibutanoic acid.
  • the composition further comprises not more than 0.1% of an impurity having a RRT of approximately 0.90.
  • the impurity having an RRT of approximately 0.90 is 4,4’-1,4-phenylene dibutanoic acid.
  • the Attorney Docket No.38709-0035WO1 composition further comprises not more than 0.1% of an impurity having a RRT of 0.90.
  • the impurity having an RRT of 0.90 is 4,4’-1,4-phenylene dibutanoic acid. In some embodiments, the composition further comprises not more than 0.5% of an impurity having a RRT of about 0.92. In some embodiments, the impurity having an RRT of about 0.92 is 4,4’-1,3-phenylene dibutanoic acid. In some embodiments, the composition further comprises not more than 0.5% of an impurity having a RRT of approximately 0.92. In some embodiments, the impurity having an RRT of approximately 0.92 is 4,4’-1,3-phenylene dibutanoic acid. In some embodiments, the composition further comprises not more than 0.5% of an impurity having a RRT of 0.92.
  • the impurity having an RRT of 0.92 is 4,4’-1,3-phenylene dibutanoic acid. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of about 0.92. In some embodiments, the impurity having an RRT of about 0.92 is 4,4’-1,3-phenylene dibutanoic acid. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of approximately 0.92. In some embodiments, the impurity having an RRT of approximately 0.92 is 4,4’-1,3-phenylene dibutanoic acid. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of 0.92.
  • the impurity having an RRT of 0.92 is 4,4’-1,3-phenylene dibutanoic acid. In some embodiments, the composition further comprises not more than 0.13% of an impurity having a RRT of about 0.96. In some embodiments, the impurity having an RRT of about 0.96 is 4-(8-oxo-5,6,7,8-tetrahydronaphthalen-2-yl) butanoic acid. In some embodiments, the composition further comprises not more than 0.13% of an impurity having a RRT of approximately 0.96.
  • the impurity having an RRT of approximately 0.96 is 4-(8-oxo-5,6,7,8-tetrahydronaphthalen-2-yl) butanoic acid. In some embodiments, the composition further comprises not more than 0.13% of an impurity having a RRT of 0.96. In some embodiments, the impurity having an RRT of 0.96 is 4-(8-oxo-5,6,7,8-tetrahydronaphthalen-2-yl) butanoic acid. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of about 0.96.
  • the impurity having an RRT of about 0.96 is 4-(8-oxo-5,6,7,8-tetrahydronaphthalen-2-yl) butanoic acid.
  • the composition further comprises not more than 0.1% of an impurity Attorney Docket No.38709-0035WO1 having a RRT of approximately 0.96.
  • the impurity having an RRT of approximately 0.96 is 4-(8-oxo-5,6,7,8-tetrahydronaphthalen-2-yl) butanoic acid.
  • the composition further comprises not more than 0.1% of an impurity having a RRT of 0.96.
  • the impurity having an RRT of 0.96 is 4-(8-oxo-5,6,7,8-tetrahydronaphthalen-2-yl) butanoic acid.
  • the composition further comprises not more than 0.1% of an impurity having a RRT of about 0.98. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of approximately 0.98. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of 0.98. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of about 1.04. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of approximately 1.04.
  • the composition further comprises not more than 0.1% of an impurity having a RRT of 1.04.
  • the impurity having a RRT of 1.04 is 3,4-dihydronaphthalen-1(2H)-one.
  • the composition further comprises not more than 0.1% of an impurity having a RRT of about 0.17.
  • the composition further comprises not more than 0.1% of an impurity having a RRT of approximately 0.17.
  • the composition further comprises not more than 0.1% of an impurity having a RRT of 0.17.
  • the composition further comprises not more than 0.1% of an impurity having a RRT of about 0.21.
  • the composition further comprises not more than 0.1% of an impurity having a RRT of approximately 0.21. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of 0.21. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of about 0.22. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of approximately 0.22. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of 0.22. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of about 0.23.
  • the composition Attorney Docket No.38709-0035WO1 further comprises not more than 0.1% of an impurity having a RRT of approximately 0.23. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of 0.23. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of about 0.25. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of approximately 0.25. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of 0.25. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of about 0.27.
  • the composition further comprises not more than 0.1% of an impurity having a RRT of approximately 0.27. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of 0.27. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of about 0.28. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of approximately 0.28. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of 0.28. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of about 0.29.
  • the composition further comprises not more than 0.1% of an impurity having a RRT of approximately 0.29. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of 0.29. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of about 0.30. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of approximately 0.30. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of 0.30. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of about 0.33.
  • the composition further comprises not more than 0.1% of an impurity having a RRT of approximately 0.33. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of 0.33. Attorney Docket No.38709-0035WO1 In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of about 0.34. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of approximately 0.34. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of 0.34. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of about 0.39.
  • the composition further comprises not more than 0.1% of an impurity having a RRT of approximately 0.39. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of 0.39. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of about 0.40. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of approximately 0.40. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of 0.40. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of about 0.41.
  • the composition further comprises not more than 0.1% of an impurity having a RRT of approximately 0.41. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of 0.41. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of about 0.43. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of approximately 0.43. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of 0.43. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of about 0.47.
  • the composition further comprises not more than 0.1% of an impurity having a RRT of approximately 0.53. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of 0.53. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of about 0.60. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of approximately 0.60. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of 0.60. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of about 0.61.
  • the composition further comprises not more than 0.1% of an impurity having a RRT of approximately 0.61. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of 0.61. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of about 0.66. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of approximately 0.66. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of 0.66. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of about 0.68.
  • the composition further comprises not more than 0.1% of an impurity having a RRT of approximately 0.68. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of 0.68. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of about 0.73. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of approximately 0.73. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of 0.73. Attorney Docket No.38709-0035WO1 In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of about 0.77.
  • the composition further comprises not more than 0.1% of an impurity having a RRT of approximately 0.77. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of 0.77. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of about 0.80. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of approximately 0.80. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of 0.80. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of about 0.82.
  • the composition further comprises not more than 0.1% of an impurity having a RRT of approximately 0.82. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of 0.82. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of about 0.83. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of approximately 0.83. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of 0.83. In some embodiments, the impurity having a RRT of 0.83 is 4-(4-formylphenyl)butanoic acid.
  • the composition further comprises not more than 0.1% of an impurity having a RRT of about 0.84. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of approximately 0.84. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of 0.84. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of about 0.85. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of approximately 0.85. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of 0.85.
  • the impurity having a RRT of 0.85 is 4-(3-formylphenyl)butanoic acid.
  • Attorney Docket No.38709-0035WO1 the composition further comprises not more than 0.1% of an impurity having a RRT of about 0.90. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of approximately 0.90. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of 0.90. In some embodiments, the impurity having a RRT of 0.90 is 4-[4-(3-carboxypropyl)-phenyl]-butyric acid.
  • the composition further comprises not more than 0.1% of an impurity having a RRT of about 0.91. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of approximately 0.91. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of 0.91. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of about 0.92. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of approximately 0.92. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of 0.92.
  • the impurity having a RRT of 0.92 is 4,4’-(1,3-phenylene)dibutanoic acid.
  • the composition further comprises not more than 0.1% of an impurity having a RRT of about 0.94. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of approximately 0.94. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of 0.94. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of about 0.96. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of approximately 0.96.
  • the composition further comprises not more than 0.1% of an impurity having a RRT of 0.96.
  • the impurity having a RRT of 0.96 is 4-(8-oxo-5,6,7,8-tetrahydronapthalen-2-yl)butanoic acid.
  • the composition further comprises not more than 0.1% of an impurity having a RRT of about 0.97.
  • the composition further comprises not more than 0.1% of an impurity having a RRT of approximately 0.97.
  • the composition further comprises not more than 0.1% of an impurity having a RRT of 0.97.
  • the composition further comprises not more than 0.1% of an impurity having a RRT of about 0.98. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of approximately 0.98. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of 0.98. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of about 1.66. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of approximately 1.66. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of 1.66.
  • the composition further comprises not more than 0.1% of an impurity having a RRT of about 1.68. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of approximately 1.68. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of 1.68. In some embodiments, the composition further comprises not more than 0.1% of glucosylisomaltol. In some embodiments, the composition further comprises not more than 0.1% of 4-cyclohexylbutanoic acid. In some embodiments, the composition further comprises not more than 0.1% of taurine.
  • the composition further comprises about 0% to about 1% (e.g., about 0% to about 0.125%, about 0% to about 0.5%, about 0% to about 1%, about 0.125%, about 0.5%, or about 1%) w/w ursodeoxycholic acid (UDCA). In some embodiments, the composition further comprises about 0% to about 0.125% w/w Ursodeoxycholic acid (UDCA). In some embodiments, the composition further comprises not more than 1% (e.g., not more than 0.5%, not more than 0.2%, or not more than 0.1%) of UDCA. In some embodiments, the composition further comprises about 0% to about 0.08% w/w UDCA.
  • the amount of each impurity is determined after about 1 week of storage at about 25°C and about 60% relative humidity. In some embodiments, the amount of each impurity is determined after about 2 weeks of storage at about 25°C and about 60% relative humidity. Attorney Docket No.38709-0035WO1 In some embodiments, the amount of each impurity is determined after about 3 weeks of storage at about 25°C and about 60% relative humidity. In some embodiments, the amount of each impurity is determined after about 1 month of storage at about 25°C and about 60% relative humidity. In some embodiments, the amount of each impurity is determined after about 2 months of storage at about 25°C and about 60% relative humidity.
  • the amount of each impurity is determined after about 3 months of storage at about 25°C and about 60% relative humidity. In some embodiments, the amount of each impurity is determined after about 4 months of storage at about 25°C and about 60% relative humidity. In some embodiments, the amount of each impurity is determined after about 5 months of storage at about 25°C and about 60% relative humidity. In some embodiments, the amount of each impurity is determined after about 6 months of storage at about 25°C and about 60% relative humidity. In some embodiments, the amount of each impurity is determined after about 9 months of storage at about 25°C and about 60% relative humidity. In some embodiments, the amount of each impurity is determined after about 12 months of storage at about 25°C and about 60% relative humidity.
  • the amount of each impurity is determined after about 15 months of storage at about 25°C and about 60% relative humidity. In some embodiments, the amount of each impurity is determined after about 18 months of storage at about 25°C and about 60% relative humidity. In some embodiments, the amount of each impurity is determined after about 24 months of storage at about 25°C and about 60% relative humidity. In some embodiments, the amount of each impurity is determined after about 36 months of storage at about 25°C and about 60% relative humidity. In some embodiments, the amount of each impurity is determined after about 1 week of storage at about 40°C and about 75% relative humidity. In some embodiments, the amount of each impurity is determined after about 2 weeks of storage at about 40°C and about 75% relative humidity.
  • the amount of each impurity is determined after about 24 months of storage at about 40°C and about 75% relative humidity. In some embodiments, the amount of each impurity is determined after about 36 months of storage at about 40°C and about 75% relative humidity.
  • the composition is formulated as a unit dosage form. In some embodiments, the unit dosage form is a sachet. In some embodiments, the unit dosage form has substantially the same weight as the initial weight of the unit dosage form after about 1 week of storage at about 40°C and about 75% relative humidity. In some embodiments, the unit dosage form has substantially the same weight as the initial weight of the unit dosage form after about 2 weeks of storage at about 40°C and about 75% relative humidity.
  • the unit dosage form has substantially the same weight as the initial weight of the unit dosage form after about 2 weeks of storage at about 40°C and about 75% relative humidity. In some embodiments, the unit dosage form has substantially the same weight as the initial weight of the unit dosage form after about 1 month of storage at about 40°C and about 75% relative humidity. In some embodiments, the unit dosage form has substantially the same weight as the initial weight of the unit dosage form after about 2 months of storage at about 40°C and about 75% relative humidity. In some embodiments, the unit dosage form has substantially the same weight as the initial weight of the unit dosage form after about 3 months of storage at about 40°C and about 75% relative humidity.
  • the unit dosage form has substantially the same weight as the initial weight of the unit dosage form after about 4 months of storage at about 40°C and about 75% relative humidity. In some embodiments, the unit dosage form has substantially the same weight as the initial weight of the unit dosage form after about 5 months of storage at about 40°C and about 75% relative humidity. In some embodiments, the unit dosage form has substantially the same weight as the initial weight of the unit dosage form after about 6 months of storage at about 40°C and about 75% relative humidity. In some embodiments, the unit dosage form has substantially the same weight as the initial weight of the unit dosage form after about 9 months of storage at about 40°C and about 75% relative humidity.
  • the unit dosage form has substantially the same weight as the initial weight of the unit dosage form after about 12 months of storage at about 40°C and about 75% relative humidity. In some embodiments, the unit dosage form has substantially the same weight as the initial weight of the unit dosage form after about 15 months of storage at about 40°C and about 75% relative humidity. In some embodiments, the unit dosage form has substantially the same weight as the initial weight of the unit dosage form after about 18 months of storage at about 40°C and about 75% relative humidity.
  • Attorney Docket No.38709-0035WO1 In some embodiments, the unit dosage form has substantially the same weight as the initial weight of the unit dosage form after about 24 months of storage at about 40°C and about 75% relative humidity.
  • the unit dosage form has substantially the same weight as the initial weight of the unit dosage form after about 36 months of storage at about 40°C and about 75% relative humidity.
  • the composition comprises not more than 1.2% (w/w) total degradation products characterized at 260 nm.
  • the composition comprises not more than 0.1% total degradation products characterized at 260 nm after about 1 month of storage at about 25°C and about 60% relative humidity.
  • the composition comprises not more than 0.1% total degradation products characterized at 260 nm after about 3 months of storage at about 25°C and about 60% relative humidity.
  • the composition comprises not more than 0.2% total degradation products characterized at 260 nm after about 6 months of storage at about 25°C and about 60% relative humidity. In some embodiments, the composition comprises not more than 0.3% total degradation products characterized at 260 nm after about 9 months of storage at about 25°C and about 60% relative humidity. In some embodiments, the composition comprises not more than 0.3% total degradation products characterized at 260 nm after about 12 months of storage at about 25°C and about 60% relative humidity. In some embodiments, the composition comprises not more than 0.3% total degradation products characterized at 260 nm after about 15 months of storage at about 25°C and about 60% relative humidity.
  • the composition comprises not more than 0.4% total degradation products characterized at 260 nm after about 18 months of storage at about 25°C and about 60% relative humidity. In some embodiments, the composition comprises not more than 0.5% total degradation products characterized at 260 nm after about 24 months of storage at about 25°C and about 60% relative humidity. Attorney Docket No.38709-0035WO1 In some embodiments, the composition comprises not more than 0.5% total degradation products characterized at 260 nm after about 36 months of storage at about 25°C and about 60% relative humidity. In some embodiments, the composition comprises not more than 3.4% total degradation products characterized at 203 nm. In some embodiments, the composition comprises not more than 1.5% total degradation products characterized at 203 nm.
  • the composition comprises not more than 1.2% total degradation products characterized at 203 nm. In some embodiments, the composition comprises not more than 0.5% total degradation products characterized at 203 nm. In some embodiments, the degradation products comprise bile acids. In some embodiments, the degradation products comprise taurochenodeoxycholic acid (TCDC). In some embodiments, the degradation products are bile acids. In some embodiments, the composition comprises not more than 1.5% TCDC. In some embodiments, the composition comprises not more than 1.2% TCDC. In some embodiments, the composition comprises not more than 1% TCDC. In some embodiments, the composition comprises not more than 0.5% TCDC. In some embodiments, the composition comprises not more than 0.14% TCDC.
  • the composition comprises not more than 0.5% of non-TCDC bile acids.
  • Some embodiments provide a composition comprising approximately 8% to approximately 12% w/w of taurursodiol (TURSO); approximately 27% to approximately 32% w/w of sodium phenylbutyrate; wherein the composition comprises not more than 0.1% of glucosylisomaltol; 0.1% of UDCA; 1.5% of TCDC; 0.1% of 4-oxo-4-phenylbutanoic acid; 0.1% of 3,4-dihydronaphthalen-1(2H)-one; 0.1% of 4-cyclohexylbutanoic acid; 0.1% of 4-[4-(3-carboxypropyl)-phenyl]-4-oxobutanoic acid; 0.1% of 4-(4-formylphenyl)butanoic acid; 0.1% of 4-(3-formylphenyl)butanoic acid; 0.1% of 4-[4-(3-carboxypropyl)
  • each RRT is determined relative to sodium phenylbutyrate using the HPLC method in Example 1.
  • TURSO and sodium phenylbutyrate can be formulated for use as or in pharmaceutical compositions.
  • the methods described herein can include administering an effective amount of a composition comprising TURSO and sodium phenylbutyrate.
  • effective amount refer to an amount or a concentration of one or more drugs administered for a period of time (including acute or chronic administration and periodic or continuous administration) that is effective within the context of its administration for causing an intended effect or physiological outcome.
  • the composition can include about 5% to about 15% w/w (e.g., about 6% to about 14%, about 7% to about 13 %, about 8% to about 12%, about 8% to about 11%, about 9% to about 10 %, or about 9.7% w/w) of TURSO and about 15% to about 45% w/w (e.g., about 20% to about 40%, about 25% to about 35%, about 27% to about 32%, about 28% to about 32%, or about 29% to about 30%, e.g., about 29.2% w/w) of sodium phenylbutyrate.
  • the composition includes about 9.7% w/w of TURSO and 29.2% w/w of sodium phenylbutyrate.
  • the composition comprises about 5% to about 15% w/w (e.g., about 6% to about 14%, about 7% to about 13 %, about 8% to about 12%, about 8% to about 11%, about 9% to about 10 %, or about 9.7% w/w) of TURSO. In some embodiments, the composition includes about 9.7% w/w of TURSO. In some embodiments, the composition comprises about 15% to about 45% w/w (e.g., about 20% to about 40%, about 25% to about 35%, about 27% to about 32%, about 28% to about 32%, or about 29% to about 30%, e.g., about 29.2% w/w) of sodium phenylbutyrate.
  • the composition includes about 29.2% w/w of sodium phenylbutyrate.
  • the sodium phenylbutyrate and TURSO can be present in the composition at a ratio by weight of between about 1:1 to about 4:1 (e.g., about 2:1 or about 3:1). In some embodiments, the ratio between sodium phenylbutyrate and TURSO is about 3:1.
  • the compositions described herein can include any pharmaceutically acceptable carrier, adjuvant, and/or vehicle.
  • pharmaceutically acceptable Attorney Docket No.38709-0035WO1 carrier or adjuvant refers to a carrier or adjuvant that may be administered to a patient, together with a compound disclosed herein, and which does not destroy the pharmacological activity thereof and is nontoxic when administered in doses sufficient to deliver a therapeutic amount of the compound.
  • pharmaceutically acceptable carrier includes saline, solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration.
  • the pharmaceutical compositions may contain any conventional non-toxic pharmaceutically-acceptable carriers, adjuvants or vehicles.
  • compositions of the present disclosure can include about 8% to about 24% w/w of dextrates (e.g., about 9% to about 23%, about 10% to about 22%, about 10% to about 20%, about 11% to about 21%, about 12% to about 20%, about 13% to about 19%, about 14% to about 18%, about 14% to about 17%, about 15% to about 16%, or about 15.6% w/w of dextrates). Both anhydrous and hydrated dextrates are contemplated herein.
  • the dextrates of the present disclosure can include a mixture of saccharides developed from controlled enzymatic hydrolysis of starch. Some embodiments of any of the compositions described herein include hydrated dextrates (e.g., NF grade, obtained from JRS Pharma, Colonial Scientific, or Quadra). Compositions of the present disclosure can include about 1% to about 6% w/w of sugar alcohol (e.g., about 2% to about 5%, about 3% to about 4%, or about 3.9% w/w of sugar alcohol). Sugar alcohols can be derived from sugars and contain one hydroxyl group (-OH) attached to each carbon atom. Both disaccharides and monosaccharides can form sugar alcohols. Sugar alcohols can be natural or produced by hydrogenation of sugars.
  • Exemplary sugar alcohols include but are not limited to, sorbitol, xylitol, and mannitol.
  • the composition comprises about 1% to about 6% w/w (e.g., about 2% to about 5%, about 3% to about 4%, about 3.5% to about 4.5%, or about 3.9% w/w) of sorbitol.
  • Compositions of the present disclosure can include about 22% to about 35% w/w of maltodextrin (e.g., about 22% to about 33%, about 24% to about 31%, about 25% to about 32%, about 26% to about 30%, or about 28% to about 29% w/w, e.g., about 28.3% w/w of maltodextrin).
  • Maltodextrin can form a flexible helix enabling Attorney Docket No.38709-0035WO1 the entrapment of the active ingredients (e.g., any of the phenylbutyrate compounds and bile acids described herein) when solubilized into solution, thereby masking the taste of the active ingredients.
  • Maltodextrin produced from any suitable sources are contemplated herein, including but not limited to, pea, rice, tapioca, corn, and potato.
  • the maltodextrin is pea maltodextrin.
  • the composition includes about 28.3% w/w of pea maltodextrin.
  • pea maltodextrin obtained from Roquette KLEPTOSE® LINECAPS
  • the compositions described herein can further include sugar substitutes (e.g. sucralose).
  • the compositions can include about 0.5% to about 5% w/w of sucralose (e.g., about 1% to about 4%, about 1% to about 3%, or about 1% to about 2%, e.g., about 1.9% w/w of sucralose).
  • Other sugar substitutes contemplated herein include but are not limited to aspartame, neotame, acesulfame potassium, saccharin, and advantame.
  • the compositions include one or more flavorants.
  • compositions can include about 2% to about 15% w/w of flavorants (e.g., about 3% to about 13%, about 3% to about 12%, about 4% to about 9%, about 5% to about 10%, or about 5% to about 8%, e.g., about 7.3% w/w).
  • Flavorants can include substances that give another substance flavor, or alter the characteristics of a composition by affecting its taste. Flavorants can be used to mask unpleasant tastes without affecting physical and chemical stability, and can be selected based on the taste of the drug to be incorporated. Suitable flavorants include but are not limited to natural flavoring substances, artificial flavoring substances, and imitation flavors. Blends of flavorants can also be used.
  • compositions described herein can include two or more (e.g., two, three, four, five or more) flavorants.
  • Flavorants can be soluble and stable in water. Selection of suitable flavorants can be based on taste testing. For example, multiple different flavorants can be added to a composition separately, which are subjected to taste testing.
  • Exemplary flavorants include any fruit flavor powder (e.g., peach, strawberry, mango, orange, apple, grape, raspberry, cherry or mixed berry flavor powder).
  • compositions described herein can include about 0.5% to about 1.5% w/w (e.g., about 1% w/w) of a mixed berry flavor powder and/or about 5% to about 7% w/w (e.g., about 6.3% w/w) of a masking flavor.
  • Suitable masking flavors can be obtained from e.g., Firmenich. Attorney Docket No.38709-0035WO1
  • the compositions include one or more flavor-masking agents (also referred to herein as “taste masking agents” and “masking flavor”).
  • compositions can include about 2% to about 15% w/w of flavor-masking agents (e.g., about 3% to about 13%, about 3% to about 12%, about 4% to about 9%, about 5% to about 10%, or about 5% to about 8%, e.g., about 7.3% w/w).
  • Flavor masking agents attenuate undesirable flavors.
  • Exemplary flavor-masking agents include saccharin, saccharin sodium, aspartame, sucrose, fructose, glucose, mannitol, sorbitol, xylitol, erythritol, maltitol, aspartame, sucralose, neotame, saccharine, trehalose, and tagatose.
  • compositions described herein can further include silicon dioxide (or silica). Addition of silica to the composition can prevent or reduce agglomeration of the components of the composition. Silica can serve as an anti-caking agent, adsorbent, disintegrant, or glidant.
  • the compositions described herein include about 0.05% to about 2% w/w of porous silica (e.g., about 0.1% to about 2%, about 0.3% to about 1.5%, about 0.5% to about 1.2%, or about 0.8% to about 1%, e.g., 0.9% w/w).
  • Porous silica may have a higher H 2 O absorption capacity and/or a higher porosity as compared to fumed silica, at a relative humidity of about 20% or higher (e.g., about 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% or higher).
  • the porous silica can have an H 2 O absorption capacity of about 5% to about 40% (e.g. about 20% to about 40%, or about 30% to about 40%) by weight at a relative humidity of about 50%.
  • the porous silica can have a higher porosity at a relative humidity of about 20% or higher (e.g., about 30%, 40%, 50%, 60%, 70%, 80%, 90% or higher) as compared to that of fumed silica.
  • the porous silica have an average particle size of about 2 ⁇ m to about 10 ⁇ m (e.g. about 3 ⁇ m to about 9 ⁇ m, about 4 ⁇ m to about 8 ⁇ m, about 5 ⁇ m to about 8 ⁇ m, or about 7.5 ⁇ m).
  • the porous silica have an average pore volume of about 0.1 cc/gm to about 2.0 cc/gm (e.g., about 0.1 cc/gm to about 1.5 cc/gm, about 0.1 cc/gm to about 1 cc/gm, about 0.2 cc/gm to about 0.8 cc/gm, about 0.3 cc/gm to about 0.6 cc/gm, or about 0.4 cc/gm).
  • the porous silica have a bulk density of about 50 g/L to about 700 g/L (e.g.
  • compositions described herein include Attorney Docket No.38709-0035WO1 about 0.05% to about 2% w/w (e.g., any subranges of this range described herein) of Syloid® 63FP (WR Grace).
  • the compositions described herein can further include one or more buffering agents.
  • the compositions can include about 0.5% to about 5% w/w of buffering agents (e.g., about 1% to about 4% w/w, about 1.5% to about 3.5% w/w, or about 2% to about 3% w/w, e.g. about 2.7% w/w of buffering agents).
  • Buffering agents can include weak acid or base that maintain the acidity or pH of a composition near a chosen value after addition of another acid or base. Suitable buffering agents are known in the art.
  • the buffering agent in the composition provided herein is a phosphate, such as a sodium phosphate (e.g., sodium phosphate dibasic anhydrous).
  • the composition can include about 0.05% to about 5% (e.g., about 1% to about 4%, about 2% to about 3%, or about 2.7%) w/w of sodium phosphate (e.g., sodium phosphate dibasic).
  • the compositions can also include one or more lubricants.
  • the compositions can include about 0.05% to about 1% w/w of lubricants (e.g., about 0.1% to about 0.9%, about 0.2% to about 0.8 %, about 0.3% to about 0.7%, or about 0.4% to about 0.6%, e.g. about 0.5% w/w of lubricants).
  • Exemplary lubricants include, but are not limited to sodium stearyl fumarate, magnesium stearate, stearic acid, metallic stearates, talc, waxes and glycerides with high melting temperatures, colloidal silica, polyethylene glycols, alkyl sulphates, glyceryl behenate, and hydrogenated oil. Additional lubricants are known in the art.
  • the composition includes about 0.05% to about 1% w/w (e.g., any of the subranges of this range described herein) of sodium stearyl fumarate.
  • the composition can include about 0.5% w/w of sodium stearyl fumarate.
  • the composition include about 29.2% w/w of sodium phenylbutyrate, about 9.7% w/w of TURSO, about 15.6% w/w of dextrates, about 3.9% w/w of sorbitol, about 1.9% w/w of sucralose, about 28.3% w/w of maltodextrin, about 7.3% w/w of flavorants, about 0.9% w/w of silicon dioxide, about 2.7% w/w of sodium phosphate (e.g. sodium phosphate dibasic), and about 0.5% w/w of sodium stearyl fumerate.
  • sodium phosphate e.g. sodium phosphate dibasic
  • the composition can include about 3000 mg of sodium phenylbutyrate, about 1000 mg of TURSO, about 1600 mg of dextrates, about 400 mg of sorbitol, about 200 mg of sucralose, about 97.2 mg of silicon dioxide, about 2916 mg of maltodextrin, Attorney Docket No.38709-0035WO1 about 746 mg of flavorants (e.g. about 102 mg of mixed berry flavor and about 644 mg of masking flavor), about 280 mg of sodium phosphate (e.g. sodium phosphate dibasic), and about 48.6 mg of sodium stearyl fumerate.
  • flavorants e.g. about 102 mg of mixed berry flavor and about 644 mg of masking flavor
  • sodium phosphate e.g. sodium phosphate dibasic
  • 48.6 mg of sodium stearyl fumerate e.g. sodium stearyl fumerate.
  • the composition comprises: about 14% to about 17% w/w of dextrates; about 3.5% to about 4.5% w/w of sorbitol; about 25% to about 32% w/w of maltodextrin; and about 0.05% to about 1.5% w/w of porous silica.
  • the composition comprises: about 0.5% to about 5% w/w of sucralose; about 2% to about 15% w/w of flavorants; about 0.5% to about 5% w/w of a buffering agent; and about 0.05% to about 1% w/w of a lubricant.
  • the composition comprises: about 15.6% w/w of dextrates; about 3.9% w/w of sorbitol; about 1.9% w/w of sucralose; about 28.3% w/w of maltodextrin; about 7.3% w/w of flavorants; about 0.9% w/w of porous silica; about 2.7% w/w of sodium phosphate; and about 0.5% w/w of sodium stearyl fumarate.
  • compositions such as but not limited to, xylose, ribose, glucose, mannose, galactose, fructose, dextrose, sucrose, maltose, steviol glycosides, partially hydrolyzed starch, and corn syrup solid.
  • Water soluble artificial sweeteners are contemplated herein, such as the soluble saccharin salts (e.g., sodium or calcium saccharin salts), cyclamate salts, acesulfam potassium (acesulfame K), and the free acid form of saccharin and aspartame based sweeteners such as L-aspartyl- phenylalanine methyl ester, Alitame® or Neotame®.
  • the amount of sweetener or taste masking agents can vary with the desired amount of sweeteners or taste masking agents selected for a particular final composition.
  • Attorney Docket No.38709-0035WO1 Pharmaceutically acceptable binders in addition to those described above are also contemplated.
  • Examples include cellulose derivatives including microcrystalline cellulose, low-substituted hydroxypropyl cellulose (e.g. LH 22, LH 21, LH 20, LH 32, LH 31, LH30); starches, including potato starch; croscarmellose sodium (i.e. cross- linked carboxymethylcellulose sodium salt; e.g. Ac-Di-Sol®); alginic acid or alginates; insoluble polyvinylpyrrolidone (e.g. Polyvidon® CL, Polyvidon® CL-M, Kollidon® CL, Polyplasdone® XL, Polyplasdone® XL-10); and sodium carboxymethyl starch (e.g. Primogel® and Explotab®).
  • croscarmellose sodium i.e. cross- linked carboxymethylcellulose sodium salt
  • alginic acid or alginates alginic acid or alginates
  • insoluble polyvinylpyrrolidone e.g. Polyvidon® CL, Polyvidon®
  • Additional fillers, diluents or binders may be incorporated such as polyols, sucrose, sorbitol, mannitol, Erythritol®, Tagatose®, lactose (e.g., spray-dried lactose, ⁇ -lactose, ⁇ -lactose, Tabletose®, various grades of Pharmatose®, Microtose or Fast- Floc®), microcrystalline cellulose (e.g., various grades of Avicel®, such as Avicel® PH101, Avicel® PH102 or Avicel® PH105, Elcema® P100, Emcocel®, Vivacel®, Ming Tai® and Solka-Floc®), hydroxypropylcellulose, L-hydroxypropylcellulose (low-substituted) (e.g.
  • the compositions described herein can be formulated or adapted for administration to a subject via any route (e.g. any route approved by the Food and Drug Administration (FDA)).
  • FDA Food and Drug Administration
  • compositions are typically formulated to be compatible with its intended route of administration.
  • routes of administration include parenteral (subcutaneous, intracutaneous, intravenous, intradermal, intramuscular, intra-articular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques), oral (e.g., inhalation or through a feeding tube), transdermal (topical), transmucosal, and rectal administration.
  • compositions can be in the form of a solution or powder for inhalation and/or nasal administration.
  • the pharmaceutical composition is formulated as a powder filled sachet.
  • Suitable powders may include those that are substantially soluble in water.
  • Pharmaceutical compositions may be Attorney Docket No.38709-0035WO1 formulated according to techniques known in the art using suitable dispersing or wetting agents (such as, for example, Tween 80) and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non- toxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3- butanediol.
  • Suitable vehicles and solvents that may be employed are mannitol, water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions.
  • oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, or carboxymethyl cellulose or similar dispersing agents which are commonly used in the formulation of pharmaceutically acceptable dosage forms such as emulsions and or suspensions.
  • a long-chain alcohol diluent or dispersant or carboxymethyl cellulose or similar dispersing agents which are commonly used in the formulation of pharmaceutically acceptable dosage forms such as emulsions and or suspensions.
  • Other commonly used surfactants such as Tweens or Spans and/or other similar emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.
  • the compositions can be orally administered in any orally acceptable dosage form including, but not limited to, powders, capsules, tablets, emulsions and aqueous suspensions, dispersions and solutions.
  • the powders can be substantially dissolved in water prior to administration.
  • carriers which are commonly used include lactose and corn starch.
  • Lubricating agents such as magnesium stearate, may be added.
  • useful diluents include lactose and dried corn starch.
  • the active ingredient may be suspended or dissolved in an oily phase is combined with emulsifying and/or suspending agents. If desired, certain sweetening and/or flavoring and/or coloring agents may be added.
  • the compositions can be administered by nasal aerosol or inhalation.
  • compositions are prepared according to techniques well- known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters Attorney Docket No.38709-0035WO1 to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents known in the art.
  • therapeutic compositions disclosed herein can be formulated for sale in the US, imported into the US, and/or exported from the US.
  • the pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration.
  • the disclosure provides kits that include the bile acid and phenylbutyrate compounds.
  • the kit may also include instructions for the physician and/or patient, syringes, needles, box, bottles, vials, etc.
  • Some embodiments provide a sachet containing a compound disclosed herein.
  • the composition is vacuum-packed in the sachet.
  • the composition is packed under an inert atmosphere (e.g, under nitrogen) in the sachet.
  • the sachet contains a desiccant.
  • the desiccant is selected from silica gel, activated alumina, aerogel, bentonite clay, anhydrous magnesium sulfate, and anhydrous calcium sulfate (i.e., drierite).
  • the sachet comprises two or more layers. In some embodiments, the sachet comprises two layers. In some embodiments, the sachet comprises three layers. In some embodiments, the sachet comprises four layers. In some embodiments at least one (e.g., one) of the layers comprises aluminum. In some embodiments, the layer comprising aluminum has a surface facing the inside of the sachet.
  • the package contains six sachets. In some embodiments, the package contains eight sachets. In some embodiments, the package contains ten sachets. In some embodiments, the package contains twelve sachets. In some embodiments, the package contains an even number of sachets. In some embodiments, the package contains an odd number of sachets. In some embodiments, the package contains a number of sachets, wherein the number is a multiple of five. In some embodiments, the package contains a number of sachets, wherein the number is a multiple of ten. In Attorney Docket No.38709-0035WO1 some embodiments, the package is a box.
  • the package is a box comprising cardboard.
  • the kit comprises one or more sachets, wherein each sachet contains a composition described herein; and instructions for preparing and/or administering the composition to a subject.
  • Some embodiments provide a method of detecting one or more impurities in a composition comprising about 8% to about 12% w/w of taurursodiol (TURSO); about 27% to about 32% w/w of sodium phenylbutyrate; and one or more impurities, the method comprising: (a) dissolving the composition in a solvent comprising about 5% (v/v) acetonitrile in deionized water to form a mixture; (b) contacting a stationary phase of a C-18 reverse phase chromatography column with the mixture; (c) eluting the mixture with a mobile phase to separate out one or more of the one or more impurities, wherein the mobile phase comprises about 5% to about 95% of 0.5% (v/v) aqueous phosphoric acid and about 5% to about 95% of acetonitrile; and (d) optionally quantifying the amount of the one or more impurities in the composition.
  • TURSO taurursodiol
  • the composition has one or more characteristics described previously herein. In some embodiments, the composition was obtained from a single sachet. In some embodiments, the solvent comprising about 5% (v/v) acetonitrile in deionized water is about 5% (v/v) acetonitrile in deionized water.
  • the method comprises contacting a solvent comprising about 5% (v/v) acetonitrile in deionized water with the stationary phase before step (b); and eluting the solvent comprising about 5% (v/v) acetonitrile in deionized water with a mobile phase, wherein the mobile phase comprises about 5% to about 95% of 0.5% (v/v) aqueous phosphoric acid and about 5% to about 95% of acetonitrile.
  • the method comprises contacting and eluting the solvent comprising about 5% (v/v) acetonitrile in deionized water with the stationary phase before step (b).
  • the method comprises contacting and eluting the solvent Attorney Docket No.38709-0035WO1 comprising about 5% (v/v) acetonitrile in deionized water with the stationary phase before contacting the QL solution with the stationary phase.
  • the method comprises contacting a quantitation limit (QL) solution comprising about 2 to about 5 mg/mL TURSO and about 0.25 to about 3 mg/mL sodium phenylbutyrate dissolved in a solvent comprising about 5% (v/v) acetonitrile in deionized water with the stationary phase; and eluting the QL solution with a mobile phase, wherein the mobile phase comprises about 5% to about 95% of 0.5% (v/v) aqueous phosphoric acid and about 5% to about 95% of acetonitrile.
  • QL quantitation limit
  • the method comprises contacting a quantitation limit (QL) solution comprising about 2.25 mg/mL TURSO and about 0.75 mg/mL sodium phenylbutyrate dissolved in a solvent comprising about 5% (v/v) acetonitrile in deionized water with the stationary phase; and eluting the QL solution with a mobile phase, wherein the mobile phase comprises about 5% to about 95% of 0.5% (v/v) aqueous phosphoric acid and about 5% to about 95% of acetonitrile.
  • the method comprises contacting and eluting the QL solution with the stationary phase before step (b).
  • the method comprises contacting and eluting the QL solution with the stationary phase before contacting the resolution solution with the stationary phase.
  • the method comprises contacting a resolution solution comprising one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, or 9) impurities selected from the group consisting of: an impurity having a RRT of about 0.76, an impurity having a RRT of about 0.79 (4-oxo-4-phenylbutanoic acid), an impurity having a RRT of about 0.83, an impurity having a RRT of about 0.85, an impurity having a RRT of about 0.90, an impurity having a RRT of about 0.92, an impurity having a RRT of about 0.86, an impurity having a RRT of about 1.04 (3,4-dihydronaphthalen-1(2H)-one), and glucosylisomaltol dissolved in a solvent comprising about 5% (v/v) acet
  • the method comprises an impurity having a RRT of about 0.76, an impurity having a RRT of about 0.79 (4-oxo-4-phenylbutanoic acid), an impurity having a RRT of about 0.83, an impurity having a RRT of about 0.85, an impurity having a RRT of about 0.90, an impurity having a RRT of about 0.92, an impurity Attorney Docket No.38709-0035WO1 having a RRT of about 0.86, an impurity having a RRT of about 1.04 (3,4- dihydronaphthalen-1(2H)-one), and glucosylisomaltol dissolved in a solvent comprising about 5% (v/v) acetonitrile in deionized water.
  • the method comprises contacting a marker solution comprising about 1.5 mg/mL TURSO and about 4.5 mg/mL sodium phenylbutyrate dissolved in a solvent comprising about 5% (v/v) acetonitrile in deionized water with the stationary phase before step (b); and eluting the QL solution with a mobile phase, wherein the mobile phase comprises about 5% to about 95% of 0.5% (v/v) aqueous phosphoric acid and about 5% to about 95% of acetonitrile.
  • the method comprises contacting and eluting the marker solution with the stationary phase before step (b).
  • the method comprises contacting and eluting the marker solution with the stationary phase before contacting the flavor masking sample solution with the stationary phase.
  • the weight ratio of flavor-masking agent to sodium phenyl butyrate added to the methanolic solution of TCDC is about 6:90 to about 2:1 (e.g., about 7:45, about 8:45, about 9:45, about 9.6:45, about 10:45, about 11:45, about 12:45).
  • the weight ratio of sodium phenyl butyrate to TURSO added to the methanolic solution of TCDC is about 10:1 to about 1:1 (e.g., about 45:10, about 45:11, about 45:12, about 45:13, about 45:14, about 45:15, about 45:16, about 45:17, about 45:18, about 45:19, about 45:20).
  • the weight ratio of flavor-masking agent, sodium phenylbutyrate, and TURSO added to the methanolic solution is about 9.6:45:15.
  • the w/v ratio of the flavor-masking agent to the methanolic solution is about 50:1 to about 1:2 (e.g., about 1:1 to about 50:1, about 2:1 to about 40:1, about 5:1 to about 40:1, about 10:1 to about 40:1, about 15:1 to about 25:1, about 17:1, about 18:1, about 19:1, about 19.3:1, about 20:1, about 21:1, about 22:1, or about 23:1).
  • the w/v ratio of flavor-masking agent to the solvent comprising about 5% (v/v) acetonitrile in deionized water is about 10:1 to about 1:2 (e.g., about 5:1 to about 1:1, about 4:1 to about 1:1, about 4:1 to about 1:1, about 3:1 to about 1:1, about 2:1 to about 1:1, about 1.5:1 to about 1:1, about 2:1, about 1.38:1, about 1:1).
  • the method comprises adding flavor-masking agent, sodium phenylbutyrate, and TURSO in an about 9.6:45:15 weight ratio to a methanolic solution of 300 mg/mL taurochenodeoxycholic acid (TCDC) to form a flavor-masking agent mixture, wherein the w/v ratio of the flavor-masking agent to the methanolic solution is about 19.3:1; adding a solvent comprising about 5% (v/v) acetonitrile in deionized water to the flavor-masking agent mixture to form a diluted flavor-masking agent mixture, wherein the w/v ratio of flavor-masking agent to the solvent comprising about 5% (v/v) acetonitrile in deionized water is about 1.38:1; agitating the diluted flavor-masking agent mixture; diluting the diluted flavor-masking agent mixture with about 5 mL to about 25 mL (e.g., about 7 mL, about 9 mL, about
  • TCDC
  • the method comprises contacting the flavor masking sample solution with the stationary phase; and eluting the flavor masking sample solution with Attorney Docket No.38709-0035WO1 a mobile phase, wherein the mobile phase comprises about 5% to about 95% of 0.5% (v/v) aqueous phosphoric acid and about 5% to about 95% of acetonitrile.
  • the method comprises contacting and eluting the flavor masking sample solution with the stationary phase before step (b).
  • the method comprises contacting and eluting the flavor masking sample solution with the stationary phase before contacting the working standard solution with the stationary phase.
  • the method comprises dissolving TURSO and sodium phenylbutyrate in a solvent comprising about 5% (v/v) acetonitrile in deionized water to provide a working standard solution, wherein the concentration of TURSO in the working standard solution is about 10 mg/mL to about 1500 mg/mL (e.g., about 10 mg/mL to about 1000 mg/mL, about 10 mg/mL to about 750 mg/mL, about 10 mg/mL to about 500 mg/mL, about 10 mg/mL to about 250 mg/mL, about 10 mg/mL to about 150 mg/mL, about 40 mg/mL to about 110 mg/mL, about 50 mg/mL to about 100 mg/mL, about 60 mg/mL to about 90 mg/mL, about 65 mg/mL to about 85 mg/mL, or about 75 mg/mL) and the concentration of sodium phenylbutyrate in the working standard solution is about 225 mg/mL.
  • the method comprises dissolving TURSO and sodium phenylbutyrate in a solvent comprising about 5% (v/v) acetonitrile in deionized water to provide a working standard solution, wherein the concentration of TURSO in the working standard solution is about 75 mg/mL and the concentration of sodium phenylbutyrate in the working standard solution is about 225 mg/mL.
  • the method comprises contacting the working standard solution with the stationary phase; and eluting the working standard solution with a mobile phase, wherein the mobile phase comprises about 5% to about 95% of 0.5% (v/v) aqueous phosphoric acid and about 5% to about 95% of acetonitrile.
  • the method comprises contacting and eluting the working standard solution with the stationary phase before step (b). In some embodiments, the method comprises contacting and eluting the working standard solution with the stationary phase before contacting the placebo sample solution with the stationary phase. In some embodiments, the contacting and eluting is performed at least two consecutive times (e.g., three consecutive times, four consecutive times, five consecutive times, or six consecutive times). In some embodiments, the contacting and eluting is performed six consecutive times. In some embodiments, when the contacting and eluting is performed Attorney Docket No.38709-0035WO1 at leas two consecutive times, the at least two consecutive times are performed before contacting the placebo sample solution with the stationary phase.
  • the method comprises adding one or more of hydrated dextrates, sorbitol, sucralose, silicon dioxide, maltodextrin, sodium phosphate dibasic anhydrous, sodium stearyl fumarate, a flavorant, and a flavor-masking agent to about 5% (v/v) acetonitrile in deionized water to form a placebo mixture; agitating the placebo mixture; diluting the placebo mixture with about 5 mL to about 25 mL (e.g., about 7 mL, about 9 mL, about 11 mL, about 13 mL, about 15 mL, about 17 mL, about 19 mL, about 21 mL, about 23 mL, or about 25 mL) additional 5% (v/v) acetonitrile in deionized water; and filtering to provide a placebo sample solution.
  • a placebo mixture e.g., about 7 mL, about 9 mL, about 11 mL, about 13 m
  • the method comprises adding hydrated dextrates, sorbitol, sucralose, silicon dioxide, maltodextrin, sodium phosphate dibasic anhydrous, sodium stearyl fumarate, a flavorant, and a flavor-masking agent to about 5% (v/v) acetonitrile in deionized water to form a placebo mixture; agitating the placebo mixture; diluting the placebo mixture with about 5 mL to about 25 mL (e.g., about 7 mL, about 9 mL, about 11 mL, about 13 mL, about 15 mL, about 17 mL, about 19 mL, about 21 mL, about 23 mL, or about 25 mL) additional 5% (v/v) acetonitrile in deionized water; and filtering to provide a placebo sample solution.
  • a placebo mixture e.g., about 7 mL, about 9 mL, about 11 mL, about 13 mL, about 15
  • the ratio of sorbitol to 5% (v/v) acetonitrile in deionized water is about 0.1:1 to about 10:1 (e.g., about 0.4:1 to about 3:1, about 0.5:1 to about 2:1, about 0.6:1 to about 1.5:1, about 0.7:1 to about 1:1, about 0.8:1 to about 0.9:1, or about 0.85:1).
  • the placebo mixture is filtered through a 0.45 mm pore size polytetrafluoroethylene (PTFE) filter.
  • the method comprises adding hydrated dextrates, sorbitol, sucralose, silicon dioxide, maltodextrin, sodium phosphate dibasic anhydrous, sodium stearyl fumarate, a flavorant, and a flavor-masking agent in an about 1600:400:200:97:2916:280:49:644:102 weight ratio to about 5% (v/v) acetonitrile in deionized water, wherein the ratio of sorbitol to 5% (v/v) acetonitrile in deionized water is about 0.85:1, to form a placebo mixture; agitating the placebo mixture; diluting the placebo mixture with about 5 mL to about 25 mL (e.g., about 7 mL, about 9 mL, about 11 mL, about 13 mL, about 15 mL, about 17 mL, about 19 mL, about 21 mL, about 23 mL, or about 25 mL) additional 5% (v
  • the method comprises contacting the placebo Attorney Docket No.38709-0035WO1 sample solution with the stationary phase; and eluting the working standard solution with a mobile phase, wherein the mobile phase comprises about 5% to about 95% of 0.5% (v/v) aqueous phosphoric acid and about 5% to about 95% of acetonitrile; wherein the contacting and eluting are performed before step (b).
  • the column has a diameter of about 4.6 mm.
  • the column has a length of about 150 mm.
  • the phosphoric acid is o-phosphoric acid.
  • the volume of mixture contacted with the column in step (b) is about 5 mL to about 35 mL (e.g., about 10 mL to about 30 mL, about 15 mL to about 25 mL, about 17 mL to about 23 mL). In some embodiments, the volume of mixture contacted in step (b) is about 20 mL. In some embodiments, the contacting of step (b) comprises injecting the mixture into the column.
  • the mobile phase comprises a gradient that starts at about 95% of 0.5% (v/v) aqueous phosphoric acid and about 5% of acetonitrile and over a time period of 2-30 minutes changes to about 5% of 0.5% (v/v) aqueous phosphoric acid and about 95% of acetonitrile. In some embodiments, the mobile phase comprises a gradient that starts at about 95% of 0.5% (v/v) aqueous phosphoric acid and about 5% of acetonitrile and over a time period of 10-25 minutes changes to about 5% of 0.5% (v/v) aqueous phosphoric acid and about 95% of acetonitrile.
  • the mobile phase comprises a gradient that starts at about 95% of 0.5% (v/v) aqueous phosphoric acid and about 5% of acetonitrile and over a time period of 13-23 minutes changes to about 5% of 0.5% (v/v) aqueous phosphoric acid and about 95% of acetonitrile.
  • the time period is about 5 minutes to about 30 minutes (e.g., about 10 minutes to about 25 minutes, about 15 minutes to about 21 minutes, about 20 minutes to about 30 minutes, about 23 minutes to about 27 minutes, about 18 minutes, or about 25 minutes). In some embodiments, the time period is about 18 minutes. In some embodiments, the time period is about 25 minutes.
  • the mobile phase comprises a gradient that starts at about 95% of 0.5% (v/v) aqueous phosphoric acid and about 5% of acetonitrile and over a Attorney Docket No.38709-0035WO1 time period of about 15 minutes to about 21 minutes changes to about 5% of 0.5% (v/v) aqueous phosphoric acid and about 95% of acetonitrile.
  • the mobile phase comprises a gradient that starts at about 95% of 0.5% (v/v) aqueous phosphoric acid and about 5% of acetonitrile and over a time period of about 18 minutes changes to about 5% of 0.5% (v/v) aqueous phosphoric acid and about 95% of acetonitrile. In some embodiments, the mobile phase comprises a gradient that starts at about 95% of 0.5% (v/v) aqueous phosphoric acid and about 5% of acetonitrile and over a time period of 25 minutes changes to about 5% of 0.5% (v/v) aqueous phosphoric acid and about 95% of acetonitrile.
  • the mobile phase comprises a gradient that starts at about 95% of 0.5% (v/v) aqueous phosphoric acid and about 5% of acetonitrile; over a time period of about 18 minutes changes to about 5% of 0.5% (v/v) aqueous phosphoric acid and about 95% of acetonitrile; and over a time period of about 7 minutes changes to about 95% of 0.5% (v/v) aqueous phosphoric acid and about 5% of acetonitrile.
  • the mobile phase comprises: a gradient that starts at about 95% of 0.5% (v/v) aqueous phosphoric acid and about 5% of acetonitrile, and over a time period of about 7 minutes to about 11 minutes changes to about 55% of 0.5% (v/v) aqueous phosphoric acid and about 45% of acetonitrile; an isocratic elution of about 55% of 0.5% (v/v) aqueous phosphoric acid and about 45% of acetonitrile over a time period of about 3 minutes to about 7 minutes; a gradient that changes over a time period of about 2 minutes to about 6 minutes to about 5% of 0.5% (v/v) aqueous phosphoric acid and about 95% of acetonitrile; an isocratic elution of about 5% of 0.5% (v/v) aqueous phosphoric acid and about 95% of acetonitrile over a time period of about 1 minute to about 3 minutes; and an isocratic
  • the mobile phase comprises: a gradient that starts at about 95% of 0.5% (v/v) aqueous phosphoric acid and about 5% of acetonitrile, and over a time period of about 9 minutes changes to about 55% of 0.5% (v/v) aqueous phosphoric acid and about 45% of acetonitrile; Attorney Docket No.38709-0035WO1 an isocratic elution of about 55% of 0.5% (v/v) aqueous phosphoric acid and about 45% of acetonitrile over a time period of about 5 minutes; a gradient that changes over a time period of about 4 minutes to about 5% of 0.5% (v/v) aqueous phosphoric acid and about 95% of acetonitrile; an isocratic elution of about 5% of 0.5% (v/v) aqueous phosphoric acid and about 95% of acetonitrile over a time period of about 2 minutes; and an isocratic el
  • the flow rate of the mobile phase is about 50 ⁇ L/minute to about 2 mL/minute. In some embodiments, the flow rate of a mobile phase of step (c) is about 0.5 mL/minute to about 1.5 mL/minute. In some embodiments, the flow rate of a mobile phase of step (c) is about 1 mL/minute. In some embodiments, the contacting of step (b) and the eluting of step (c) are performed at about 20 o C to about 30 o C (e.g., about 22 o C to about 28 o C, about 24 o C to about 26 o C, or about 25 o C).
  • the contacting of step (c) and the eluting of step (b) are performed at about 25 o C.
  • the method comprises detecting one or more impurities by collecting UV spectral data.
  • the method comprises detecting one or more impurities by collecting UV spectral data, wherein the UV spectral data is collected at 203 nM ( ⁇ 1 nM) or 260 nM ( ⁇ 1 nM).
  • the UV spectral data is collected at 203 nM ( ⁇ 1 nM).
  • the UV spectral data is collected at 260 nM ( ⁇ 1 nM).
  • the UV spectral data is collected at 203 nM ( ⁇ 1 nM) and 260 nM ( ⁇ 1 nM).
  • the method comprises quantifying the amount of the one or more impurities in the composition.
  • quantifying the amount of each of the one or more impurities in the composition comprises: generating a first chromatogram from eluting the mixture in step (b); measuring a peak area of each impurity from the first chromatogram; and determining the amount of each impurity.
  • the potency of the reference standard is 1.
  • AWSTD is an average of the peak areas of TURSO from the second chromatograms
  • W STD is the weight of TURSO dissolved to provide the working standard solution
  • P STD is the potency of the reference standard
  • DF SPL is the volume of TURSO dissolved in the solvent comprising about 5% (v/v) acetonitrile in deionized water in step (a) divided by the volume of the mixture formed in step (a);
  • DF STD is the volume of TURSO dissolved in the working standard solution divided by the volume of the working standard solution
  • Wavg is the average of the weights of the composition in two or more sachets that contain the composition
  • WSPL is the weight of the composition dissolved in the solvent comprising about 5% (v/v) acetonitrile in deionized water in step (a)
  • LC is the label claim of TURSO
  • RRF is the relative response factor of the impurity.
  • WSTD is an average of the peak areas of sodium phenylbutyrate from the second chromatograms; WSTD is the weight of sodium phenylbutyrate dissolved to provide the working standard solution; P STD is the potency of the reference standard; DFSPL is the volume of sodium phenylbutyrate dissolved in the solvent comprising about 5% (v/v) acetonitrile in deionized water in step (a) divided by the volume of the mixture formed in step (a); DFSTD is the volume of sodium phenylbutyrate dissolved in the working standard solution divided by the volume of the working standard solution; W avg is the average of the weights of the composition in two or more sachets that contain the composition; WSPL is the weight of the composition dissolved in the solvent comprising about 5% (v/v) acetonitrile in deionized water in step (a); LC is the label claim of sodium phen
  • the label claim of TURSO is 1000 mg. In some embodiments, the label claim of sodium phenylbutyrate is 3000 mg.
  • the relative response factor is 1.157. In some embodiments, when the impurity is glucosylisomaltol, the relative response factor is 0.044. In some embodiments, when the impurity is not known, the relative response factor is 1.
  • the neurodegenerative disease is selected from the group consisting of: amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), Multiple Sclerosis (MS), Parkinson's disease, Huntington’s disease, Pick’s Disease, Multi-Infarct Dementia, Creutzfeldt-Jakob’s Disease, Dementia with Lewy bodies, Mixed dementia, Wolfram syndrome, progressive supranuclear palsy, and frontotemporal dementia (e.g., amyotrophic lateral sclerosis (ALS) or Alzheimer's disease (AD)).
  • the neurodegenerative disease is amyotrophic lateral sclerosis (ALS).
  • the neurodegenerative disease is Alzheimer's disease (AD). In some embodiments, the neurodegenerative disease is Alzheimer's disease (AD). In some embodiments, the neurodegenerative disease is Multiple Sclerosis (MS). In some embodiments, the neurodegenerative disease is Parkinson's disease. In some embodiments, the neurodegenerative disease is Huntington’s disease. In some embodiments, the neurodegenerative disease is Pick’s Disease. In some embodiments, the neurodegenerative disease is Multi-Infarct Dementia. In some embodiments, the neurodegenerative disease is Creutzfeldt-Jakob’s Disease. In some embodiments, the neurodegenerative disease is Dementia with Lewy bodies. In some embodiments, the neurodegenerative disease is Mixed dementia.
  • the neurodegenerative disease is Wolfram syndrome. In some embodiments, the neurodegenerative disease is progressive supranuclear palsy (PSP). In some embodiments, the neurodegenerative disease is frontotemporal dementia (e.g. amyotrophic lateral sclerosis (ALS) or Alzheimer's disease (AD)). In some embodiments, the neurodegenerative disease is amyotrophic lateral sclerosis (ALS). In some embodiments, the neurodegenerative disease is Alzheimer's disease (AD). In some instances, methods can include selection of a human subject who has or had a condition or disease (e.g., a neurodegenerative condition or disease, e.g., ALS).
  • a condition or disease e.g., a neurodegenerative condition or disease, e.g., ALS
  • suitable subjects include, for example, subjects who have or had a condition or disease but that resolved the disease or an aspect thereof, present reduced symptoms of disease (e.g., relative to other subjects (e.g., the majority of subjects) with the same condition or disease), and/or that survive for extended periods of time with the condition or disease (e.g., relative to other subjects (e.g., the majority of subjects) with the same condition or disease), e.g., in an asymptomatic state (e.g., relative to other subjects (e.g., the majority of subjects) with the same condition or disease).
  • asymptomatic state e.g., relative to other subjects (e.g., the majority of subjects) with the same condition or disease.
  • subject selection can include obtaining a sample from a subject (e.g., a candidate subject) and testing the sample for an indication that the subject is suitable for selection.
  • the subject can be confirmed or identified, e.g. by a health care professional, as having had or having a condition or disease.
  • exhibition of a positive immune response towards a condition or disease can be made from patient records, family history, and/or detecting an indication of a positive immune response.
  • multiple parties can be included in subject selection. For example, a first party can obtain a sample from a candidate subject and a second party can test the sample.
  • subjects can be selected and/or referred by a medical practitioner (e.g., a general practitioner).
  • subject selection can include obtaining a sample from a selected subject and storing the sample and/or using the in the methods disclosed herein.
  • Samples can include, for example, cells or populations of cells.
  • the methods disclosed herein can be applied to a wide range of species, e.g., humans, non-human primates (e.g., monkeys), horses, cattle, pigs, sheep, deer, elk, goats, dogs, cats, rabbits, guinea pigs, hamsters, rats, and mice.
  • Treating a neurodegenerative disease does not require 100% abolition of the disease or disease symptoms in the subject. Any relief or reduction in the severity of symptoms or features of the disease is contemplated. Treating a neurodegenerative disease also refers to a delay in onset of symptoms (e.g., in prophylaxis treatment) or delay in progression of symptoms or the loss of function associated with the disease. Treating a neurodegenerative disease also refers to eliminating or reducing one or more side effects of a treatment (e.g. those caused by any of the therapeutic agents for treating a neurodegenerative disease disclosed herein or known in the art).
  • Treating” a neurodegenerative disease also refers to eliminating or reducing one or more direct or indirect effects of a neurodegenerative disease progression.
  • the subject may not exhibit signs of a neurodegenerative disease but may be at risk for a neurodegenerative disease.
  • the subject may carry mutations in genes associated with a neurodegenerative disease, have elevated biomarker levels suggesting a risk of developing a neurodegenerative disease (e.g., but not limited to, total tau, phospho-tau, or YKL-40).
  • the subject may exhibit early signs of the disease Attorney Docket No.38709-0035WO1 or display symptoms of established or progressive disease.
  • the disclosure contemplates any degree of delay in the onset of symptoms, alleviation of one or more symptoms of the disease, or delay in the progression of any one or more disease symptoms.
  • the treatment provided in the present disclosure can be initiated at any stage during disease progression. For example, treatment can be initiated prior to onset (e.g., for subjects at risk for developing a neurodegenerative disease, for instance, those with elevated total tau or phospho-tau), at symptom onset or immediately following detection of a neurodegenerative disease (e.g., a tauopathy like PSP) symptoms, upon observation of any one or more symptoms (e.g., decline in cognitive functions) that would lead a skilled practitioner to suspect that the subject may be developing a neurodegenerative disease (e.g., a tauopathy like PSP).
  • a neurodegenerative disease e.g., a tauopathy like PSP
  • Treatment can also be initiated at later stages.
  • treatments methods can include a single administration, multiple administrations, and repeating administration as required for the prophylaxis or treatment of the disease or condition from which the subject is suffering.
  • treatment methods can include assessing a level of disease in the subject prior to treatment, during treatment, and/or after treatment. In some instances, treatment can continue until a decrease in the level of disease in the subject is detected.
  • administered refers to ingesting, implanting, absorbing, injecting, or inhaling, the composition, regardless of form. In some instances, the compositions described herein can be administered to a subject orally.
  • the methods herein include administration of an effective amount of a composition described herein to achieve the desired or stated effect.
  • Specific dosage and treatment regimens for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health status, sex, diet, time of administration, rate of excretion, drug combination, the severity and course of the disease, condition or symptoms, the patient’s disposition to the disease, condition or symptoms, and the judgment of the treating physician.
  • the subject can be evaluated to detect, assess, or determine their level of disease. In some instances, treatment can continue until a change (e.g., reduction) in the level of disease in the subject is detected.
  • a maintenance dose of a compound, composition or combination of this invention may be administered, if necessary. Subsequently, the dosage or frequency of administration, or both, may be reduced, as a function of the symptoms, to a level at which the improved condition is retained. Patients may, however, require intermittent treatment on a long-term basis upon any recurrence of disease symptoms.
  • the compositions described herein can be administered daily (e.g. once a day, twice a day, or three times a day or more), weekly, monthly, or quarterly.
  • compositions described herein can be administered over a period of weeks, months, or years.
  • the compositions can be administered over a period of at least or about 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 1 year, 2 years, 3 years, 4 years, or at least or about 5 years, or more.
  • the compositions described herein can be administered once a day or twice a day for 60 days or less (e.g., 55 days, 50 days, 45 days, 40 days, 35 days, 30 days or less).
  • compositions described herein can be administered once a day or twice a day for more than 60 days (e.g., more than 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 130, 140, 150, 160, 180, 200, 250, 300, 400, 500, 600 days).
  • the methods described herein include administering to a subject about 5 mg/kg to about 100 mg/kg of body weight of TURSO (e.g.
  • about 10 to about 50 about 5 to about 10, about 10 to about 15, about 15 to about 20, about 20 to about 25, about 25 to about 30, about 30 to about 35, about 35 to about 40, about 40 to about 45, about 45 to about 50, about 50 to about 55, about 55 to about 60, about 60 to about 65, about 65 to about 70, about 70 to about 75, about 75 to about 80, about 80 to about 85, about 85 to about 90, about 90 to about 95, or about 95 to about 100 mg/kg).
  • the methods described herein include administering to a subject about 10 mg/kg to about 400 mg/kg of body weight of sodium phenylbutyrate (e.g., about 10 to about 15, about 15 to about 20, about 20 to about 25, about 25 to about 30, about 30 to about 35, about 35 to about 40, about 40 to about 45, about 45 to about 50, about 50 to about 55, about 55 to about 60, about 60 to Attorney Docket No.38709-0035WO1 about 65, about 65 to about 70, about 70 to about 100, about 100 to about 150, about 150 to about 200, about 200 to about 300, or about 300 to about 400 mg/kg).
  • sodium phenylbutyrate e.g., about 10 to about 15, about 15 to about 20, about 20 to about 25, about 25 to about 30, about 30 to about 35, about 35 to about 40, about 40 to about 45, about 45 to about 50, about 50 to about 55, about 55 to about 60, about 60 to Attorney Docket No.38709-0035WO1 about 65, about 65 to about 70
  • TURSO is administered in an amount of about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 mg/kg of body weight.
  • sodium phenylbutyrate is administered in an amount of about 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 100, or 150 mg/kg of body weight.
  • liver enzymes e.g., TURSO and PB
  • gallbladder function e.g., ion absorption and secretion, levels of cholesterol transport proteins.
  • TURSO and PB administered compounds
  • Any of the factors described herein may affect drug exposure by the subject. For instance, decreased clearance of the compounds can result in increased drug exposure, while improved renal function can reduce the actual drug exposure.
  • the extent of drug exposure may be correlated with the subject’s response to the administered compounds and the outcome of the treatment. In some instances, the subject has been diagnosed with a neurodegenerative disease.
  • the subject may have been diagnosed with a neurodegenerative disease for about 24 months or less (e.g., about 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 month or less).
  • the subject may have been diagnosed with a neurodegenerative disease for 1 week or less, or on the same day that the presently disclosed treatments are administered.
  • the subject may have been diagnosed with the neurodegenerative disease for more than about 24 months (e.g., more than about 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 76, or 80 months).
  • the compositions described herein can be administered shortly after a meal (e.g., within two hours of a meal) or under fasting conditions.
  • the subject may have consumed food items (e.g., solid foods or liquid foods) less than 2 hours before administration of the compositions described herein.
  • Food items may affect the rate and extent of absorption of the TURSO and/or the PB.
  • food can change the bioavailability of the compounds by delaying gastric emptying, stimulating bile flow, Attorney Docket No.38709-0035WO1 changing gastrointestinal pH, increasing splanchnic blood flow, changing luminal metabolism of the substance, or physically or chemically interacting with a dosage form or the substance.
  • the nutrient and caloric contents of the meal, the meal volume, and the meal temperature can cause physiological changes in the GI tract in a way that affects drug transit time, luminal dissolution, drug permeability, and systemic availability.
  • the methods provided herein can further include administering to the subject a plurality of food items, for example, less than 2 hours (e.g., less than 1.5 hour, 1 hour, or 0.5 hour) before or after administering (i) or (ii).
  • the subject can be e.g., older than about 18 years of age (e.g., between 18-100, 18-90, 18-80, 18-70, 18-60, 18-50, 18-40, 18-30, 18-25, 25-100, 25-90, 25-80, 25-70, 25-60, 25-50, 25-40, 25-30, 30-100, 30-90, 30-80, 30-70, 30-60, 30-50, 30-40, 40-100, 40-90, 40-80, 40-70, 40-60, 40-50, 50-100, 50-90, 50-80, 50-70, 50-60, 60-100, 60-90, 60-80, 60-70, 70-100, 70-90, 70-80, 80-100, 80-90, or 90-100 years of age).
  • 18 years of age e.g., between 18-100, 18-90, 18-80, 18-70, 18-60, 18-50, 18-40, 18-30, 18-25, 25-100, 25-90, 25-80, 25-70, 25-60, 25-50
  • the subject can have a BMI of between about 18.5-30 kg/m 2 (e.g., between 18.5-28, 18.5-26, 18.5- 24, 18.5-22, 18.5-20, 20-30, 20-28, 20-26, 20-24, 20-22, 22-30, 22-28, 22-26, 22-24, 24-30, 24-28, 24-26, 26-30, 26-28, or 28-30 kg/m 2 ).
  • Some embodiments provide a method of treating or preventing amyotrophic lateral sclerosis (ALS) in a subject in need thereof, comprising administering a composition described herein to the subject.
  • ALS amyotrophic lateral sclerosis
  • ALS myotrophic lateral sclerosis
  • classical ALS e.g., ALS that affects both lower and upper motor neurons
  • PLS Primary Lateral Sclerosis
  • PBP Progressive Bulbar Palsy
  • PMA Progressive Muscular Atrophy
  • the terms include sporadic and familial (hereditary) ALS, ALS at any rate of progression (e.g., rapid, non-slow or slow progression) and ALS at any stage (e.g., prior to onset, at onset and late stages of ALS).
  • the subjects in the methods described herein may exhibit one or more symptoms associated with ALS, or have been diagnosed with ALS.
  • the subjects may be suspected as having ALS, and/or at risk for developing ALS.
  • the subjects in the methods described herein may exhibit one or more symptoms associated with benign fasciculation syndrome (BFS) or cramp-fasciculation syndrome (CFS).
  • BFS benign fasciculation syndrome
  • CFS cramp-fasciculation syndrome
  • Some embodiments of any of the methods described herein can further include determining that a subject has or is at risk for developing ALS, diagnosing a subject as having or at risk for developing ALS, or selecting a subject having or at risk for developing ALS. Likewise, some embodiments of any of the methods described herein can further include determining that a subject has or is at risk for developing benign fasciculation syndrome or cramp fasciculation syndrome, diagnosing a subject as having or at risk for developing BFS or CFS , or selecting a subject having or at risk for developing BFS or CFS.
  • the subject has shown one or more symptoms of ALS for about 24 months or less (e.g., about 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1 month, or 1 week or less). In some embodiments, the subject has shown one or more symptoms of ALS for about 36 months or less (e.g., about 35, 34, 33, 32, 31, 30, 29, 28, 27, 26, or 25 months or less).
  • the order and type of ALS symptoms displayed by a subject may depend on which motor neurons in the body are damaged first, and consequently which muscles in the body are damaged first. For example, bulbar onset, limb onset, or respiratory onset ALS may present with similar or different symptoms.
  • ALS symptoms may include muscle weakness or atrophy (e.g., affecting upper body, lower body, and/or speech), muscle fasciculation (twitching), cramping, or stiffness of affected muscles.
  • Early symptoms of ALS may include those of the arms or legs, difficulty in speaking clearly or swallowing (e.g., in bulbar onset ALS).
  • Other symptoms include loss of tongue mobility, respiratory difficulties, difficulty breathing or abnormal pulmonary function, difficulty chewing, and/or difficulty walking (e.g., resulting in stumbling).
  • Subjects may have respiratory muscle weakness as the initial manifestation of ALS symptoms. Such subjects may have very poor prognosis and in some instances have a median survival time of about two months from diagnosis.
  • the time of onset of respiratory muscle weakness can be used as a prognostic factor.
  • Attorney Docket No.38709-0035WO1 ALS symptoms can also be classified by the part of the neuronal system that is degenerated, namely, upper motor neurons or lower motor neurons.
  • Lower motor neuron degeneration manifests, for instance, as weakness or wasting in one or more of the bulbar, cervical, thoracic, and/or lumbosacral regions.
  • Upper motor neuron degeneration can include increased tendon reflexes, spasticity, pseudo bulbar features, Hoffmann reflex, extensor plantar response, and exaggerated reflexes (hyperreflexia) including an overactive gag reflex.
  • symptom onset can be determined based on information from subject and/or subject’s family members.
  • the median time from symptom onset to diagnosis is about 12 months. In some instances, the subject has been diagnosed with ALS.
  • the subject may have been diagnosed with ALS for about 24 months or less (e.g., about 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 month or less).
  • the subject may have been diagnosed with ALS for 1 week or less, or on the same day that the presently disclosed treatments are administered.
  • the subject may have been diagnosed with ALS for more than about 24 months (e.g., more than about 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 76, or 80 months).
  • Methods of diagnosing ALS are known in the art.
  • the subject can be diagnosed based on clinical history, family history, physical or neurological examinations (e.g., signs of lower motor neuron or upper motor neuron degeneration).
  • the subject can be confirmed or identified, e.g. by a healthcare professional, as having ALS.
  • Multiple parties may be included in the process of diagnosis.
  • a first party can obtain a sample from a subject and a second party can test the sample.
  • the subject is diagnosed, selected, or referred by a medical practitioner (e.g., a general practitioner).
  • the subject fulfills the El Escorial criteria for probable or definite ALS, i.e.
  • the subject may be determined to be one of the following categories: A. Clinically Definite ALS, defined on clinical evidence alone by the presence of UMN, as well as LMN signs, in three regions. B. Clinically Probable ALS, defined on clinical evidence alone by UMN and LMN signs in at least two regions with some UMN signs necessarily rostral to (above) the LMN signs. C. Clinically Probable ALS - Laboratory-supported, defined when clinical signs of UMN and LMN dysfunction are in only one region, or when UMN signs alone are present in one region, and LMN signs defined by EMG criteria are present in at least two limbs, with proper application of neuroimaging and clinical laboratory protocols to exclude other causes. D.
  • Clinically Possible ALS defined when clinical signs of UMN and LMN dysfunction are found together in only one region or UMN signs are found alone in two or more regions; or LMN signs are found rostral to UMN signs and the diagnosis of Clinically Probable - Laboratory-supported.
  • the subject has clinically definite ALS (e.g., based on the El Escorial criteria).
  • the subject can be evaluated and/or diagnosed using the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R).
  • the ALSFRS-R is an ordinal rating scale (ratings 0-4) used to determine subjects' assessment of their capability and Attorney Docket No.38709-0035WO1 independence in 12 functional activities relevant in ALS.
  • ALSFRS-R scores calculated at diagnosis can be compared to scores throughout time to determine the speed of progression. Change in ALSFRS-R scores can be correlated with change in strength over time, and can be associated with quality of life measures and predicted survival. ALSFRS-R demonstrates a linear mean slope and can be used as a prognostic indicator (See e.g., Berry et al. Amyotroph Lateral Scler Frontotemporal Degener 15:1–8, 2014; Traynor et al., Neurology 63:1933–1935, 2004; Simon et al., Ann Neurol 76:643–657, 2014; and Moore et al. Amyotroph Lateral Scler Other Motor Neuron Disord 4:42, 2003).
  • ALSFRS-R functions mediated by cervical, trunk, lumbosacral, and respiratory muscles are each assessed by 3 items. Each item is scored from 0-4, with 4 reflecting no involvement by the disease and 0 reflecting maximal involvement. The item scores are added to give a total. Total scores reflect the impact of ALS, with the following exemplary categorization: >40 (minimal to mild); 39-30 (mild to moderate); ⁇ 30 (moderate to severe); ⁇ 20 (advanced disease).
  • a subject can have an ALSFRS-R score (e.g., a baseline ALSFRS- R score) of 40 or more (e.g., at least 41, 42, 43, 44, 45, 46, 47, or 48), between 30 and 39, inclusive (e.g., 31, 32, 33, 34, 35, 36, 37, or 38), or 30 or less (e.g., 21, 22, 23, 24, 25, 26, 27, 28, or 29).
  • an ALSFRS-R score e.g., a baseline ALSFRS- R score
  • 40 or more e.g., at least 41, 42, 43, 44, 45, 46, 47, or 48
  • the subject has an ALSFRS-R score (e.g., a baseline ALSFRS-R score) of 40 or less (e.g., 39, 38, 37, 36, 35, 34, 33, 32, 31, 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10 or less).
  • the subject has an ALSFRS-R score (e.g., a baseline ALSFRS-R score) of 20 or less (e.g., 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5 or less).
  • ALS is a progressive disease, all patients generally will progress over time.
  • ⁇ FS (48 – ALSFRS-R score at the time of evaluation)/duration from onset to time of evaluation (month).
  • the ⁇ FS score represents the number of ALSFRS-R points lost per month since symptom onset, and can be a significant predictor of progression and/or survival in subjects with ALS (See e.g., Labra et al. J Neurol Neurosurg Psychiatry 87:628–632, 2016 and Kimura et al. Neurology 66:265-267, 2006).
  • the subject may have a disease progression rate ( ⁇ FS) of about 0.50 or less (e.g., about 0.45, 0.40, 0.35, 0.30, 0.25, 0.20, 0.15, or 0.10 or less); between about 0.50 and about 1.20 inclusive (e.g., about 0.55, 0.60, 0.65, 0.70, 0.75, 0.80, 0.85, 0.90, 0.95, 1.00, 1.05, 1.10, or 1.15); or about 1.20 or greater (e.g., about 1.25, 1.30, 1.35, 1.40, 1.45, 1.50, 1.55, 1.60, 1.75, 1.80, 1.85, 1.90, 1.95, or 2.00 or greater).
  • ⁇ FS disease progression rate
  • the subject can have an ALS disease progression rate ( ⁇ FS) of about 0.50 or greater (e.g., about 0.55, 0.60, 0.65, 0.70, 0.75, 0.80, 0.85, 0.90, 0.95, 1.00, 1.05, 1.10, 1.15, 1.20, 1.25, 1.30, 1.35, 1.40, 1.45, 1.50, 1.55, 1.60, 1.75, 1.80, 1.85, 1.90, 1.95, or 2.00 or greater).
  • ⁇ FS ALS disease progression rate
  • the ⁇ FS score is a predictor of patient progression, and may under or overestimate a patient’s progression once under evaluation.
  • the subject since initial evaluation, the subject has lost on average about 0.8 to about 2 (e.g., about 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, or 1.9) ALSFRS-R points per month over 3-12 months. In some embodiments, the subject has lost on average more than about 1.2 ALSFRS-R points per month over 3-12 months since initial evaluation.
  • the subject may have had a decline of at least 3 points (e.g., at least 4, 6, 8, 10, 12, 14, 16, 20, 24, 28, or 32 points) in ALSFRS-R score over 3-12 months since initial evaluation.
  • the subject has lost on average about 0.8 to about 2 (e.g., about 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, or 1.9) ALSFRS-R points per month over the previous 3-12 months. In some embodiments, the subject has lost on average more than about 1.2 (e.g., more than about 1.5, 1.8, 2.0, 2.5, or 3) ALSFRS-R points per month over the previous 3-12 months. In some embodiments of any of the methods described herein, the presence or level of a marker in a sample obtained from the subject may be used for ALS diagnosis or prognosis, or to track disease activity and treatment responses.
  • Suitable samples include, for example, cells, tissues, or body fluids (e.g. blood, urine, or cerebral spinal fluid (CSF) samples).
  • CSF cerebral spinal fluid
  • levels of phosphorylated neurofilament heavy subunit (pNF-H) or neurofilament light chain (NfL) in the CSF and/or blood can be Attorney Docket No.38709-0035WO1 used as a biomarker for ALS diagnosis, prognosis, or to track disease activity or treatment outcomes.
  • pNF-H is a main component of the neuronal cytoskeleton and is released into the CSF and the bloodstream with neuronal damage.
  • Levels of pNF-H may correlate with the level of axonal loss and/or burden of motor neuron dysfunction (See, e.g., De Schaepdryver et al. Journal of Neurology, Neurosurgery & Psychiatry 89:367-373, 2018).
  • the concentration of pNF-H in the CSF and/or blood of a subject with ALS may significantly increase in the early disease stage.
  • Higher levels of pNF-H in the plasma, serum and/or CSF may be associated with faster ALS progression (e.g., faster decline in ALSFRS-R), and/or shorter survival.
  • pNF-H concentration in plasma may be higher in ALS subjects with bulbar onset than those with spinal onset.
  • an imbalance between the relative expression levels of the neurofilament heavy and light chain subunits can be used for ALS diagnosis, prognosis, or tracking disease progression.
  • Methods of detecting pNF-H and NfL are known in the art and include but are not limited to, ELISA and Simoa assays (See e.g., Shaw et al. Biochemical and Biophysical Research Communications 336:1268–1277, 2005; Ganesalingam et al. Amyotroph Lateral Scler Frontotemporal Degener 14(2):146-9, 2013; De Schaepdryver et al.
  • NfL assay kits based on the Simoa technology, such as those produced by Quanterix can also be used (See, e.g., Thouvenot et al. European Journal of Neurology 27:251- 257, 2020).
  • Factors affecting pNF-H and NfL levels or their detection in serum or plasma in relation to disease course may differ from those in CSF.
  • the levels of neurofilament (e.g. pNF-H and/or NfL) in the CSF and serum may be correlated (See, e.g., Wilke et al. Clin Chem Lab Med 57(10):1556-1564, 2019).
  • Subjects described herein may have a CSF or blood pNF-H level of about 300 pg/mL or higher (e.g., about 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1050, 1100, 1150, 1200, 1250, 1300, 1350, 1400, 1450, 1500, 1550, 1600, Attorney Docket No.38709-0035WO1 1650, 1700, 1750, 1800, 1850, 1900, 1950, 2000, 2050, 2100, 2150, 2200, 2250, 2300, 2350, 2400, 2450, 2500, 2550, 2600, 2650, 2700, 2750, 2800, 2850, 2900, 3000, 3200, 3500, 3800, or 4000 pg/mL or higher).
  • a CSF or blood pNF-H level of about 300 pg/mL or higher (e.g., about 350, 400,
  • the serum pNF-H level can be about 70 to about 1200 pg/mL (e.g., about 70 to about 1000, about 70 to about 800, about 80 to about 600, or about 90 to about 400 pg/mL).
  • the CSF pNF-H level can be about 1000 to about 5000 pg/mL (e.g., about 1500 to about 4000, or about 2000 to about 3000 pg/mL).
  • the subjects may have a CSF or blood level of NfL of about 50 pg/mL or higher (e.g., about 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, or 250 pg/mL or higher).
  • a CSF or blood level of NfL of about 50 pg/mL or higher (e.g., about 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, or 250 pg/mL or higher).
  • the serum NfL level can be about 50 to about 300 pg/mL (e.g., about 50 to about 280, about 50 to about 250, about 50 to about 200, about 50 to about 150, about 50 to about 100, about 100 to about 300, about 100 to about 250, about 100 to about 200, about 100 to about 150, about 150 to about 300, about 150 to about 250, about 150 to about 200, about 200 to about 300, about 200 to about 250, or about 250 to about 300 pg/mL).
  • pg/mL e.g., about 50 to about 280, about 50 to about 250, about 50 to about 200, about 50 to about 150, about 50 to about 100, about 100 to about 300, about 100 to about 250, about 100 to about 200, about 100 to about 150, about 150 to about 300, about 150 to about 250, about 150 to about 200, about 200 to about 300, about 200 to about 250, or about 250 to about 300 pg/mL).
  • the CSF NfL level can be about 2000 to about 40,000 pg/mL (e.g., about 2000 to about 35,000, about 2000 to about 30,000, about 2000 to about 25,000, about 2000 to about 20,000, about 2000 to about 15,000, about 2000 to about 10,000, about 2000 to about 8000, about 2000 to about 6000, about 2000 to about 4000, about 4000 to about 40,000, about 4000 to about 35,000, about 4000 to about 30,000, about 4000 to about 25,000, about 4000 to about 20,000, about 4000 to about 15,000, about 4000 to about 10,000, about 4000 to about 8000, about 4000 to about 6000, about 6000 to about 40,000, about 6000 to about 35,000, about 6000 to about 30,000, about 6000 to about 25,000, about 6000 to about 20,000, about 6000 to about 15,000, about 6000 to about 10,000, about 6000 to about 8000, about 8000 to about 40,000, about 8000 to about 35,000, about 8000 to about 30,000, about 8000, about 6000
  • biomarkers useful for ALS diagnosis, prognosis, and disease progression monitoring are contemplated herein, including but are not limited to, CSF levels of S100- ⁇ , cystatin C, and chitotriosidase (CHIT) (See e.g., Chen et al. BMC Neurol 16:173, 2016).
  • Serum levels of uric acid can be used as a biomarker for prognosing ALS (See e.g., Atassi et al. Neurology 83(19):1719-1725, 2014).
  • Akt phosphorylation can also be used as a biomarker for prognosing ALS (See e.g., WO2012/160563).
  • Urine levels of p75ECD and ketones can be used as a biomarker for ALS diagnosis (See e.g., Shepheard et al. Neurology 88:1137-1143, 2017). Serum and urine levels of creatinine can also be used as a biomarker. Other useful blood, CSF, neurophysiological, and neuroradiological biomarkers for ALS are described in e.g., Turner et al. Lancet Neurol 8:94-109, 2009. Any of the markers described herein can be used for diagnosing a subject as having ALS, or determining that a subject is at risk for developing ALS. A subject may also be identified as having ALS, or at risk for developing ALS, based on genetic analysis.
  • genes associated with ALS include but are not limited to: ANG, TARDBP, VCP, VAPB, SQSTM1, DCTN1, FUS, UNC13A, ATXN2, HNRNPA1, CHCHD10, MOBP, C21ORF2, NEK1, TUBA4A, TBK1, MATR3, PFN1, UBQLN2, TAF15, OPTN, TDP-43, and DAO. Additional description of genes associated with ALS can be found at Therrien et al. Curr Neurol Neurosci Rep 16:59-71, 2016; Peters et al. J Clin Invest 125:2548, 2015, and Pottier et al. J Neurochem, 138:Suppl 1:32-53, 2016.
  • Genetic variants associated with ALS can affect the ALS progression rate in a subject, the pharmacokinetics of the administered compounds in a subject, and/or the efficacy of the administered compounds for a subject.
  • the subjects may have a mutation in the gene encoding CuZn-Superoxide Dismutase (SOD1). Mutation causes the SOD1 protein to be more prone to aggregation, resulting in the deposition of cellular inclusions that contain misfolded SOD1 aggregates (See e.g., Andersen et al., Nature Reviews Neurology 7:603-615, 2011).
  • SOD1 mutations are further described in, e.g., Rosen et al. Hum. Mol. Genet.3, 981-987, 1994 and Rosen et al. Nature 362:59-62, 1993.
  • the subject has a mutation in the C9ORF72 gene.
  • the methods described herein can include, prior to administration of a bile acid and a phenylbutyrate compound, detecting a SOD1 mutations and/or a C9ORF72 mutation in the subject. Methods for screening for mutations are well known in the art. Suitable methods include, but are not limited to, genetic sequencing. See, e.g., Hou et al. Scientific Reports 6:32478, 2016; and Vajda et al.
  • liver function e.g. levels of liver enzymes
  • renal function e.g., renal function
  • gallbladder function e.g., ion absorption and secretion, levels of cholesterol transport proteins.
  • the administered compounds e.g., bile acid and a phenylbutyrate compound
  • the extent of drug exposure may be correlated with the subject’s response to the administered compounds and the outcome of the treatment.
  • the subject can be e.g., older than about 18 years of age (e.g., between 18-100, 18-90, 18-80, 18-70, 18-60, 18-50, 18-40, 18-30, 18-25, 25-100, 25-90, 25-80, 25-70, 25-60, 25-50, 25-40, 25-30, 30-100, 30-90, 30-80, 30-70, 30-60, 30-50, 30-40, 40-100, 40-90, 40-80, 40-70, 40-60, 40-50, 50-100, 50-90, 50-80, 50-70, 50-60, 60-100, 60-90, 60-80, 60-70, 70-100, 70-90, 70-80, 80-100, 80-90, or 90-100 years of age).
  • the subject can have a BMI of between about 18.5-30 kg/m 2 (e.g., between 18.5-28, 18.5-26, 18.5- Attorney Docket No.38709-0035WO1 24, 18.5-22, 18.5-20, 20-30, 20-28, 20-26, 20-24, 20-22, 22-30, 22-28, 22-26, 22-24, 24-30, 24-28, 24-26, 26-30, 26-28, or 28-30 kg/m 2 ).
  • Having a mutation in any of the ALS-associated genes described herein or presenting with any of the biomarkers described herein may suggest that a subject is at risk for developing ALS.
  • Such subjects can be treated with the methods provided herein for preventative and prophylaxis purposes.
  • the subjects have one or more symptoms of benign fasciculation syndrome (BFS) or cramp-fasciculation syndrome (CFS).
  • BFS and CFS are peripheral nerve hyperexcitability disorders, and can cause fasciculation, cramps, pain, fatigue, muscle stiffness, and paresthesia. Methods of identifying subjects with these disorders are known in the art, such as by clinical examination and electromyography.
  • Some embodiments provide a method of treating or preventing Wolfram syndrome in a subject in need thereof, comprising administering a therapeutically effective amount of a composition described herein to the subject.
  • the methods described herein can be used for treating or ameliorating at least one symptom of Wolfram syndrome.
  • the methods can also be used for prophylactically treating a subject at risk for developing Wolfram syndrome.
  • the methods can be used to treat subjects who display one or more conditions including, e.g., diabetes insipidus, diabetes mellitus (e.g. juvenile-onset diabetes), optic nerve atrophy, progressive neurodegeneration, hearing loss, endocrine deficiencies and neurological and psychiatric conditions, cerebellar ataxia, autonomic dysfunction, dementia or intellectual disability, psychiatric disease, seizures, neurogenic bladder or bladder dyssynergia, bowel dysfunction, delayed/absent puberty, hypogonadism in males, non- autoimmune hypothyroidism, growth retardation, cardiomyopathy or structural congenital heart defects.
  • the subject has or is at risk for developing diabetes, for example, insulin-dependent diabetes or juvenile onset diabetes.
  • the subject has or is at risk for developing optic nerve atrophy or a hearing impairment.
  • the subject has one or more mutations in the WFS1 gene.
  • the subject may have the c.1672C>T, p.R558C mutation in the WFS1 gene or the c.2654C>T, p.P885L mutation in the WFS1 gene.
  • Attorney Docket No.38709-0035WO1 the subject has one or more mutations in the CDGSH iron sulfur domain protein 2 (CISD2) gene.
  • administration of the combination of TURSO and sodium phenylbutyrate results in improved treatment of one or more symptoms of Wolfram syndrome as compared to each compound alone.
  • Treatment with a combination of TURSO and sodium phenylbutyrate can lead to symptom reduction for the subjects described herein to a greater extent or at a faster rate than each compound alone.
  • Methods described in the present disclosure can include treatment of Wolfram syndrome per se, as well as treatment for one or more symptoms of Wolfram syndrome. “Treating” Wolfram syndrome does not require 100% abolition of the disease or disease symptoms in the subject. Any relief or reduction in the severity, duration, and/or frequency of symptoms or features of the disease is contemplated. “Treating” Wolfram syndrome also refers to a delay in onset of symptoms (e.g., in prophylaxis treatment) or delay in progression of symptoms or the loss of function associated with the disease.
  • Treating” Wolfram syndrome also refers to eliminating or reducing one or more side effects of a treatment (e.g. those caused by any of the therapeutic agents for treating Wolfram syndrome disclosed herein or known in the art). “Treating” Wolfram syndrome also refers to eliminating or reducing one or more direct or indirect effects of Wolfram syndrome disease progression.
  • the subject may not exhibit signs of Wolfram syndrome but may be at risk for Wolfram syndrome. For instance, the subject may carry mutations in genes associated with Wolfram syndrome, have family history of having Wolfram syndrome. The subject may exhibit early signs of the disease or display symptoms of established or progressive disease.
  • the disclosure contemplates any degree of delay in the onset of symptoms, alleviation of one or more symptoms of the disease, or delay in the progression of any one or more disease symptoms.
  • treatment can be initiated at any stage during disease progression.
  • treatment can be initiated prior to onset (e.g., for subjects at risk for developing Wolfram syndrome), at symptom onset or immediately following detection of Wolfram syndrome symptoms, upon observation of any one or more symptoms that would lead a skilled practitioner to suspect that the subject may be developing Wolfram syndrome.
  • Treatment can also be initiated at later stages.
  • treatment may be initiated at progressive stages of the disease.
  • Treatment methods can include a single administration, multiple administrations, and repeating administration as required for the prophylaxis or treatment of Wolfram syndrome, or at least one symptom of Wolfram syndrome.
  • the duration of prophylaxis treatment can be a single dosage or the treatment may continue (e.g., multiple dosages), e.g., for years or indefinitely for the lifespan of the subject.
  • a subject at risk for Wolfram syndrome may be treated with the methods provided herein for days, weeks, months, or even years so as to prevent the disease from occurring or fulminating.
  • treatment methods can include assessing a level of disease in the subject prior to treatment, during treatment, and/or after treatment.
  • the treatment provided herein can be administered one or more times daily, or it can be administered weekly or monthly. In some embodiments, treatment can continue until a decrease in the level of disease in the subject is detected.
  • the subject can be evaluated to detect, assess, or determine their level of Wolfram syndrome disease.
  • treatment can continue until a change (e.g., reduction) in the level of disease in the subject is detected.
  • a maintenance dose of a compound, composition or combination of this disclosure may be administered, if necessary.
  • the dosage or frequency of administration, or both may be reduced, as a function of the symptoms, to a level at which the improved condition is retained.
  • Patients may, however, require intermittent treatment on a long-term basis upon any recurrence of disease symptoms.
  • the methods described herein can further include administering to the subject one or more additional therapeutic agents, e.g. in amounts effective for treating or achieving a modulation of at least one symptom of Wolfram syndrome.
  • additional therapeutic agents e.g. include valproic acid, glucagon-like peptide (GLP)-1 receptor agonists, dantrolene sodium, and ER Ca2+ stabilizer.
  • GLP glucagon-like peptide
  • dantrolene sodium e.g., ER Ca2+ stabilizer.
  • Some embodiments provide a method of treating or preventing progressive supranuclear palsy (PSP) in a subject in need thereof, comprising administering a composition described herein to the subject.
  • PSP progressive supranuclear palsy
  • Appendix No.38709-0035WO1 Some embodiments provides methods of treating at least one symptom of PSP in a human subject. Also contemplated are methods of slowing PSP disease progression (e.g., reducing the PSP disease progression rate); and methods of reducing the progressive decline of cognitive functions, including loss of declarative and procedural memory, decreased learning ability, reduced attention span, and severe impairment in thinking ability, judgment, and decision making. Also provided are methods of increasing survival time of a human subject having one or more symptoms of PSP.
  • Also provided are methods of ameliorating one or more biomarkers that is affected in a human subject with PSP for example, lowering the levels of total tau and phospho-tau, both may be elevated in PSP or lowering the levels of YKL-40, which may also be elevated in PSP.
  • Any of the methods described herein can include administering to the subject a composition described herein.
  • Any of the human subjects in the methods described herein may exhibit one or more symptoms associated with PSP, or have been diagnosed with PSP. In some embodiments, the subjects may be suspected as having PSP, and/or at risk for developing PSP.
  • Some embodiments of any of the methods described herein can further include determining that a human subject has or is at risk for developing PSP, diagnosing a human subject as having or at risk for developing PSP, or selecting a human subject having or at risk for developing PSP.
  • the human subject has shown one or more symptoms of PSP for about 24 months or less (e.g., about 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1 month, or 1 week or less).
  • the subject has shown one or more symptoms of PSP for about 36 months or less (e.g., about 35, 34, 33, 32, 31, 30, 29, 28, 27, 26, or 25 months or less).
  • the human subject has been diagnosed with PSP.
  • the subject may have been diagnosed with PSP for about 24 months or less (e.g., about 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 month or less).
  • the subject may have been diagnosed with PSP for 1 week or less, or on the same day that the presently disclosed treatments are administered.
  • the subject may have been diagnosed with PSP for longer than about 24 months (e.g., longer than about 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 76, or 80 Attorney Docket No.38709-0035WO1 months).
  • Methods of diagnosing PSP are known in the art.
  • the subject can be diagnosed based on clinical history, family history, physical or neurological examinations.
  • the subject can be confirmed or identified, e.g. by a healthcare professional, as having PSP.
  • Multiple parties may be included in the process of diagnosis.
  • a first party can obtain a sample from a subject and a second party can test the sample.
  • the subject is diagnosed, selected, or referred by a medical practitioner (e.g., a general practitioner).
  • diagnosis of PSP is known in the art. Symptoms of PSP usually first appear at the age of 60 and worsen until death.
  • PSP People with PSP commonly die from pneumonia, choking or other complications caused by the loss of functional brain cells, resulting in loss of autonomic and motor function (e.g. the ability to swallow).
  • Signs and symptoms of PSP include movement, cognitive and psychiatric disorders. Voluntary movement can be impaired in PSP and include pseudobulbar palsy (i.e. inability to control facial movements), bradykinesia (i.e. slow or abnormal muscle movement), neck and trunk rigidity, impaired gait, impaired balance, posture instability and difficulty with speech and swallowing. Individuals who become unable to swallow food can be fitted with a feeding tube to provide nutrition.
  • a most obvious, outward sign of the disease is an inability to coordinate and move the eyes normally, resulting in a vertical gaze palsy.
  • Cognitive impairments include loss of executive functions (e.g. attention control, inhibitory control, working memory, cognitive flexibility, reasoning, problem solving and planning) and diminished fluency.
  • Associated psychiatric symptoms include depression, feelings of irritability, sadness or apathy, insomnia, fatigue and loss of energy. Progressive supranuclear palsy can be difficult to diagnose because signs and symptoms are similar to those of Parkinson's disease. Those of skill in the art may distinguish PSP from Parkinson’s based on the lack of tremors, a lot of unexplained falls, little to no response to Parkinson's medications, and/or difficulty moving eyes, particularly downward.
  • a subject can be identified as having PSP using the MDS PSP Diagnostic Criteria (as described in, e.g., Hoglinger et al., Mov. Disord. 31:644- 652, 2016).
  • the diagnostic criteria addresses four functional domains (ocular motor Attorney Docket No.38709-0035WO1 dysfunction, postural instability, akinesia, and cognitive dysfunction) as clinical predictors of PSP.
  • Some embodiments of any of the methods described herein can include monitoring the progression of PSP in the subject, e.g., by assessing the severity of PSP in the subject over time, e.g., using the Progressive Supranuclear Palsy Rating Scale (PSPRS) (e.g., as described in Golbe et al., Brain 130(6):1552-1565, 2007).
  • PSPRS Progressive Supranuclear Palsy Rating Scale
  • the PSPRS evaluates subjects according to their ability to perform daily activities, behavior, bulbar function, ocular motor function, limb motor function, and gait.
  • the full PSPRS includes 28 items in six areas. The available total score ranges from 0 (normal) to 100 (maximally disabled).
  • the History/Daily Activities area includes seven items with a total maximum of 24 points, the Mentation area four items with 16 points, the Bulbar area two items with 8 points, the Ocular Motor area four items with 16 points, the Limb Motor area six items with 16 points, and the Gait area five items with 20 points.
  • a subject can be identified as being at increased risk of developing PSP or identified as having PSP (e.g., any of the types of PSP described herein), e.g., at least in part, by detecting a genetic alteration in a gene encoding the microtubule-associated protein tau (MAPT) (e.g., any of the inversion polymorphisms in the MAPT gene, any of the haplotype-specific polymorphisms in the MAPT gene, the rare-coding MAPT variant (A152T), or mutations that enhance splicing of exon 10 in the MAPT gene described, e.g., in Hoglinger et al., Nature Genet.43:699-705, 2011, and Hinz et al., Cold Spring Harb.
  • MTT microtubule-associated protein tau
  • Non-limiting examples of genetic alterations in a gene encoding MAPT include mutations that result in the production of MAPT protein that include one or more point mutations of: S285R, L284R, P301L, and G303V. Additional specific genetic mutations in a gene encoding MAPT protein that can be used to identify a subject as having an increased risk of developing PSP or can be used to identify a subject as having PSP (e.g., any of the types of PSP described herein) are described in, e.g., Boxer et al., Lancet 16:552-563, 2017.
  • a subject can be identified as having an increased risk of developing PSP or identified as having PSP (e.g., any of the types of PSP described herein), e.g., at least in part, by detecting tau protein deposits (e.g., 4-repeat tau protein deposits), detecting of atrophy of the midbrain and/or superior cerebellar peduncles Attorney Docket No.38709-0035WO1 (e.g., using any of the imaging techniques described herein or known in the art, e.g., magnetic resonance imaging (MRI) or positron emission tomography (PET) scans), and/or detecting of hypometabolism in the frontal cortex, caudate, and/or thalamus in the subject (e.g., using any of the imaging techniques described herein or known in the art, e.g., MRI, CT scan, or PET scan).
  • tau protein deposits e.g., 4-repeat tau protein deposits
  • a subject can be identified or diagnosed as having PSP (e.g., any of the types of PSP described herein), e.g., at least in part, by using MRI to detect brain atrophy (Min et al., Nat. Med. 21:1154-1162, 2015; Yanamandra et al., Ann. Clin. Transl. Neurol. 2:278-288, 2015), changes in regional gray and white matter volume to detect atrophy (see, e.g., Josephs et al., Brain 137:2783-2795, 2014; Santos-Santos et al., JAMA Neurol.
  • PSP e.g., any of the types of PSP described herein
  • a subject can be identified or diagnosed as having PSP (e.g., any of the types of PSP described herein), e.g., at least in part, by administering to a subject a tau protein tracer (e.g., AV1451 or PBB3) and detecting tau protein in the subject's brain using a PET scan (see, e.g., Marquie et al., Ann. Neurol.
  • a tau protein tracer e.g., AV1451 or PBB3
  • a subject can be diagnosed or identified as having PSP (e.g., any of the types of PSP described herein), e.g., at least in part, by detecting the difference in binaural masking level in the subject using a PET scan (see, e.g., Hughes et al., J. Neurophysiol. 112:3086-3094, 2014).
  • PSP e.g., any of the types of PSP described herein
  • a subject can be identified as being at increased risk of developing PSP or identified as having PSP (e.g., any of the types of PSP described herein), e.g., at least in part, by detecting the presence of, or an elevated level (e.g., as compared to a level in a healthy control subject) of, one or more biomarkers in a subject.
  • a subject can be identified as being at increased risk of developing PSP or identified as having PSP by having plasma or CSF total tau level that is elevated as compared to a healthy subject.
  • the subject may have plasma or CSF total tau level of about 100 pg/mL or higher.
  • the subjects have plasma or CSF total tau level of about 300 pg/mL or higher (e.g., about 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1050, 1100, Attorney Docket No.38709-0035WO1 1150, 1200, 1250, 1300, 1350, 1400, 1450, 1500, 1550, 1600, 1650, 1700, 1750, 1800, 1850, 1900, 1950, 2000, 2050, 2100, 2150, 2200, 2250, 2300, 2350, 2400, 2450, 2500, 2550, 2600, 2650, 2700, 2750, 2800, 2850, 2900, 3000, 3200, 3500, 3800, or 4000 pg/mL or higher).
  • a subject can be identified as being at increased risk of developing PSP or identified as having PSP by having plasma or CSF phospho-tau (e.g. phospho-tau 181, phospho-tau 199, and/or phosphor-tau 231) that is elevated as compared to a healthy subject.
  • the subject may have plasma or CSF phospho-tau level of about 30 pg/mL or higher.
  • the subjects have plasma or CSF phospho-Tau (e.g. phosphor-tau 181) level about 70 pg/mL or higher (e.g., about 75, 100, 125, 150, 175, or 200 pg/mL or higher).
  • a subject can be identified or diagnosed as having PSP (e.g., any of the types of PSP described herein), e.g., at least in part, by detecting the presence of, or detection of an elevated level (e.g., as compared to a level in a healthy control subject) of, neurofilament light (NfL) chain in the blood and/or cerebrospinal fluid in a subject (e.g., using any of the immunoassays described in Scherling et al., Ann. Neurol. 75:116-126, 2014; Bacioglu et al., Neuron 91:56-66, 2016; and Rojas et al., Ann. Clin. Transl. Neurol.
  • NfL for example, in the cerebrospinal fluid, plasma, or serum
  • Methods of NfL are known in the art and include but are not limited to, ELISA and Simoa assays (See e.g., Shaw et al. Biochemical and Biophysical Research Communications 336:1268–1277, 2005; Ganesalingam et al. Amyotroph Lateral Scler Frontotemporal Degener 14(2):146-9, 2013; De Schaepdryver et al. Annals of Clinical and Translational Neurology 6(10): 1971–1979, 2019; Wilke et al. Clin Chem Lab Med 57(10):1556- 1564, 2019; Poesen et al.
  • NfL assay kits based on the Simoa technology, such as those produced by Quanterix can also be used (See, e.g., Thouvenot et al. European Journal of Neurology 27:251-257, 2020).
  • Factors affecting NfL levels or their detection in serum or plasma in relation to disease course may differ from those in CSF.
  • the levels of neurofilament (e.g. pNF-H and/or NfL) in the CSF and serum may be correlated (See, e.g., Wilke et al.
  • a subject can be identified or diagnosed as having PSP (e.g., any of the types of PSP described herein), e.g., at least in part, by detecting the presence of, or detection of an elevated level (e.g., as compared to a level in a healthy control subject) of, YKL-40 in plasma or cerebrospinal fluid from the subject (see, e.g., Magdalinou et al., J. Neurol. Neurosurg. Psychiatry 2014 October; 85(10): 1065-1075; and Magdalinou et al., J. Neurol.
  • a subject can be identified or diagnosed as having PSP (e.g., any of the types of PSP described herein), e.g., at least in part, by detecting a decreased ratio of 33 kDa tau to 55 kDa tau in the plasma or CSF of a subject (e.g., as compared to the ratio of 33 kDa tau to 55 kDa tau in a healthy subject).
  • PSP e.g., any of the types of PSP described herein
  • a subject can be identified or diagnosed as having PSP (e.g., any of the types of PSP described herein), e.g., at least in part, by detecting the presence of, or detecting an elevated level of protein tyrosine phosphatase 1 (Ptpn1) (e.g., as described in Santiago et al., Mov. Discord. 29(4):550-555, 2014).
  • Ptpn1 protein tyrosine phosphatase 1
  • a subject can be identified or diagnosed as having PSP (e.g., any of the types of PSP described herein), e.g., at least in part, by detecting the presence of, or detecting an elevated level of neurogranin (see, e.g., Xiang Y, Xin J, Le W, Yang Y. Neurogranin: A Potential Biomarker of Neurological and Mental Diseases. Front Aging Neurosci. 2020 Oct 6;12:584743. doi: 10.3389/fnagi.2020.584743.).
  • a subject can be identified or diagnosed as having PSP (e.g., any of the types of PSP described herein), e.g., at least in part, by detecting decreased saccade velocity and gain in the subject using infrared oculography (see, e.g., Boxer et al., Arch. Neurol. 69:509-517, 2012; Boxer et al., Lancet Neurol. 132:676- 685, 2014).
  • PSP e.g., any of the types of PSP described herein
  • a subject can be identified or diagnosed as having PSP (e.g., any of the types of PSP described herein), e.g., at least in part, by detecting a spontaneous and evoked blink rate associated with PSP in the subject (see, e.g., Bologna et al., Brain 132:502-510, 2009).
  • a subject can be identified or diagnosed as having PSP (e.g., any of the types of PSP described herein), e.g., at least in part, by detecting decreased retinal thickness in a subject's eye using optical coherence tomography (see, e.g., Schneider et al., J. Neural Transm.121:41-47, 2014).
  • a subject can be identified or diagnosed as having PSP (e.g., any of the types of PSP described herein), e.g., at least in part, by detecting Attorney Docket No.38709-0035WO1 disrupted circadian rhythms and sleep in the subject (see, e.g., Walsh et al., Sleep Med. 22; 50-56, 2016).
  • the subjects described herein have an “elevated level” of a biomarker (e.g., tau, phospho-tau, NfL, YKL-40, Ptpn1, or neurogranin) in the CSF or blood as compared to a healthy subject who does not have PSP.
  • a biomarker e.g., tau, phospho-tau, NfL, YKL-40, Ptpn1, or neurogranin
  • an elevated level of a PSP subject can be an elevation or an increase of about 1% to about 500%, about 1% to about 450%, about 1% to about 400%, about 1% to about 350%, about 1% to about 300%, about 1% to about 250%, about 1% to about 200%, about 1% to about 150%, about 1% to about 100%, about 1% to about 50%, about 1% to about 25%, about 1% to about 20%, about 1% to about 15%, about 1% to about 10%, about 1% to about 5%, about 2% to about 500%, about 2% to about 450%, about 2% to about 400%, about 2% to about 350%, about 2% to about 300%, about 2% to about 250%, about 2% to about 200%, about 2% to about 150%, about 2% to about 100%, about 2% to about 50%, about 2% to about 25%, about 2% to about 20%, about 2% to about 15%, about 2% to about 10%, about 5% to about 500%, about 5% to about 5% to about
  • the subjects after administration with any of the compositions described herein, have a reduction in the level (plasma or CSF) of a biomarker (e.g., tau, phospho-tau, NfL, YKL-40, or Ptpn1).
  • a biomarker e.g., tau, phospho-tau, NfL, YKL-40, or Ptpn1.
  • FIG. 1 Representative chromatograms of the diluent are shown in FIG. 1.
  • Needle wash combine 30 mL ACN with 70 mL D.I water and mix well.
  • Mobile phase A Pipette 5.0 mL phosphoric acid into 1000 mL D.I water; mix well and degas before use.
  • Mobile phase B 100% CAN; degas before use
  • Preparation of working standard solution Accurately weigh and transfer 45 ⁇ 4 mg PB and about 15 ⁇ 2 mg TUDCA reference standard into a 200 mL volumetric flask. Add about 160 mL of diluent, then solicit for 5 min. Add diluent to the volume line and mix well.
  • the working standard solution is stable up to 14 days at room temperature and under storage at 2-8° C.
  • Representative chromatograms of the working standard solution are shown in FIG. 2.
  • Concentration of PB is about 225 mg/mL
  • Concentration TUDCA is about 75 mg/mL
  • Representative chromatograms of the QL solution are shown in FIG. 3.
  • Concentration of PB is about 2.25 mg/mL
  • Concentration TUDCA is about 0.75 mg/mL
  • Preparation of resolution solution A.
  • Glucosylisomaltol stock solution Attorney Docket No.38709-0035WO1 Accurately weigh and transfer about 4.5 mg glucosylisomaltol into a 50 mL volumetric flask. Add 35 mL MeOH to dissolve, then dilute to volume with diluent and mix well. Concentration of glucosylisomaltol is about 90 mg/mL C.
  • TCDC stock solution Accurately weigh and transfer about 6 mg TCDC into a 20 mL volumetric flask. Add 14 mL MeOH to dissolve, then dilute to volume with diluent and mix well. Concentration of TCDC is about 300 mg/mL D.
  • Approximate concentrations are as follows: PB: 4.5 TUDCA: 1.5 RRT 0.90: 45 RRT 0.92: 45 Glucosylisomaltol: 4.5 TCDC: 15 Resolution solution can be stored under refrigeration and used as long as all known peaks can be accurately identified. Representative chromatograms are shown in FIG. 4 - FIG. 8. Preparation of marker solution: Sample lot 1524711, stored at 40° C/ 75% relative humidity from stability studies is used to confirm that peak for impurity TCDC and peak of PB-related impurity at RRT 0.96 (RRT 1.17 at 203 nm based on TUDCA) are well separated. The preparation of this solution is disclosed herein.
  • PB is about 4.5 mg/mL
  • TUDCA is about 1.5 mg/mL
  • Marker solution can be stored under refrigeration and used as long as the two peaks can be accurately identified. Representative chromatograms are shown in FIG.9 - FIG. 10.
  • Preparation of flavor masking sample solution spiked with TCDC at 1% level Accurately weigh and transfer 96.6 mg flavour masking excipient equivalent to 450 mg PB and 150 mg TUDCA into a 100 mL volumetric flask. Pipette 5.0 mL TCDC stock standard solution into the same volumetric flask. Add about 70 mL diluent and sonicate for 10 min with intermittent swirling.
  • AMX-0035 sample solution is stable up to 3 days at room temperature and under storage at 2-8° C. Representative chromatograms and UV spectra of impurities observed in AMX-0035 sample solutions are shown in Figs 15-28. Approximate concentrations: PB is about 4.5 mg/mL TUDCA is about 1.5 mg/mL Instrument parameters: Column: XBridge C183.5 mm, 4.6 X 150 mm Column Temperature: 25° C Detection: TUDCA at 203 nm (bandwidth 1 nm); PB at 260 nm (bandwidth 1 nm); collect DAD (200-400 nm) Injection volume: 20 mL Needle wash 30% CAN Flow rate: 1.0 mL/min Run time: 25 min Mobile phase A: 0.5% H 3 PO 4 in water solution Mobile phase B: 100% CAN Table 3.
  • HPLC run Gradient Attorney Docket No.38709-0035WO1 Injection procedure 1. make two injections of the diluent 2. make one injection of the QL solution 3. make one injection of the resolution solution 4. make one injection of the marker solution 5. make one injection of the flavor masking sample solution 6. make 6 consecutive injections of the working standard solution 7. make one injection of the placebo sample solution 8. make one injection of each sample solution 9. make one injection of the working standard solution after every six sample solution injections and at the end of the sequence.
  • the USP tailing factor of the TUDCA and PB peak in the first injection of the working standard solution should be ⁇ 2.0.
  • Number of theoretical plates Attorney Docket No.38709-0035WO1
  • the number of theoretical plates per column, N is calculated using the following equation: Where t is the retention time of the TUDCA and PB peak and W is the peak width of TUDCA and PB peak, obtained the extrapolating the relatively straight sides of the peak to the base line.
  • the number of theoretical places per column for TUDCA and PB peaks in the first injection of the working standard solution should be ⁇ 40000.
  • QL solution The signal –to-noise ratio (s/n) of the TUDCA and PB peaks from the injection of the QL solution should not be less than 10.
  • Resolution From the injection of the resolution solution, calculate the resolution factor, R, between adjacent known related substances and actives using the following equation:
  • the resolution between impurity RRT 0.90 and RRT 0.92 at 260 for PB related substances should be NLT 1.5 in resolution solution.
  • the resolution between impurity TUDCA and TCDC at 203 nm should be NLT 2.0 in resolution solution.
  • the resolution between impurity TCDC (RRT 1.15) and peak (RRT 1.17) should be NLT 1.5 in marker solution.
  • the excipient peak (before TCDC) can be separated with TCDC peak identified.
  • System Drift Make one injection of the working standard solution after injection of every six sample injections, and again at the end of the sequence run.
  • a SKC is the peak area of TUDCA or PB from the system drift injection of the working standard solution and AWSTD is the average peak area of the TUDCA or PB from the first 6 system suitability injections of the working standard solution.
  • %RS (A RS /A WSTD ) x W STD x P STD x (DF SPL /DF STD ) x (W avg / (W SPL x LC)) x RRF x 100
  • %RS (ARS/AWSTD) x WSTD x PSTD x (DFSPL/DFSTD) x (1/ (WSPL x %w/w)) x RRF x 100
  • Each individual related substance equal to or above QL is reported by name or by RRT for unknown related substances. Report to two decimal places. 5. If any individual related substance is detected below QL but is greater than or equal to DL, report a value ⁇ QL. 6. If any individual related substance is detected below DL, report as ND (not detected).
  • PB and TUDCA related known and unknown impurities are listed in Tables 4 and 5. Table 4. PB related known and unknown impurities GSM is glucosylisomaltol Table 5. TUDCA related known and unknown impurities GSM is glucosylisomaltol B. Total related substances: Sum all peaks ⁇ QL, report to one decimal place.
  • PB related substances do not include impurity RRT 0.76, impurity A (RRT 0.79), impurity RRT 0.83, Impurity Attorney Docket No.38709-0035WO1 0.85, impurity 0.90, impurity 0.92, impurity 0.96, impurity B (RRT 1.04) in total related substance calculation, these are process impurities.
  • Table 6 lists the PB related impurities not required to report in this method.
  • Table 6 PB related impurities not required to report in this method Example 2. Stability testing of batch 1592787 ICH Q1A stability testing of new drug substances and drug products defines the stability data package for a new drug substance or drug product that is sufficient for a registration application within the ICH regions.
  • the example herein discloses stability testing of batch 1592787 using the HPLC method of Example 1.
  • the stability of AMX0035 Packaged Batch (3 g Sodium phenylbutyrate + 1 g TUDCA) were evaluated for 24-months storage at 25°C ⁇ 2°C/60% RH ⁇ 5%, 12- months at 30°C ⁇ 2°C/65% RH ⁇ 5%, and 6-months at 40°C ⁇ 2°C/75% RH ⁇ 5%.
  • the results of these studies are summarized the following tables.
  • AMX0035 Packaged Batch 1592787 (Bulk Batch CBTDN) Stored at 25°C ⁇ 2°C/60% RH ⁇ 5%
  • AMX0035 Packaged Batch 1592787 (Bulk Batch CBTDN) Stored at 30°C ⁇ 2°C/65% RH ⁇ 5%
  • AMX0035 Packaged Batch 1592787 (Bulk Batch CBTDN) Stored at 40°C ⁇ 2°C/75% RH ⁇ 5%
  • ICH Q1A stability testing of new drug substances and drug products defines the stability data package for a new drug substance or drug product that is sufficient for a registration application within the ICH regions.
  • the example herein discloses stability testing of batch 1631705 using the HPLC method of Example 1.
  • Attorney Docket No.38709-0035WO1 The stability of AMX0035 Packaged Batch (3 g Sodium phenylbutyrate + 1 g TUDCA) were evaluated for 18-months storage at 25°C ⁇ 2°C/60% RH ⁇ 5%, 12- months at 30°C ⁇ 2°C/65% RH ⁇ 5%, and 6-months at 40°C ⁇ 2°C/75% RH ⁇ 5%.
  • AMX0035 Packaged Batch 1631705 (Bulk Batch CBXHX) Stored at 30°C ⁇ 2°C/65% RH ⁇ 5%
  • AMX0035 Packaged Batch 1631705 (Bulk Batch CBXHX) Stored at 40°C ⁇ 2°C/75% RH ⁇ 5%
  • Stability testing of batch 1660499 ICH Q1A stability testing of new drug substances and drug products defines the stability data package for a new drug substance or drug product that is sufficient for a registration application within the ICH regions.
  • the example herein discloses stability testing of batch 1631705 using the HPLC method of Example 1.
  • the stability of AMX0035 Packaged Batch (3 g Sodium phenylbutyrate + 1 g TUDCA) were evaluated for 18-months storage at 25°C ⁇ 2°C/60% RH ⁇ 5%, 12- months at 30°C ⁇ 2°C/65% RH ⁇ 5%, and 6-months at 40°C ⁇ 2°C/75% RH ⁇ 5%.
  • Table 13 The results of these studies are summarized the following tables. Table 13.
  • AMX0035 Packaged Batch 1660499 (Bulk Batch CBXHY) Stored at 25°C ⁇ 2°C/60% RH ⁇ 5%
  • Attorney Docket No.38709-0035WO1 Attorney Docket No.38709-0035WO1 a conforms as off-white fine to large granules, clumping absent; b off-white cloudy solution with particles on surface and bottom;
  • AMX0035 Packaged Batch 1660499 (Bulk Batch CBXHY) Stored at 30°C ⁇ 2°C/65% RH ⁇ 5%
  • AMX0035 Packaged Batch 1660499 (Bulk Batch CBXHY) Stored at 40°C ⁇ 2°C/75% RH ⁇ 5%
  • ICH Q1A stability testing of new drug substances and drug products defines the stability data package for a new drug substance or drug product that is sufficient for a registration application within the ICH regions.
  • the example herein discloses stability testing of batch 1631705 using the HPLC method of Example 1.
  • the stability of AMX0035 Packaged Batch (3 g Sodium phenylbutyrate + 1 g TUDCA) were evaluated for 18-months storage at 25°C ⁇ 2°C/60% RH ⁇ 5%, 12- months at 30°C ⁇ 2°C/65% RH ⁇ 5%, and 6-months at 40°C ⁇ 2°C/75% RH ⁇ 5%.
  • Table 16 Table 16.
  • AMX0035 Packaged Batch 1660500 (Bulk Batch CCPKP) Stored at 25°C ⁇ 2°C/60% RH ⁇ 5%
  • AMX0035 Packaged Batch 1660500 (Bulk Batch CCPKP) Stored at Stored at 30°C ⁇ 2°C/65% RH ⁇ 5%
  • AMX0035 Packaged Batch 1660500 (Bulk Batch CCPKP) Stored at 40°C ⁇ 2°C/75% RH ⁇ 5%
  • Stability testing of batch 1697227 ICH Q1A stability testing of new drug substances and drug products defines the stability data package for a new drug substance or drug product that is sufficient for a registration application within the ICH regions.
  • the example herein discloses stability testing of batch 1697227 using the HPLC method of Example 1.
  • the stability of AMX0035 Packaged Batch (3 g Sodium phenylbutyrate + 1 g TUDCA) were evaluated for Data are provided for 6-months storage at 25°C ⁇ 2°C/60% RH ⁇ 5%, 30°C ⁇ 2°C/65% RH ⁇ 5%, and 40°C ⁇ 2°C/75% RH ⁇ 5% for stability batch 1697227 (bulk batch CFGGB) Table 19.
  • AMX0035 Packaged Batch 1697227 (Bulk Batch CFGGB) Stored at 25°C ⁇ 2°C/60% RH ⁇ 5%
  • Attorney Docket No.38709-0035WO1 a off-white fine to large granules, clumping absent; b white fine to large granules, clumping absent; c off-white cloudy solution with particles on surface and bottom;
  • d NMT not more than; e average of two measurements;
  • AMX0035 Packaged Batch 1697227 (Bulk Batch CFGGB) Stored at 30°C ⁇ 2°C/65% RH ⁇ 5%
  • Attorney Docket No.38709-0035WO1 Attorney Docket No.38709-0035WO1 clumping absent; c light yellow fine to large granules, clumping absent; d off-white cloudy solution with particles on surface and bottom; e slightly yellow cloudy solution with particles on the surface and bottom;
  • AMX0035 Packaged Batch 1697227 (Bulk Batch CFGGB) Stored at 40°C ⁇ 2°C/75% RH ⁇ 5%
  • Stability testing of batch 1697228 ICH Q1A stability testing of new drug substances and drug products defines the stability data package for a new drug substance or drug product that is sufficient for a registration application within the ICH regions.
  • the example herein discloses stability testing of batch 1697227 using the HPLC method of Example 1.
  • AMX0035 Packaged Batch (3 g Sodium phenylbutyrate + 1 g TUDCA) were evaluated for Data are provided for 6-months storage at 25°C ⁇ 2°C/60% RH ⁇ 5%, 30°C ⁇ 2°C/65% RH ⁇ 5%, and 40°C ⁇ 2°C/75% RH ⁇ 5% for stability batch 1697228 (Bulk Batch CGBSG) Attorney Docket No.38709-0035WO1 Table 22.
  • AMX0035 Packaged Batch 1697228 (Bulk Batch CGBSG) Stored at 25°C ⁇ 2°C/60% RH ⁇ 5%
  • Attorney Docket No.38709-0035WO1 a off-White fine to large granules clumping absent; b off-white cloudy solution with particles on surface and bottom;
  • AMX0035 Packaged Batch 1697228 (Bulk Batch CGBSG) Stored at 30°C ⁇ 2°C/65% RH ⁇ 5%
  • AMX0035 Packaged Batch 1697228 (Bulk Batch CGBSG) Stored at 40°C ⁇ 2°C/75% RH ⁇ 5%
  • Attorney Docket No.38709-0035WO1 Attorney Docket No.38709-0035WO1 a white fine to large granules clumping absent; b yellow fine to large granules, clumping present; c yellow fine to large granules.
  • the third batch (1660500) was manufactured at the 200 kg scale.
  • Attorney Docket No.38709-0035WO1 Significant changes in appearance and other parameters were observed at the 40°C ⁇ 2°C/ 75% RH ⁇ 5% storage condition for all batches; therefore, the 30°C ⁇ 2°C/ 65% RH ⁇ 5% storage condition samples have been tested. There is no observed significant change for these batches at the 25°C ⁇ 2°C/ 60% RH ⁇ 5% storage condition.
  • Detailed information regarding the primary stability batches is provided in Table 25.
  • Table 25 Information regardinging Primary Stability Batches
  • the stability protocol for primary stability batches is provided in Table 26.
  • Table 26. Stability Protocol for Primary and Supportive Stability Batches A tabular summary of the available data for each batch is provided in Table 27.
  • Table 27 Summary of Results for Primary Stability Batches Attorney Docket No.38709-0035WO1 As specified in ICH Q1A, data from additional stability studies are provided to support the proposed shelf life and the label storage conditions. Three batches manufactured using sodium phenylbutyrate manufactured at Sri Krishna Pharmaceuticals were stored using the protocol provided in Table 27. Significant changes in appearance and other parameters were observed at the Attorney Docket No.38709-0035WO1 40°C ⁇ 2°C/ 75% RH ⁇ 5% storage condition for all batches; therefore, the 30°C ⁇ 2°C/ 65% RH ⁇ 5% storage condition samples have been tested.
  • Appearance of Reconstituted Solution Attorney Docket No.38709-0035WO1 Results at all storage conditions for the primary and supportive stability batches met specifications for appearance of reconstituted solution.
  • Reconstitution Time Results at all storage conditions for the primary and supportive stability batches met specifications for reconstitution time.
  • API assay Results at all storage conditions for the primary and supportive stability batches met specifications for assay.
  • FIG. 29 shows the PB assay values for the proposed storage condition stability data and
  • FIG. 30 shows the taurursodiol assay values for the proposed storage condition stability data. All results were within the stability specification and do not show a degradation trend. There are no observable differences in the results obtained for the primary and supportive stability batches at the proposed storage conditions.
  • results for specified degradation products met specifications for the primary and supportive stability batches at all storage conditions.
  • Results for unspecified degradation products were OOS for multiple studies on storage of as little as 3-months at the intermediate storage condition and as little as 1-month at the accelerated storage condition.
  • Results for total 260 nm degradation products were within specifications at the proposed storage conditions and intermediate storage conditions for the primary and supportive stability batches.
  • Out of specification results were obtained for the primary and supportive stability batches at the 6-month timepoint for stability studies at accelerated conditions.
  • the RRT 0.18/0.19 degradation products at 260 nm are shown in FIG. 31, the RRT 0.31/0.32 degradation products at 260 nm are shown in FIG. 32, and the RRT 0.37 degradation product at 260 nm is shown in FIG. 32.
  • the total degradation products at 260 nm at the proposed storage conditions are shown in Fig 33. All results are within the stability specification and do not show a clear degradation trend. There are no observable differences in the results obtained for the primary and supportive stability batches at the proposed storage conditions.
  • 203 nm Degradation Products Results for specified, unspecified, and total degradation products at 203 nm met Attorney Docket No.38709-0035WO1 specifications at all storage conditions for the primary and supportive stability batches.
  • FIG.35 and FIG.36 show the TCDC results, and the total degradation products results at the proposed storage conditions, respectively. All results are within the stability specification and do not show a degradation trend. The results for TCDC and total impurities at 203 nm are lower in the primary stability batches vs.
  • Microbial Limits Microbial limits met specifications at all storage conditions for the primary and supportive stability batches.
  • Justification for Container-Closure Pouch Size Change All stability batches were filled into 3” x 5” pouches. Commercial batches will be filled into 2.5” x 5” pouches. From a performance viewpoint with considerations on the container closure functionality and drug delivery, the difference in changing to a 2.5” x 5” sachet is negligible.
  • the main area of consideration would be the reduction in the volume and surface area. This reduction would not impact fill volume or dispensability of the powder.
  • a description of the surface area (product contact area) and seal area for each size sachet is provided in Table 31.
  • the in-use stability data indicate that the reconstituted drug product remains within all stability specifications for at least 120 minutes both when batches are newly made and after ⁇ 32 months of storage. The aged sample would be considered stable up to 180 minutes.
  • Forced Degradation AMX0035 was subjected to forced degradation and the degradation products were determined by HPLC. Forced degradation studies show drug product is susceptible to oxidation as well as temperature and humidity, but stable under acidic or basic conditions, possibly due to the use of a buffered formulation. The following is observed for PB-related impurities • Known PB USP impurity A and Impurity B do not appear to be degradation-related products. • The impurity at ⁇ RRT 0.31/0.32 appears to be a degradation product under thermal conditions.
  • the proposed expiry is based on the following available stability data and the principles of ICH Q1E: ⁇ Stability data from the primary batches: ⁇ 18-months on one pilot scale batch ⁇ 6-months data on one pilot scale batch ⁇ 6-months data on one full scale batch ⁇ Stability data from the supportive batches ⁇ 24 months data on one pilot scale batch ⁇ 18-months data on two pilot scale batches An expiry period of 24 months is proposed for AMX0035 Powder for Oral Suspension. As agreed in the CMC Pre-NDA Meeting, the expiration dating may be extended in an Annual Reports based on data from the primary stability batches. Example 9.
  • a forced degradation study for AMX-0035 Powder in Sachet (label claim: 3g Sodium Phenylbutyrate (PB) and 1g Tauroursodeoxycholic Acid (TUDCA) per sachet) was carried out according to the protocol described herein.
  • the forced degradation study included stressing samples of PB API, TUDCA API, placebo, and AMX-0035 Powder in Sachet under Thermal, Thermal-Humidity, Light, Oxidation, Acid, and Base conditions. The control and stressed samples were assayed for potency using the HPLC method described in Example 1.
  • the purpose of performing forced degradation study include: • To obtain information on degradation profile for APIs, product, and analytically prepared placebo powder under various forced degradation conditions. • To establish whether the HPLC procedure described in this protocol is stability-indicating.
  • the compounds of interest in this example are shown in Table 33.
  • Table 33. Substances of interest in the forced degradation study of AMX-0035 Attorney Docket No.38709-0035WO1 Standards and samples used: ⁇ AMX-0035 Powder in Sachets, 10 g, CTM, Lot 1631705 Sodium Phenylbutyrate drug substance, Lot 1075127. ⁇ Tauroursodeoxycholic Acid (TUDCA) drug substance, Lot 1081598 Sodium Phenylbutyrate Reference Standard, Lot F1M546.
  • TDCA Tauroursodeoxycholic Acid
  • TDCA Tauroursodeoxycholic Acid Reference Standard, Lot 2014120413 Dextrates Hydrated, NF (Emdex), Lot 1079302. ⁇ Sorbitol, NF (Neosorb P110), Lot 1070429 Sucralose, NF/Ph. Eur., Lot 1079439. ⁇ Silicon Dioxide, NF (Syloid 63FP), Lot 1079403 Maltodextrin, NF/Ph. Eur. (Kleptose), Lot 1077438 Sodium Phosphate Dibasic Anhydrous, USP, Lot 1071325 Sodium Stearyl Fumarate, NF/ EP (PRUV), Lot 1082156 Flavour Masking, Lot 1083533.
  • Table 34 Accuracy Study Results for Assay Sample Preparation Samples of PB API, TUDCA API, Placebo mixture, and AMX-0035 Powder in Sachet were stressed under the conditions listed in Table 35 for the duration specified. Table 35. Forced Degradation Conditions Attorney Docket No.38709-0035WO1 Results and Discussion The assay results of the control and stress sample are summarized in Table 36. The results for related substances (RS) are summarized in Table 4 (TUDCA related substances) and Table 5 (PB related substances). The Relative Mass Balance Deficit values are listed in Table 6.
  • the representative chromatograms of the control and stress samples are presented in section 7.0 (assay) and 8.0 (related substances).
  • the PB API did not degrade in any of the forced degradation conditions studied.
  • the TUDCA API also did not degrade in thermal and light conditions. It degraded slightly in acidic condition by Day 7 and in oxidation and base condition by Day 3. By Day 7, TUDCA API degraded by ⁇ 17% in base condition.
  • the TUDCA API in Thermal-Humidity condition completely changed in nature or precipitated in solution as no TUDCA peak was detected in the assay sample solution.
  • the exposure of placebo mixture to forced degradation conditions did not generate any peaks that interfered at the retention times of active peaks.
  • PB and TUDCA in AMX-0035 Powder in Sachet did not degrade in acid, base, and light conditions.
  • PB in sachet did not degrade in oxidation condition, but degraded by approximately 8% and 4% in Thermal and Thermal-Humidity condition, respectively.
  • TUDCA in sachet slightly degraded in oxidation condition and by 19% and 10% in Thermal and Thermal-Humidity condition, respectively.
  • the extend of TUDCA degradation in Thermal-Humidity condition was much lower in sachet compared to full degradation in TUDCA API sample.
  • the PB peaks (of PB API and AMX-0035 Powder in Sachet) were spectrally pure in all the assay sample solutions and in the RS solutions for Control, Oxidation, Acid, and Base conditions.
  • the PB peaks (of PB API and AMX-0035 Powder in Sachet) were not pure in the RS sample solutions for Thermal, Thermal-Humidity, Light Control, and Light conditions. Since the UV absorbance values are very high in RS sample solutions ( ⁇ 1.0 AU), peak purity values are not very reliable. The UV absorbance values are not linear at high absorbance.
  • the TUDCA peaks did not pass peak purity requirements in any of the samples (Assay and RS sample solutions).
  • Table 36 Assay Results for Forced Degradation of PB API Attorney Docket No.38709-0035WO1 Table 37. Assay Results for Forced Degradation of TUDCA API Table 38. Assay Results for Forced Degradation of Placebo Attorney Docket No.38709-0035WO1 Table 39. Assay Results for Forced Degradation of AMX-0035 Powder in Sachet Attorney Docket No.38709-0035WO1 Table 40A. TUDCA Related Substances Results a for Forced Degradation Study Samples a results in % w/w Table 40B.
  • TUDCA Related Substances Results a for Forced Degradation Study Samples Attorney Docket No.38709-0035WO1 a results in % w/w Table 41A. PB Related Substances Results for Forced Degradation Study Samples. Table 41B. PB Related Substances Results for Forced Degradation Study Samples. Attorney Docket No.38709-0035WO1 Table 41C. PB Related Substances Results for Forced Degradation Study Samples. Table 41D. PB Related Substances Results for Forced Degradation Study Samples.
  • the mass balance values were close to 100% for PB and also for TUDCA except for TUDCA in AMX-0035 powder in sachet exposed to Thermal and Thermal- Attorney Docket No.38709-0035WO1 Humidity condition and TUDCA API exposed to base condition for 7 days at 50°C where the mass balance values ranged from 81– 90%. Lower mass balance values are expected for TUDCA since CTMLP-4073 does not detect TUDCA impurities Taurine and UDCA which are monitored by another laboratory using LC-MS.
  • AMX0035 An orally administered drug candidate, AMX0035, consists of two active components: Tauroursodeoxycholic Acid (TUDCA) and Sodium Phenylbutyrate (PB), for the long-term treatment of amyotrophic lateral sclerosis (ALS).
  • TDCA Tauroursodeoxycholic Acid
  • PB Sodium Phenylbutyrate
  • ALS amyotrophic lateral sclerosis
  • a combined oral clinical dosage form (a sachet) has been prepared. This sachet is to be given twice a day. Each dose contains 3 grams of sodium phenylbutyrate and 1 gram of TUDCA.
  • RRT 0.31/0.32 has been detected in batch CBTDN of AMX0035 (see Table 43) and has substantially increased during stability. Impurity identification work is actively ongoing, but a definitive structure has not been identified to date.
  • RRT 0.31/0.32 has been present in nonclinical batch of AMX0035 at levels of 0.12% to 0.18%. Impurity identification work is actively ongoing, but a definitive structure has not been identified to date. In a different batch, impurity RRT 0.31/0.32 Attorney Docket No.38709-0035WO1 has been detected at .24% but has only been seen at 0.18% in clinical trials. A level of 0.3% is also assessed for safety. Table 44 presents a summary of the impurity present in the combined oral clinical dosage form. Table 44.
  • AMX0035 Dosage Form PB Related Impurity RRT 0.31/0.32 a. Based on daily dose of 6000 mg sodium phenylbutyrate x 0.18% Impurity RRT 0.31/0.32 ⁇ 60 kg default human b. Based on daily dose of 6000 mg sodium phenylbutyrate x 0.30% impurity RRT 0.31/0.32 ⁇ 60 kg default human c.
  • Amylyx has developed an orally administered drug candidate for the long term treatment of amyotrophic lateral sclerosis (ALS) which consists of two active components: Tauroursodeoxycholic Acid (TUDCA) and Sodium Phenylbutyrate (PB).
  • ALS amyotrophic lateral sclerosis
  • PB Sodium Phenylbutyrate
  • a combined oral clinical dosage form (a sachet) has been prepared. This 9.72 gram oral sachet is to be given twice a day. Each dose contains 3 grams of sodium phenylbutyrate and 1 gram of TUDCA. Table 45 below presents a summary of 4 impurities present in the combined oral clinical dosage form.
  • Amylyx Dosage Form Impurities aFor high-dose group (2000 mg/kg) under accelerated conditions; b Based on daily dose of 6000 mg PB (PDE ⁇ 6000 x 100) (mg); c Based on daily dose of 2000 mg TUDCA (PDE ⁇ 2000 x 100) (mg)
  • PDE Permissible Daily Exposure
  • the factors in the denominator are defined in the guideline for residual solvents in ICH Q3C.
  • Attorney Docket No.38709-0035WO1 Therfore: The safe levels of the four AMX0035 impurities discussed above have been evaluated against conservative PDE values based on systemic toxicity data.
  • Amylyx is developing an orally administered drug candidate for the long term treatment of amyotrophic lateral sclerosis (ALS) which consists of two active components: Tauroursodeoxycholic Acid (TUDCA) and Sodium Phenylbutyrate (PB).
  • ALS amyotrophic lateral sclerosis
  • PB Sodium Phenylbutyrate
  • a combined oral clinical dosage form (a sachet) has been prepared. This sachet is to be given twice a day. Each dose contains 3 grams of sodium phenylbutyrate and 1 gram of TUDCA.
  • Table 46 below presents a summary of PB levels and Table 47 presents a summary of TUDCA levels observed.
  • AMX0035 is a combination of two active pharmaceutical ingredients (API), sodium phenylbutyrate (PB) and ursodoxicoltaurine (TURSO), designed to block neuronal death and neuroinflammation through simultaneous inhibition of endoplasmic reticulum (ER) and mitochondrial stress. This drug is in a novel pharmacological class of dual ER stress and mitochondrial stress inhibitors.
  • AMX0035 is currently being developed for the treatment of AD, ALS, Wolfram syndrome, and progressive supranuclear palsy (PSP).
  • AMX0035 is supplied as a powder filled sachet. Each sachet contains 3 g PB and 1 g taurursodiol. The drug product powder is blended and is filled under cGMP conditions in an aluminum foil lined sachet, then packaged into carton boxes.
  • ⁇ RRT 0.30 Attorney Docket No.38709-0035WO1 An impurity of RRT 0.30 has been detected in multiple batches of AMX0035 and has shown levels close to the limit for unidentified degradation products (NMT 0.10%). A definitive structure for this impurity could not be determined; therefore, it is controlled in drug product by relative retention time. This impurity was studied in the same toxicological study as ⁇ RRT 0.37, below. Information regarding the level of this impurity in the toxicological study is provided in Table 4. For the impurity a Permissible Daily Exposure (PDE) was calculated according to the risk assessment procedures specified in ICH Q3C.
  • PDE Permissible Daily Exposure
  • the safe levels of the AMX0035 impurity at RRT 0.30 has been evaluated against conservative PDE values based on systemic toxicity data. Upon consideration of all the available data summarized above, it is not expected that the component should pose a significant risk to the patient at the levels provided. The impurity should be considered qualified at 0.5%. ⁇ RRT 0.31/0.32 An impurity at RRT 0.31/0.32 has been detected in batch CBTDN (packaged batch 1592787) of AMX0035 (Table 49) and has shown increase during packaged drug product stability. A definitive structure for this impurity could not be determined; therefore, it is controlled in drug product by relative retention time. Table 49.
  • minipigs (4 – 6/sex/dose) have been administered 0, 250, 423, or 845 mg/kg/day of AMX0035 for 9 months with no Attorney Docket No.38709-0035WO1 treatment-related effects seen.
  • embryofetal toxicity pilot and GLP studies in rats and mice no test-article effects were seen in maternal or offspring rats or mice at up to 1500 mg/kg/day.
  • the impurity at RRT 0.31/0.32 has been present in this nonclinical batch on stability at levels of 0.12% to 0.18% (at 6-months timepoint). In a different batch, this impurity has been detected at 0.35% on stability but had only been seen at 0.18% in clinical trials at the time the toxicology study was performed.
  • a level of 0.3% is also assessed for safety.
  • a summary of the impurity present in the combined oral clinical dosage form is provided in Table 50.
  • Table 50. AMX0035 Dosage Form PB Related Impurity at RRT 0.31/0.32 a. Based on a daily dose of 6000 mg sodium phenylbutyrate x 0.18% Impurity RRT 0.31/0.32 ⁇ 60 kg default human; b.
  • ⁇ RRT 0.37 A summary of the impurity observed at ⁇ RRT 0.37 present in the combined oral clinical dosage form is provided in Table 4. A definitive structure for this impurity could not be determined; therefore, it is controlled in drug product by relative Attorney Docket No.38709-0035WO1 retention time.
  • An additional toxicology study 14-day rat study was performed using ambient and accelerated drug product. Rats were administered 0, 1000 mg/kg (ambient), 1000 mg/kg (accelerated), or 2000 mg/kg (accelerated AMX0035 by oral gavage once daily for 14 consecutive days). Based on the results of this study, a no observed adverse effect level (NOAEL) of 2000 mg/kg was determined. Information regarding the impurity at RRT 0.37 is provided in Table 51. Table 51.
  • TCDC taurochenodeoxycholic acid
  • Other bile acids total
  • the levels of TCDC observed in the toxicology batches are provided in Table 52. Attorney Docket No.38709-0035WO1 Table 52. TCDC Observed in API Toxicology Batches.
  • AMX0035 amyotrophic lateral sclerosis
  • AMX0035 combination of PB and TURSO
  • ER endoplasmic reticulum
  • MPP + 1-methyl-4-phenylpyridinium
  • PB sodium phenylbutyrate
  • TH tyrosine hydroxylase
  • TURSO ursodoxicoltaurine
  • UPR unfolded protein response Table 54B.
  • AMX0035 amyotrophic lateral sclerosis
  • AMX0035 combination of PB and TURSO
  • ER endoplasmic reticulum
  • MPP + 1-methyl-4-phenylpyridinium
  • PB sodium phenylbutyrate
  • TH tyrosine hydroxylase
  • TURSO ursodoxicoltaurine
  • UPR unfolded protein response Attorney Docket No.38709-0035WO1 Table 54C.
  • AMX0035 amyotrophic lateral sclerosis
  • AMX0035 combination of PB and TURSO
  • ER endoplasmic reticulum
  • MPP + 1-methyl-4-phenylpyridinium
  • PB sodium phenylbutyrate
  • TH tyrosine hydroxylase
  • TURSO ursodoxicoltaurine
  • UPR unfolded protein response Table 55A.
  • Toxicology Studies Investigating of AMX0035 Attorney Docket No.38709-0035WO1 Table 55C.
  • the final population PK model estimated a 52.4% (95% confidence interval: 48.5%-56.3%) decrease in relative bioavailability and 60% (95% confidence interval: 56%-64%) decrease in the absorption rate constant when PB is administered under fed versus fasting conditions.
  • the single-dose PK of ursodoxicoltaurine and its metabolites (UDCA, GUDCA) were characterized in Study A35-002 and steady-state plasma concentrations were obtained in Study AMX3500.
  • Ursodoxicoltaurine is slowly absorbed with a median time to peak concentration of 4.5 hours.
  • Ursodoxicoltaurine plasma concentration profiles in many subjects have 2 to 3 peaks, consistent with bile acid storage and release upon a meal/snack.
  • AUC0-last and Cmax were 4360 (71.6) ng-h/mL and 741 (71.6) ng/mL, respectively, for ursodoxicoltaurine; 5540 (72.5) ng-h/mL and 639 (73.0) ng/mL respectively for UDCA; and 4140 (70.4) ng- h/ml and 381 (76.5) ng/mL, respectively for GUDCA. Terminal half-life could not be reliably determined in most subjects due to the presence of enterohepatic circulation.
  • a high-fat meal did not significantly affect the Cmax for ursodoxicoltaurine, but AUC was increased by 46%. Comparing across studies, there was little accumulation of ursodoxicoltaurine after twice daily dosing while there was substantial accumulation of UDCA and GUDCA.
  • Human Exposure Table 56 summarizes the AMX0035 clinical program. The completed studies include a Phase 1 clinical study in healthy participants (A35-002), a Phase 2 clinical study in participants living with ALS (AMX3500, with a 24-week randomized phase and additional 24 weeks in an open-label extension [OLE]), and a Phase 2, 24-week, randomized clinical study in participants with Alzheimer’s disease (AMX8000).
  • AMX0035 Alzheimer’s disease
  • ALS amyotrophic lateral sclerosis
  • ALSAQ-40 ALS assessment questionnaire of 40-item
  • ALSFRS-R Amyotrophic Lateral Sclerosis Functional Rating Scale – Revised
  • CSR clinical study report
  • OLE open-label extension
  • PK pharmacokinetic
  • QOL Quality of Life
  • SVC Slow Vital Capacity Table 56B.
  • AD Alzheimer’s disease
  • ALS amyotrophic lateral sclerosis
  • ALSAQ-40 ALS assessment questionnaire of 40-item
  • ALSFRS-R Amyotrophic Lateral Sclerosis Functional Rating Scale – Revised
  • CSR clinical study report
  • OLE open-label extension
  • PK pharmacokinetic
  • QOL Quality of Life
  • SVC Slow Vital Capacity Attorney Docket No.38709-0035WO1 Overall Risk and Benefit Assessment Therapeutic Context With a median survival of approximately 2 years from diagnosis, ALS is a universally fatal neurodegenerative disease marked by rapid loss of motor function due to degeneration of motor neurons in the CNS.
  • riluzole which blocks glutamatergic neurotransmission in the CNS. This product has only showed a modest benefit (approximately 3 to 6 months) for survival, but has not shown a slowing in physical decline. Therefore, despite the availability of riluzole, a high unmet medical need remains for patients with ALS who even with this therapy face rapid morbidity and mortality.
  • AMX0035 a combination of ursodoxicoltaurine (also known as TURSO) and sodium phenylbutyrate (PB), to simultaneously target the ER stress and mitochondrial dysfunction involved in ALS, thereby reducing or preventing downstream cell death.
  • TURSO ursodoxicoltaurine
  • PB sodium phenylbutyrate
  • the administration of AMX0035 orally (or via feeding tube) allows for individuals to take the medicine themselves and avoid additional intravenous or other routes of administration that further impair their quality of life.
  • Analyses of AMX0035’s efficacy over 24 weeks demonstrated clinically meaningful slowing of ALS (function, strength, and breathing) as well as statistically significant benefits in ALSFRS-R (primary efficacy endpoint) compared with placebo (and standard of care).
  • AMX0035 offers a new treatment in the very limited armamentarium currently available to patients with ALS and their physicians •
  • the totality of data demonstrates that AMX0035 has a favorable risk benefit profile which supports an NDA submission for a potential therapy for this debilitating and life-threatening disease.
  • ALSFRS- R loss of function
  • the results of long-term monitoring demonstrate a compelling, statistically significant, and clinically meaningful benefit on survival and key study events including hospitalizations and tracheostomies.
  • AMX0035 is the first therapeutic to show a benefit on both survival and function in ALS.

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Abstract

Disclosed herein are pharmaceutical composition comprising sodium phenylbutyrate and taurursodiol (TURSO), with levels of particular impurities specified by their HPLC relative retention time (RRT, relative to TURSO), a dosage form thereof, and methods for detecting one or more impurities within the above described pharmaceutical composition and/or dosage form.

Description

Attorney Docket No.38709-0035WO1 FORMULATION CONTAINING TAURURSODIOL AND SODIUM PHENYLBUTYRATE CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Patent Application Serial No. 63/537,224, filed September 8, 2023, which is incorporated by reference herein in its entirety. TECHNICAL FIELD The present disclosure relates to pharmaceutical compositions, methods for evaluating storage stability of the pharmaceutical compositions, and methods of detecting impurities in the pharmaceutical compositions. BACKGROUND Assessment and monitoring of the purity of pharmaceutical compositions is critical to ensuring patients have access to medicines that provide a consistently safe and effective dosage of the desired compound with minimal impurities. This requires development of robust and accurate methods of detecting impurities and for setting appropriate standards for the identification and quantification of impurities, and for determination of tolerable levels of various impurities. Indeed, this is a primary goal of Good Manufacturing Practice (GMP), the standard approach to pharmaceutical manufacturing. According to the international conference on harmonization (ICH), impurities are classified as organic impurities, inorganic impurities, or residual solvents. Of these three types, inorganic impurities and residual solvents are typically fewer in number and more straightforward to address. Organic impurities may be present in a pharmaceutical composition as a result of synthetic processes or as an unintended by-product from purification or isolation methods. Organic impurities can also arise from handling the active pharmaceutical ingredient (API), during formulation, and/or storage and transport of the final dosage form. These impurities can also arise from other sources including raw materials, side-reactions, reagents, methods or processes, atmospheric contamination during manufacturing, cross-contamination, and the like. Of particular importance are degradation-related impurities, that may occur during storage and handling, i.e., after the dosage form has left its place of manufacture. These types of impurities typically result from various breakdown mechanisms such as Attorney Docket No.38709-0035WO1 hydrolysis, oxidation, ultraviolet light, heat, or from the API interacting with excipients or storage containers. Monitoring the presence and levels of impurities is vital to ensuring consistent and safe dosage forms, and for ensuring that the storage, distribution, and handling of the final dosage form provides patients with the intended dosage form. The use of sodium phenylbutyrate and taurursodiol (TURSO) is currently used for treating amyotrophic lateral sclerosis (ALS) and is under evaluation for treating several other neurological disorders. Certain impurities may be present in a pharmaceutical composition comprising sodium phenylbutyrate and taurursodiol. Detection of these and other impurities is needed to provide a pharmaceutical composition comprising sodium phenylbutyrate and taurursodiol of suitable quality, purity, and strength for use in further clinical studies and in treatments. SUMMARY Disclosed herein is a composition comprising about 8% to about 12% w/w of taurursodiol (TURSO); about 27% to about 32% w/w of sodium phenylbutyrate; wherein the composition comprises not more than (i) 0.2% of an impurity having a relative retention time (RRT) of about 0.18; (ii) 0.4% of an impurity having a RRT of about 0.31; and (iii) 0.4% of an impurity having a RRT of about 0.37; and wherein each RRT is determined relative to sodium phenylbutyrate. Disclosed herein is a method of detecting one or more impurities in a composition comprising about 8% to about 12% w/w of taurursodiol (TURSO); about 27% to about 32% w/w of sodium phenylbutyrate; and one or more impurities, the method comprising: (a) dissolving the composition in a solvent comprising about 5% (v/v) acetonitrile in deionized water to form a mixture; (b) contacting a stationary phase of a C-18 reverse phase chromatography column with the mixture; (c) eluting the mixture with a mobile phase to separate out one or more of the one or more impurities, wherein the mobile phase comprises about 5% to about 95% of 0.5% (v/v) aqueous phosphoric acid and about 5% to about 95% of acetonitrile; and (d) optionally quantifying the amount of the one or more impurities in the composition. Attorney Docket No.38709-0035WO1 The present disclosure relates to a pharmaceutical composition comprising sodium phenylbutyrate and taurursodiol (TURSO), with levels of particular impurities specified by their HPLC relative retention time (RRT, relative to TURSO), a dosage form thereof, and methods for detecting one or more impurities within the above described pharmaceutical composition and/or dosage form. Definitions As used herein, the term "about" refers to the exact number that it precedes, as well as to modify a number to encompass a range of uncertainty of the number of from 0% to 10% of the numerical value. As used herein, the term "approximately" refers to the exact number that it precedes, as well to as modify a number to encompass a range of uncertainty of the number of from 0% to 5% of the numerical value. As used herein, when a composition comprises “not more than” a specified amount of a component (e.g., an impurity), the composition includes the component in an amount of greater than 0% and equal to or lesser than the specified amount. In some embodiments, measuring and/or determining that the composition comprises greater than 0% of the component and equal to or lesser than the specified amount is or was performed by high-performance liquid chromatography (HPLC). For example, if the composition includes not more than 0.2% of an impurity having a relative retention time (RRT) of about 0.18, the composition (i) includes the impurity having the RRT of about 0.18 as measured and/or determined by HPLC; and (ii) includes 0.2% or less of the impurity. As used herein, the term “unit dosage form(s)” includes sachets; tablets; caplets; capsules, such as soft elastic gelatin capsules; cachets; troches; lozenges; dispersions; powders; solutions; gels; liquid dosage forms suitable for oral or mucosal administration to a patient, including suspensions (e.g., aqueous or non-aqueous liquid suspensions), emulsions (e.g., oil-in-water emulsions, or a water-in-oil liquid emulsion), solutions, and elixirs; and sterile solids (e.g., crystalline or amorphous solids) that can be reconstituted to provide liquid dosage forms suitable for oral or parenteral administration to a patient. The unit dosage form does not necessarily have to be administered as a single dose. As used herein, the term “sachet” refers to a bag or pouch that contains a composition described herein. In some embodiments, the composition is vacuum- Attorney Docket No.38709-0035WO1 packed in the sachet, or alternatively or in addition, packaged under an inert atmosphere such as nitrogen or argon. In some embodiments, the sachet comprises two or more (e.g., 2, 3, 4, or 5) layers. In some embodiments, the layers are selected from, for example, paper, aluminum foil, or plastic. In some embodiments, the inner layer of the sachet comprises aluminum. “Treating” or “treatment” refers to reducing the symptoms or arresting or inhibiting further development of the disease (in whole or in part). “Treating” or “treatment” includes any effect, e.g., lessening, reducing, modulating, or eliminating, that results in the improvement of the disease and the like. The term “therapeutically effective amount,” as used herein, refers to the amount of one or more active chemical entities or pharmaceutical agent (e.g., TURSO and PB) being administered which elicits the biological or medicinal response in a tissue, system, animal, individual, or human that is being sought. In some embodiments, the response includes reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. An appropriate “therapeutically effective amount” in any individual case is determined, e.g., using any suitable technique, such as a dose escalation study. As used herein, the terms "subject" and "patient" are used interchangeably, and refer to any animal, including mammals such as mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, primates, and humans. In some embodiments, the subject is a human (e.g., a man, a woman, or a child). In some embodiments, the subject has experienced and/or exhibited at least one symptom of the disease or disorder to be treated and/or prevented. Unless otherwise defined, all terms of art, notations, and other scientific terms or terminology used herein are intended to have the meanings commonly understood by those of skill in the art to which this application pertains. In some cases, terms with commonly understood meanings are defined herein for clarity and/or for ready reference, and the inclusion of such definitions herein should not necessarily be construed to represent a substantial difference over what is generally understood in the art. Other features, objects, and advantages of the disclosure will be apparent from the description and drawings, and from the claims. Attorney Docket No.38709-0035WO1 DESCRIPTION OF DRAWINGS FIGS. 1A-1B show a representative chromatogram of diluent at (FIG. 1A) 260 nM and (FIG. 1B) 203 nm. FIGS. 2A-2B show a representative chromatogram of working standard solution at (FIG. 2A) 260 nM and (FIG. 2B) 203 nm. FIGS.3A-3B show a representative chromatogram of QL solution at (FIG.3A) 260 nM and (FIG. 3B) 203 nm. FIG. 4 shows a representative chromatogram of resolution solution at 260 nM, observed during validation of HPLC method; shows all impurities. FIG. 5 shows a representative chromatogram of resolution solution at 260 nM, observed with validated HPLC method. FIG.6 shows a representative chromatogram (expanded) of resolution solution at 260 nM, observed with validated HPLC method. FIG. 7 shows a representative chromatogram of resolution solution at 203 nM, observed with validated HPLC method. FIG.8 shows a representative chromatogram (expanded) of resolution solution at 203 nM, observed with validated HPLC method. FIG. 9 shows a representative chromatogram of marker solution at 203 nM. FIG. 10 shows a representative chromatogram of marker solution at 203 nM, expanded scale. FIG. 11 shows a representative chromatogram of flavor masking sample solution spiked with 1% TCDC at 203 nM. FIG. 12 shows a representative chromatogram of flavor masking sample solution spiked with 1% TCDC at 203 nM, expanded scale. FIG. 13 shows a representative chromatogram of placebo sample solution at 260 nM. FIG. 14 shows a representative chromatogram of placebo sample solution at 203 nM. FIG. 15 shows a representative chromatogram of AMX-0035 sample solution at 260 nM. FIG. 16 shows a representative chromatogram of AMX-0035 sample solution at 203 nM. Attorney Docket No.38709-0035WO1 FIGS. 17A-17C show a representative UV spectrum of PB and related impurities: FIG 17A is glucosylmaltol, FIG. 17B is impurity A, FIG 17C is PB. FIGS. 18A-18B shows a representative UV spectrum of PB and related impurities: FIG 18A is impurity B, FIG. 18B is PB at QL level. FIG. 19 shows a representative UV spectrum of impurity RRT 0.18/0.19 at retention time 1.2/2.2 min. FIG.20 shows a representative expanded chromatogram of AMX-0035 sample solution at 260 nM, with peaks 1-4 tabulated. FIGS. 21A-21B show a representative UV spectrum of impurities observed in AMX-0035 sample solution between 3.4 – 3.8 minutes: FIG. 21A is peak 1 and FIG. 21B is peak 2. FIGS. 22A-22B show a representative UV spectrum of impurities observed in AMX-0035 sample solution between 3.4 – 3.8 minutes: FIG. 22A is peak 3 and FIG. 22B is peak 4. FIGS. 23A-23B show a representative UV spectrum of impurities observed in AMX-0035 sample solution: FIG.23A is impurity RRT 0.37 and FIG.23B is impurity RRT 0.76. FIGS. 24A-24B show a representative UV spectrum of impurities observed in AMX-0035 sample solution: FIG.24A is impurity RRT 0.83 and FIG.24B is impurity RRT 0.85. FIGS. 25A-25B show a representative UV spectrum of impurities observed in AMX-0035 sample solution: FIG.25A is impurity RRT 0.90 and FIG.25B is impurity RRT 0.92. FIG. 26 shows a representative UV spectrum of impurity RTT 0.96 observed in AMX-0035 sample solution. FIGS. 27A-27C show a representative UV spectrum of TUDCA and related impurities observed in AMX-0035 sample solution: FIG.27A is TUDCA, FIG.27B is TCDC, and FIG. 27C is UDCA. FIG. 28 shows a representative UV spectrum of TUDCA observed in AMX- 0035 sample solution at QL level. FIG. 29 shows PB assay results for AMX-0035 batches under the proposed storage condition (25°C ± 2°C/ 60% RH ± 5%). Attorney Docket No.38709-0035WO1 FIG. 30 shows taurursodiol assay results for AMX-0035 batches under the proposed storage condition (25°C ± 2°C/ 60% RH ± 5%). FIG. 31 shows RRT 0.18/0.19 degradation products observed at 260 nm for AMX-0035 batches under the proposed storage condition (25°C ± 2°C/ 60% RH ± 5%). FIG. 32 shows RRT 0.31/0.32 degradation products observed at 260 nm for AMX-0035 batches under the proposed storage condition (25°C ± 2°C/ 60% RH ± 5%). FIG. 33 shows RRT 0.37 degradation product observed at 260 nm for AMX- 0035 batches under the proposed storage condition (25°C ± 2°C/ 60% RH ± 5%). FIG. 34 shows total degradation products observed at 260 nm for AMX-0035 batches under the proposed storage condition (25°C ± 2°C/ 60% RH ± 5%). FIG.35 shows TCDC results observed at 203 nm for AMX-0035 batches under the proposed storage condition (25°C ± 2°C/ 60% RH ± 5%). FIG. 36 shows total degradation products observed at 203 nm for AMX-0035 batches under the proposed storage condition (25°C ± 2°C/ 60% RH ± 5%). FIG. 37 shows pH of reconstituted AMX-0035 batches stored under the proposed storage condition (25°C ± 2°C/ 60% RH ± 5%). FIG. 38 shows moisture content of AMX-0035 batches stored under the proposed storage condition (25°C ± 2°C/ 60% RH ± 5%). Like reference symbols in the various drawings indicate like elements. DETAILED DESCRIPTION In some aspects, provided herein is a composition comprising taurursodiol (TURSO, also referred to herein as “TUDCA”) and sodium phenylbutyrate. In some embodiments, the composition comprises about 8% to about 12% w/w of taurursodiol (TURSO). In some embodiments, the composition comprises about 27% to about 32% w/w of sodium phenylbutyrate (“NaPB”, also referred to herein as “PB”). In some embodiments, the composition comprises not more than 0.2% of an impurity having a relative retention time (RRT) of about 0.18. In some embodiments, the composition comprises not more than 0.2% of an impurity having a relative retention time (RRT) of about 0.19. In some embodiments, the composition comprises not more than 0.2% of an impurity having a relative retention time (RRT) of about 0.18 or 0.19. In some embodiments, the composition comprises not more than 0.5% of an impurity having a RRT of about 0.30. In some embodiments, the composition comprises not more than 0.4% of an impurity having a RRT of about 0.31. In some embodiments, the Attorney Docket No.38709-0035WO1 composition comprises not more than 0.3% of an impurity having a RRT of about 0.31. In some embodiments, the composition comprises not more than 0.4% of an impurity having a RRT of about 0.32. In some embodiments, the composition comprises not more than 0.4% of an impurity having a RRT of about 0.31 or 0.32. In some embodiments, the composition comprises not more than 0.4% of an impurity having a RRT of about 0.37. In some embodiments, the composition comprises not more than (i) 0.2% of an impurity having a relative retention time (RRT) of about 0.18; (ii) 0.4% of an impurity having a RRT of about 0.31; and (iii) 0.4% of an impurity having a RRT of about 0.37. In some embodiments, each RRT is determined relative to sodium phenylbutyrate. In some embodiments, when an RRT is determined relative to sodium phenylbutyrate, the RRT is determined relative to sodium phenylbutyrate in a high- performance liquid chromatography (HPLC) method. In some embodiments, the HPLC method is an HPLC method disclosed herein. For example, the HPLC method is a method delineated under “Methods of Detecting Impurities” or disclosed in Example 1. In some aspects, provided herein is a composition comprising taurursodiol (TURSO) and sodium phenylbutyrate. In some embodiments, the composition comprises approximately 8% to approximately 12% w/w of taurursodiol (TURSO). In some embodiments, the composition comprises approximately 27% to approximately 32% w/w of sodium phenylbutyrate. In some embodiments, the composition comprises not more than 0.2% of an impurity having a relative retention time (RRT) of approximately 0.18. In some embodiments, the composition comprises not more than 0.2% of an impurity having a relative retention time (RRT) of approximately 0.19. In some embodiments, the composition comprises not more than 0.2% of an impurity having a relative retention time (RRT) of approximately 0.18 or 0.19. In some embodiments, the composition comprises not more than 0.5% of an impurity having a RRT of approximately 0.30. In some embodiments, the composition comprises not more than 0.4% of an impurity having a RRT of approximately 0.31. In some embodiments, the composition comprises not more than 0.3% of an impurity having a RRT of approximately 0.31. In some embodiments, the composition comprises not more than 0.4% of an impurity having a RRT of approximately 0.32. In some embodiments, the composition comprises not more than 0.4% of an impurity having a RRT of approximately 0.31 or 0.32. In some embodiments, the composition comprises Attorney Docket No.38709-0035WO1 not more than 0.4% of an impurity having a RRT of approximately 0.37. In some embodiments, the composition comprises not more than (i) 0.2% of an impurity having a relative retention time (RRT) of approximately 0.18; (ii) 0.4% of an impurity having a RRT of approximately 0.31; and (iii) 0.4% of an impurity having a RRT of approximately 0.37. In some embodiments, each RRT is determined relative to sodium phenylbutyrate. In some aspects, provided herein is a composition comprising taurursodiol (TURSO) and sodium phenylbutyrate. In some embodiments, the composition comprises 8% to 12% w/w of taurursodiol (TURSO). In some embodiments, the composition comprises 27% to 32% w/w of sodium phenylbutyrate. In some embodiments, the composition comprises not more than 0.2% of an impurity having a relative retention time (RRT) of 0.18. In some embodiments, the composition comprises not more than 0.2% of an impurity having a relative retention time (RRT) of 0.19. In some embodiments, the composition comprises not more than 0.2% of an impurity having a relative retention time (RRT) of 0.18 or 0.19. In some embodiments, the composition comprises not more than 0.5% of an impurity having a RRT of 0.30. In some embodiments, the composition comprises not more than 0.4% of an impurity having a RRT of 0.31. In some embodiments, the composition comprises not more than 0.3% of an impurity having a RRT of 0.31. In some embodiments, the composition comprises not more than 0.4% of an impurity having a RRT of 0.32. In some embodiments, the composition comprises not more than 0.4% of an impurity having a RRT of 0.31 or 0.32. In some embodiments, the composition comprises not more than 0.4% of an impurity having a RRT of 0.37. In some embodiments, the composition comprises not more than (i) 0.2% of an impurity having a relative retention time (RRT) of 0.18; (ii) 0.4% of an impurity having a RRT of 0.31; and (iii) 0.4% of an impurity having a RRT of 0.37. In some embodiments, each RRT is determined relative to sodium phenylbutyrate. Some embodiments provide a composition comprising about 8% to about 12% w/w of taurursodiol (TURSO); about 27% to about 32% w/w of sodium phenylbutyrate; wherein the composition comprises not more than (i) 0.2% of an impurity having a relative retention time (RRT) of about 0.18; (ii) 0.4% of an impurity having a RRT of about 0.31; and (iii) 0.4% of an impurity having a RRT of about 0.37; and Attorney Docket No.38709-0035WO1 wherein each RRT is determined relative to sodium phenylbutyrate using the HPLC method disclosed in Example 1. Some embodiments provide a composition comprising about 8% to about 12% w/w of taurursodiol (TURSO); about 27% to about 32% w/w of sodium phenylbutyrate; wherein the composition comprises not more than (i) 0.2% of an impurity having a relative retention time (RRT) of about 0.18; (ii) 0.4% of an impurity having a RRT of about 0.31; and (iii) 0.4% of an impurity having a RRT of about 0.37; and wherein each RRT is determined relative to sodium phenylbutyrate. Some embodiments provide a composition comprising approximately 8% to approximately 12% w/w of taurursodiol (TURSO); approximately 27% to approximately 32% w/w of sodium phenylbutyrate; wherein the composition comprises not more than (i) 0.2% of an impurity having a relative retention time (RRT) of approximately 0.18; (ii) 0.4% of an impurity having a RRT of approximately 0.31; and (iii) 0.4% of an impurity having a RRT of approximately 0.37; and wherein each RRT is determined relative to sodium phenylbutyrate. Some embodiments provide a composition comprising 8% to 12% w/w of taurursodiol (TURSO); 27% to 32% w/w of sodium phenylbutyrate; wherein the composition comprises not more than (i) 0.2% of an impurity having a relative retention time (RRT) of 0.18; (ii) 0.4% of an impurity having a RRT of 0.31; and (iii) 0.4% of an impurity having a RRT of 0.37; and wherein each RRT is determined relative to sodium phenylbutyrate. Some embodiments provide a composition comprising about 8% to about 12% w/w of taurursodiol (TURSO); about 27% to about 32% w/w of sodium phenylbutyrate; wherein the composition comprises not more than (i) 0.2% of an impurity having a relative retention time (RRT) of about 0.18; (ii) 0.5% of an impurity having a RRT of about 0.30; (iii) 0.4% of an impurity having a RRT of about 0.31; and (iv) 0.4% of an impurity having a RRT of about 0.37; and wherein each RRT is determined relative to sodium phenylbutyrate. Some embodiments provide a composition comprising approximately 8% to approximately 12% w/w of taurursodiol (TURSO); approximately 27% to approximately 32% w/w of sodium phenylbutyrate; Attorney Docket No.38709-0035WO1 wherein the composition comprises not more than (i) 0.2% of an impurity having a relative retention time (RRT) of approximately 0.18; (ii) 0.5% of an impurity having a RRT of approximately 0.30; (iii) 0.4% of an impurity having a RRT of approximately 0.31; and (iv) 0.4% of an impurity having a RRT of approximately 0.37; and wherein each RRT is determined relative to sodium phenylbutyrate. Some embodiments provide a composition comprising 8% to 12% w/w of taurursodiol (TURSO); 27% to 32% w/w of sodium phenylbutyrate; wherein the composition comprises not more than (i) 0.2% of an impurity having a relative retention time (RRT) of 0.18; (ii) 0.5% of an impurity having a RRT of 0.30; (iii) 0.4% of an impurity having a RRT of 0.31; and (iv) 0.4% of an impurity having a RRT of 0.37; and wherein each RRT is determined relative to sodium phenylbutyrate. Some embodiments provide a composition comprising about 8% to about 12% w/w of taurursodiol (TURSO); about 27% to about 32% w/w of sodium phenylbutyrate; wherein the composition comprises not more than (i) 0.2% of an impurity having a relative retention time (RRT) of about 0.18 or 0.19; (ii) 0.5% of an impurity having a RRT of about 0.30; (iii) 0.4% of an impurity having a RRT of about 0.31 or 0.32; and (iv) 0.4% of an impurity having a RRT of about 0.37; and wherein each RRT is determined relative to sodium phenylbutyrate. Some embodiments provide a composition comprising approximately 8% to approximately 12% w/w of taurursodiol (TURSO); approximately 27% to approximately 32% w/w of sodium phenylbutyrate; wherein the composition comprises not more than (i) 0.2% of an impurity having a relative retention time (RRT) of approximately 0.18 or 0.19; (ii) 0.5% of an impurity having a RRT of approximately 0.30; (iii) 0.4% of an impurity having a RRT of approximately 0.31 or 0.32; and (iv) 0.4% of an impurity having a RRT of approximately 0.37; and wherein each RRT is determined relative to sodium phenylbutyrate. Some embodiments provide a composition comprising 8% to 12% w/w of taurursodiol (TURSO); 27% to 32% w/w of sodium phenylbutyrate; wherein the composition comprises not more than (i) 0.2% of an impurity having a relative retention time (RRT) of 0.18 or 0.19; (ii) 0.5% of an impurity having Attorney Docket No.38709-0035WO1 a RRT of 0.30; (iii) 0.4% of an impurity having a RRT of 0.31 or 0.32; and (iv) 0.4% of an impurity having a RRT of 0.37; and wherein each RRT is determined relative to sodium phenylbutyrate. In some embodiments, the composition comprises not more than 0.2% of an impurity having a relative retention time (RRT) of about 0.18. In some embodiments, the composition comprises not more than 0.1% of an impurity having a relative retention time (RRT) of about 0.18. In some embodiments, the composition comprises not more than 0.2% of an impurity having a relative retention time (RRT) of approximately 0.18. In some embodiments, the composition comprises not more than 0.1% of an impurity having a relative retention time (RRT) of approximately 0.18. In some embodiments, the composition comprises not more than 0.2% of an impurity having a relative retention time (RRT) of 0.18. In some embodiments, the composition comprises not more than 0.1% of an impurity having a relative retention time (RRT) of 0.18. In some embodiments, the composition comprises not more than 0.2% of an impurity having a relative retention time (RRT) of about 0.19. In some embodiments, the composition comprises not more than 0.1% of an impurity having a relative retention time (RRT) of about 0.19. In some embodiments, the composition comprises not more than 0.2% of an impurity having a relative retention time (RRT) of approximately 0.19. In some embodiments, the composition comprises not more than 0.1% of an impurity having a relative retention time (RRT) of approximately 0.19. In some embodiments, the composition comprises not more than 0.2% of an impurity having a relative retention time (RRT) of 0.19. In some embodiments, the composition comprises not more than 0.1% of an impurity having a relative retention time (RRT) of 0.19. In some embodiments, the composition comprises not more than 0.2% of an impurity having a relative retention time (RRT) of about 0.18 or 0.19. In some embodiments, the composition comprises not more than 0.1% of an impurity having a relative retention time (RRT) of about 0.18 or 0.19. In some embodiments, the composition comprises not more than 0.2% of an impurity having a relative retention time (RRT) of approximately 0.18 or 0.19. In some embodiments, the composition comprises not more than 0.1% of an impurity having a relative retention time (RRT) of approximately 0.18 or 0.19. In some embodiments, the composition comprises not Attorney Docket No.38709-0035WO1 more than 0.2% of an impurity having a relative retention time (RRT) of 0.18 or 0.19. In some embodiments, the composition comprises not more than 0.1% of an impurity having a relative retention time (RRT) of 0.18 or 0.19. In some embodiments, the composition comprises not more than 0.5% of an impurity having a RRT of about 0.30. In some embodiments, the composition comprises not more than 0.4% of an impurity having a RRT of about 0.30. In some embodiments, the composition comprises not more than 0.3% of an impurity having a RRT of about 0.30. In some embodiments, the composition comprises not more than 0.2% of an impurity having a RRT of about 0.30. In some embodiments, the composition comprises not more than 0.1% of an impurity having a RRT of about 0.30. In some embodiments, the composition comprises not more than 0.5% of an impurity having a RRT of approximately 0.30. In some embodiments, the composition comprises not more than 0.4% of an impurity having a RRT of approximately 0.30. In some embodiments, the composition comprises not more than 0.3% of an impurity having a RRT of approximately 0.30. In some embodiments, the composition comprises not more than 0.2% of an impurity having a RRT of approximately 0.30. In some embodiments, the composition comprises not more than 0.1% of an impurity having a RRT of approximately 0.30. In some embodiments, the composition comprises not more than 0.5% of an impurity having a RRT of 0.30. In some embodiments, the composition comprises not more than 0.4% of an impurity having a RRT of 0.30. In some embodiments, the composition comprises not more than 0.3% of an impurity having a RRT of 0.30. In some embodiments, the composition comprises not more than 0.2% of an impurity having a RRT of 0.30. In some embodiments, the composition comprises not more than 0.1% of an impurity having a RRT of 0.30. In some embodiments, the composition comprises not more than 0.4% of an impurity having a RRT of about 0.31. In some embodiments, the composition comprises not more than 0.3% of an impurity having a RRT of about 0.31. In some embodiments, the composition comprises not more than 0.2% of an impurity having a RRT of about 0.31. In some embodiments, the composition comprises not more than 0.1% of an impurity having a RRT of about 0.31. In some embodiments, the composition comprises not more than 0.4% of an impurity having a RRT of approximately 0.31. In some embodiments, the composition comprises not more than 0.3% of an impurity having a RRT of approximately 0.31. In some embodiments, the Attorney Docket No.38709-0035WO1 composition comprises not more than 0.2% of an impurity having a RRT of approximately 0.31. In some embodiments, the composition comprises not more than 0.1% of an impurity having a RRT of approximately 0.31. In some embodiments, the composition comprises not more than 0.4% of an impurity having a RRT of 0.31. In some embodiments, the composition comprises not more than 0.3% of an impurity having a RRT of 0.31. In some embodiments, the composition comprises not more than 0.2% of an impurity having a RRT of 0.31. In some embodiments, the composition comprises not more than 0.1% of an impurity having a RRT of 0.31. In some embodiments, the composition comprises not more than 0.4% of an impurity having a RRT of about 0.32. In some embodiments, the composition comprises not more than 0.3% of an impurity having a RRT of about 0.32. In some embodiments, the composition comprises not more than 0.2% of an impurity having a RRT of about 0.32. In some embodiments, the composition comprises not more than 0.1% of an impurity having a RRT of about 0.32. In some embodiments, the composition comprises not more than 0.4% of an impurity having a RRT of approximately 0.32. In some embodiments, the composition comprises not more than 0.3% of an impurity having a RRT of approximately 0.32. In some embodiments, the composition comprises not more than 0.2% of an impurity having a RRT of approximately 0.32. In some embodiments, the composition comprises not more than 0.1% of an impurity having a RRT of approximately 0.32. In some embodiments, the composition comprises not more than 0.4% of an impurity having a RRT of 0.32. In some embodiments, the composition comprises not more than 0.3% of an impurity having a RRT of 0.32. In some embodiments, the composition comprises not more than 0.2% of an impurity having a RRT of 0.32. In some embodiments, the composition comprises not more than 0.1% of an impurity having a RRT of 0.32. In some embodiments, the composition comprises not more than 0.4% of an impurity having a RRT of about 0.31 or 0.32. In some embodiments, the composition comprises not more than 0.3% of an impurity having a RRT of about 0.31 or 0.32. In some embodiments, the composition comprises not more than 0.2% of an impurity having a RRT of about 0.31 or 0.32. In some embodiments, the composition comprises not more than 0.1% of an impurity having a RRT of about 0.31 or 0.32. In some embodiments, the composition comprises not more than 0.4% of an impurity having a RRT of approximately 0.31 or 0.32. In some embodiments, the composition comprises Attorney Docket No.38709-0035WO1 not more than 0.3% of an impurity having a RRT of approximately 0.31 or 0.32. In some embodiments, the composition comprises not more than 0.2% of an impurity having a RRT of approximately 0.31 or 0.32. In some embodiments, the composition comprises not more than 0.1% of an impurity having a RRT of approximately 0.31 or 0.32. In some embodiments, the composition comprises not more than 0.4% of an impurity having a RRT of 0.31 or 0.32. In some embodiments, the composition comprises not more than 0.3% of an impurity having a RRT of 0.31 or 0.32. In some embodiments, the composition comprises not more than 0.2% of an impurity having a RRT of 0.31 or 0.32. In some embodiments, the composition comprises not more than 0.1% of an impurity having a RRT of 0.31 or 0.32. In some embodiments, the composition comprises not more than 0.4% of an impurity having a RRT of about 0.37. In some embodiments, the composition comprises not more than 0.3% of an impurity having a RRT of about 0.37. In some embodiments, the composition comprises not more than 0.2% of an impurity having a RRT of about 0.37. In some embodiments, the composition comprises not more than 0.1% of an impurity having a RRT of about 0.37. In some embodiments, the composition comprises not more than 0.4% of an impurity having a RRT of approximately 0.37. In some embodiments, the composition comprises not more than 0.3% of an impurity having a RRT of approximately 0.37. In some embodiments, the composition comprises not more than 0.2% of an impurity having a RRT of approximately 0.37. In some embodiments, the composition comprises not more than 0.1% of an impurity having a RRT of approximately 0.37. In some embodiments, the composition comprises not more than 0.4% of an impurity having a RRT of 0.37. In some embodiments, the composition comprises not more than 0.3% of an impurity having a RRT of 0.37. In some embodiments, the composition comprises not more than 0.2% of an impurity having a RRT of 0.37. In some embodiments, the composition comprises not more than 0.1% of an impurity having a RRT of 0.37. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of about 0.38. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of approximately 0.38. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of 0.38. Attorney Docket No.38709-0035WO1 In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of about 0.62. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of approximately 0.62. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of 0.62. In some embodiments, the composition further comprises not more than 0.15% of an impurity having a RRT of about 0.63. In some embodiments, the composition further comprises not more than 0.15% of an impurity having a RRT of approximately 0.63. In some embodiments, the composition further comprises not more than 0.15% of an impurity having a RRT of 0.63. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of about 0.63. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of approximately 0.63. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of 0.63. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of about 0.64. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of approximately 0.64. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of 0.64. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of about 0.67. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of approximately 0.67. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of 0.67. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of about 0.68. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of approximately 0.68. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of 0.68. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of about 0.70. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of approximately Attorney Docket No.38709-0035WO1 0.70. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of 0.70. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of about 0.71. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of approximately 0.71. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of 0.71. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of about 0.73. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of approximately 0.73. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of 0.73. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of about 0.74. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of approximately 0.74. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of 0.74. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of about 0.76. In some embodiments, the impurity having a RRT of about 0.76 is 4-[4-(3-carboxypropyl)phenyl]-4-oxobutanoic acid. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of approximately 0.76. In some embodiments, the impurity having a RRT of approximately 0.76 is 4-[4-(3-carboxypropyl)phenyl]-4-oxobutanoic acid. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of 0.76. In some embodiments, the impurity having a RRT of 0.76 is 4-[4-(3-carboxypropyl)phenyl]-4-oxobutanoic acid. In some embodiments, the composition further comprises not more than 0.2% of an impurity having a RRT of about 0.79. In some embodiments, the composition further comprises not more than 0.2% of an impurity having a RRT of approximately 0.79. In some embodiments, the composition further comprises not more than 0.2% of an impurity having a RRT of 0.79. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of about 0.79. In some embodiments, the composition further comprises not more than 0.1% of an impurity Attorney Docket No.38709-0035WO1 having a RRT of approximately 0.79. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of 0.79. In some embodiments, the impurity having a RRT of 0.79 is 4-oxo-4-phenylbutanoic acid. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of about 0.80. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of approximately 0.80. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of 0.80. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of about 0.83. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of approximately 0.83. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of 0.83. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of about 0.85. In some embodiments, the impurity having an RRT of about 0.85 is 4-(3-formylphenyl)butanoic acid. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of approximately 0.85. In some embodiments, the impurity having an RRT of approximately 0.85 is 4-(3-formylphenyl)butanoic acid. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of 0.85. In some embodiments, the impurity having an RRT of 0.85 is 4-(3- formylphenyl)butanoic acid. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of about 0.86. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of approximately 0.86. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of 0.86. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of about 0.90. In some embodiments, the impurity having an RRT of about 0.90 is 4,4’-1,4-phenylene dibutanoic acid. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of approximately 0.90. In some embodiments, the impurity having an RRT of approximately 0.90 is 4,4’-1,4-phenylene dibutanoic acid. In some embodiments, the Attorney Docket No.38709-0035WO1 composition further comprises not more than 0.1% of an impurity having a RRT of 0.90. In some embodiments, the impurity having an RRT of 0.90 is 4,4’-1,4-phenylene dibutanoic acid. In some embodiments, the composition further comprises not more than 0.5% of an impurity having a RRT of about 0.92. In some embodiments, the impurity having an RRT of about 0.92 is 4,4’-1,3-phenylene dibutanoic acid. In some embodiments, the composition further comprises not more than 0.5% of an impurity having a RRT of approximately 0.92. In some embodiments, the impurity having an RRT of approximately 0.92 is 4,4’-1,3-phenylene dibutanoic acid. In some embodiments, the composition further comprises not more than 0.5% of an impurity having a RRT of 0.92. In some embodiments, the impurity having an RRT of 0.92 is 4,4’-1,3-phenylene dibutanoic acid. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of about 0.92. In some embodiments, the impurity having an RRT of about 0.92 is 4,4’-1,3-phenylene dibutanoic acid. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of approximately 0.92. In some embodiments, the impurity having an RRT of approximately 0.92 is 4,4’-1,3-phenylene dibutanoic acid. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of 0.92. In some embodiments, the impurity having an RRT of 0.92 is 4,4’-1,3-phenylene dibutanoic acid. In some embodiments, the composition further comprises not more than 0.13% of an impurity having a RRT of about 0.96. In some embodiments, the impurity having an RRT of about 0.96 is 4-(8-oxo-5,6,7,8-tetrahydronaphthalen-2-yl) butanoic acid. In some embodiments, the composition further comprises not more than 0.13% of an impurity having a RRT of approximately 0.96. In some embodiments, the impurity having an RRT of approximately 0.96 is 4-(8-oxo-5,6,7,8-tetrahydronaphthalen-2-yl) butanoic acid. In some embodiments, the composition further comprises not more than 0.13% of an impurity having a RRT of 0.96. In some embodiments, the impurity having an RRT of 0.96 is 4-(8-oxo-5,6,7,8-tetrahydronaphthalen-2-yl) butanoic acid. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of about 0.96. In some embodiments, the impurity having an RRT of about 0.96 is 4-(8-oxo-5,6,7,8-tetrahydronaphthalen-2-yl) butanoic acid. In some embodiments, the composition further comprises not more than 0.1% of an impurity Attorney Docket No.38709-0035WO1 having a RRT of approximately 0.96. In some embodiments, the impurity having an RRT of approximately 0.96 is 4-(8-oxo-5,6,7,8-tetrahydronaphthalen-2-yl) butanoic acid. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of 0.96. In some embodiments, the impurity having an RRT of 0.96 is 4-(8-oxo-5,6,7,8-tetrahydronaphthalen-2-yl) butanoic acid. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of about 0.98. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of approximately 0.98. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of 0.98. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of about 1.04. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of approximately 1.04. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of 1.04. In some embodiments, the impurity having a RRT of 1.04 is 3,4-dihydronaphthalen-1(2H)-one. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of about 0.17. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of approximately 0.17. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of 0.17. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of about 0.21. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of approximately 0.21. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of 0.21. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of about 0.22. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of approximately 0.22. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of 0.22. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of about 0.23. In some embodiments, the composition Attorney Docket No.38709-0035WO1 further comprises not more than 0.1% of an impurity having a RRT of approximately 0.23. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of 0.23. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of about 0.25. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of approximately 0.25. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of 0.25. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of about 0.27. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of approximately 0.27. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of 0.27. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of about 0.28. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of approximately 0.28. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of 0.28. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of about 0.29. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of approximately 0.29. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of 0.29. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of about 0.30. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of approximately 0.30. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of 0.30. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of about 0.33. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of approximately 0.33. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of 0.33. Attorney Docket No.38709-0035WO1 In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of about 0.34. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of approximately 0.34. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of 0.34. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of about 0.39. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of approximately 0.39. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of 0.39. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of about 0.40. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of approximately 0.40. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of 0.40. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of about 0.41. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of approximately 0.41. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of 0.41. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of about 0.43. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of approximately 0.43. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of 0.43. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of about 0.47. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of approximately 0.47. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of 0.47. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of about 0.50. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of approximately Attorney Docket No.38709-0035WO1 0.50. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of 0.50. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of about 0.53. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of approximately 0.53. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of 0.53. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of about 0.60. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of approximately 0.60. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of 0.60. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of about 0.61. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of approximately 0.61. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of 0.61. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of about 0.66. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of approximately 0.66. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of 0.66. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of about 0.68. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of approximately 0.68. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of 0.68. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of about 0.73. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of approximately 0.73. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of 0.73. Attorney Docket No.38709-0035WO1 In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of about 0.77. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of approximately 0.77. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of 0.77. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of about 0.80. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of approximately 0.80. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of 0.80. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of about 0.82. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of approximately 0.82. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of 0.82. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of about 0.83. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of approximately 0.83. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of 0.83. In some embodiments, the impurity having a RRT of 0.83 is 4-(4-formylphenyl)butanoic acid. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of about 0.84. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of approximately 0.84. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of 0.84. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of about 0.85. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of approximately 0.85. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of 0.85. In some embodiments, the impurity having a RRT of 0.85 is 4-(3-formylphenyl)butanoic acid. Attorney Docket No.38709-0035WO1 In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of about 0.90. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of approximately 0.90. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of 0.90. In some embodiments, the impurity having a RRT of 0.90 is 4-[4-(3-carboxypropyl)-phenyl]-butyric acid. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of about 0.91. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of approximately 0.91. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of 0.91. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of about 0.92. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of approximately 0.92. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of 0.92. In some embodiments, the impurity having a RRT of 0.92 is 4,4’-(1,3-phenylene)dibutanoic acid. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of about 0.94. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of approximately 0.94. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of 0.94. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of about 0.96. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of approximately 0.96. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of 0.96. In some embodiments, the impurity having a RRT of 0.96 is 4-(8-oxo-5,6,7,8-tetrahydronapthalen-2-yl)butanoic acid. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of about 0.97. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of approximately 0.97. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of 0.97. Attorney Docket No.38709-0035WO1 In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of about 0.98. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of approximately 0.98. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of 0.98. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of about 1.66. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of approximately 1.66. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of 1.66. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of about 1.68. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of approximately 1.68. In some embodiments, the composition further comprises not more than 0.1% of an impurity having a RRT of 1.68. In some embodiments, the composition further comprises not more than 0.1% of glucosylisomaltol. In some embodiments, the composition further comprises not more than 0.1% of 4-cyclohexylbutanoic acid. In some embodiments, the composition further comprises not more than 0.1% of taurine. In some embodiments, the composition further comprises about 0% to about 1% (e.g., about 0% to about 0.125%, about 0% to about 0.5%, about 0% to about 1%, about 0.125%, about 0.5%, or about 1%) w/w ursodeoxycholic acid (UDCA). In some embodiments, the composition further comprises about 0% to about 0.125% w/w Ursodeoxycholic acid (UDCA). In some embodiments, the composition further comprises not more than 1% (e.g., not more than 0.5%, not more than 0.2%, or not more than 0.1%) of UDCA. In some embodiments, the composition further comprises about 0% to about 0.08% w/w UDCA. In some embodiments, the amount of each impurity is determined after about 1 week of storage at about 25°C and about 60% relative humidity. In some embodiments, the amount of each impurity is determined after about 2 weeks of storage at about 25°C and about 60% relative humidity. Attorney Docket No.38709-0035WO1 In some embodiments, the amount of each impurity is determined after about 3 weeks of storage at about 25°C and about 60% relative humidity. In some embodiments, the amount of each impurity is determined after about 1 month of storage at about 25°C and about 60% relative humidity. In some embodiments, the amount of each impurity is determined after about 2 months of storage at about 25°C and about 60% relative humidity. In some embodiments, the amount of each impurity is determined after about 3 months of storage at about 25°C and about 60% relative humidity. In some embodiments, the amount of each impurity is determined after about 4 months of storage at about 25°C and about 60% relative humidity. In some embodiments, the amount of each impurity is determined after about 5 months of storage at about 25°C and about 60% relative humidity. In some embodiments, the amount of each impurity is determined after about 6 months of storage at about 25°C and about 60% relative humidity. In some embodiments, the amount of each impurity is determined after about 9 months of storage at about 25°C and about 60% relative humidity. In some embodiments, the amount of each impurity is determined after about 12 months of storage at about 25°C and about 60% relative humidity. In some embodiments, the amount of each impurity is determined after about 15 months of storage at about 25°C and about 60% relative humidity. In some embodiments, the amount of each impurity is determined after about 18 months of storage at about 25°C and about 60% relative humidity. In some embodiments, the amount of each impurity is determined after about 24 months of storage at about 25°C and about 60% relative humidity. In some embodiments, the amount of each impurity is determined after about 36 months of storage at about 25°C and about 60% relative humidity. In some embodiments, the amount of each impurity is determined after about 1 week of storage at about 40°C and about 75% relative humidity. In some embodiments, the amount of each impurity is determined after about 2 weeks of storage at about 40°C and about 75% relative humidity. In some embodiments, the amount of each impurity is determined after about 3 weeks of storage at about 40°C and about 75% relative humidity. Attorney Docket No.38709-0035WO1 In some embodiments, the amount of each impurity is determined after about 1 month of storage at about 40°C and about 75% relative humidity. In some embodiments, the amount of each impurity is determined after about 2 months of storage at about 40°C and about 75% relative humidity. In some embodiments, the amount of each impurity is determined after about 3 months of storage at about 40°C and about 75% relative humidity. In some embodiments, the amount of each impurity is determined after about 4 months of storage at about 40°C and about 75% relative humidity. In some embodiments, the amount of each impurity is determined after about 5 months of storage at about 40°C and about 75% relative humidity. In some embodiments, the amount of each impurity is determined after about 6 months of storage at about 40°C and about 75% relative humidity. In some embodiments, the amount of each impurity is determined after about 9 months of storage at about 40°C and about 75% relative humidity. In some embodiments, the amount of each impurity is determined after about 12 months of storage at about 40°C and about 75% relative humidity. In some embodiments, the amount of each impurity is determined after about 15 months of storage at about 40°C and about 75% relative humidity. In some embodiments, the amount of each impurity is determined after about 18 months of storage at about 40°C and about 75% relative humidity. In some embodiments, the amount of each impurity is determined after about 24 months of storage at about 40°C and about 75% relative humidity. In some embodiments, the amount of each impurity is determined after about 36 months of storage at about 40°C and about 75% relative humidity. In some embodiments, the composition is formulated as a unit dosage form. In some embodiments, the unit dosage form is a sachet. In some embodiments, the unit dosage form has substantially the same weight as the initial weight of the unit dosage form after about 1 week of storage at about 40°C and about 75% relative humidity. In some embodiments, the unit dosage form has substantially the same weight as the initial weight of the unit dosage form after about 2 weeks of storage at about 40°C and about 75% relative humidity. Attorney Docket No.38709-0035WO1 In some embodiments, the unit dosage form has substantially the same weight as the initial weight of the unit dosage form after about 2 weeks of storage at about 40°C and about 75% relative humidity. In some embodiments, the unit dosage form has substantially the same weight as the initial weight of the unit dosage form after about 1 month of storage at about 40°C and about 75% relative humidity. In some embodiments, the unit dosage form has substantially the same weight as the initial weight of the unit dosage form after about 2 months of storage at about 40°C and about 75% relative humidity. In some embodiments, the unit dosage form has substantially the same weight as the initial weight of the unit dosage form after about 3 months of storage at about 40°C and about 75% relative humidity. In some embodiments, the unit dosage form has substantially the same weight as the initial weight of the unit dosage form after about 4 months of storage at about 40°C and about 75% relative humidity. In some embodiments, the unit dosage form has substantially the same weight as the initial weight of the unit dosage form after about 5 months of storage at about 40°C and about 75% relative humidity. In some embodiments, the unit dosage form has substantially the same weight as the initial weight of the unit dosage form after about 6 months of storage at about 40°C and about 75% relative humidity. In some embodiments, the unit dosage form has substantially the same weight as the initial weight of the unit dosage form after about 9 months of storage at about 40°C and about 75% relative humidity. In some embodiments, the unit dosage form has substantially the same weight as the initial weight of the unit dosage form after about 12 months of storage at about 40°C and about 75% relative humidity. In some embodiments, the unit dosage form has substantially the same weight as the initial weight of the unit dosage form after about 15 months of storage at about 40°C and about 75% relative humidity. In some embodiments, the unit dosage form has substantially the same weight as the initial weight of the unit dosage form after about 18 months of storage at about 40°C and about 75% relative humidity. Attorney Docket No.38709-0035WO1 In some embodiments, the unit dosage form has substantially the same weight as the initial weight of the unit dosage form after about 24 months of storage at about 40°C and about 75% relative humidity. In some embodiments, the unit dosage form has substantially the same weight as the initial weight of the unit dosage form after about 36 months of storage at about 40°C and about 75% relative humidity. In some embodiments, the composition comprises not more than 1.2% (w/w) total degradation products characterized at 260 nm. In some embodiments, the composition comprises not more than 0.1% total degradation products characterized at 260 nm after about 1 month of storage at about 25°C and about 60% relative humidity. In some embodiments, the composition comprises not more than 0.1% total degradation products characterized at 260 nm after about 3 months of storage at about 25°C and about 60% relative humidity. In some embodiments, the composition comprises not more than 0.2% total degradation products characterized at 260 nm after about 6 months of storage at about 25°C and about 60% relative humidity. In some embodiments, the composition comprises not more than 0.3% total degradation products characterized at 260 nm after about 9 months of storage at about 25°C and about 60% relative humidity. In some embodiments, the composition comprises not more than 0.3% total degradation products characterized at 260 nm after about 12 months of storage at about 25°C and about 60% relative humidity. In some embodiments, the composition comprises not more than 0.3% total degradation products characterized at 260 nm after about 15 months of storage at about 25°C and about 60% relative humidity. In some embodiments, the composition comprises not more than 0.4% total degradation products characterized at 260 nm after about 18 months of storage at about 25°C and about 60% relative humidity. In some embodiments, the composition comprises not more than 0.5% total degradation products characterized at 260 nm after about 24 months of storage at about 25°C and about 60% relative humidity. Attorney Docket No.38709-0035WO1 In some embodiments, the composition comprises not more than 0.5% total degradation products characterized at 260 nm after about 36 months of storage at about 25°C and about 60% relative humidity. In some embodiments, the composition comprises not more than 3.4% total degradation products characterized at 203 nm. In some embodiments, the composition comprises not more than 1.5% total degradation products characterized at 203 nm. In some embodiments, the composition comprises not more than 1.2% total degradation products characterized at 203 nm. In some embodiments, the composition comprises not more than 0.5% total degradation products characterized at 203 nm. In some embodiments, the degradation products comprise bile acids. In some embodiments, the degradation products comprise taurochenodeoxycholic acid (TCDC). In some embodiments, the degradation products are bile acids. In some embodiments, the composition comprises not more than 1.5% TCDC. In some embodiments, the composition comprises not more than 1.2% TCDC. In some embodiments, the composition comprises not more than 1% TCDC. In some embodiments, the composition comprises not more than 0.5% TCDC. In some embodiments, the composition comprises not more than 0.14% TCDC. In some embodiments, the composition comprises not more than 0.5% of non-TCDC bile acids. Some embodiments provide a composition comprising approximately 8% to approximately 12% w/w of taurursodiol (TURSO); approximately 27% to approximately 32% w/w of sodium phenylbutyrate; wherein the composition comprises not more than 0.1% of glucosylisomaltol; 0.1% of UDCA; 1.5% of TCDC; 0.1% of 4-oxo-4-phenylbutanoic acid; 0.1% of 3,4-dihydronaphthalen-1(2H)-one; 0.1% of 4-cyclohexylbutanoic acid; 0.1% of 4-[4-(3-carboxypropyl)-phenyl]-4-oxobutanoic acid; 0.1% of 4-(4-formylphenyl)butanoic acid; 0.1% of 4-(3-formylphenyl)butanoic acid; 0.1% of 4-[4-(3-carboxypropyl)-phenyl]-butyric acid; Attorney Docket No.38709-0035WO1 0.1% of 4,4’-(1,3-phenylene) dibutanoic acid; 0.1% of 4-(8-oxo-5,6,7,8-tetrahydronaphthalen-2-yl) butanoic acid; and 0.1% of taurine. In some embodiments, each RRT is determined relative to sodium phenylbutyrate using the HPLC method in Example 1. TURSO and sodium phenylbutyrate can be formulated for use as or in pharmaceutical compositions. For example, the methods described herein can include administering an effective amount of a composition comprising TURSO and sodium phenylbutyrate. The term “effective amount”, as used herein, refer to an amount or a concentration of one or more drugs administered for a period of time (including acute or chronic administration and periodic or continuous administration) that is effective within the context of its administration for causing an intended effect or physiological outcome. The composition can include about 5% to about 15% w/w (e.g., about 6% to about 14%, about 7% to about 13 %, about 8% to about 12%, about 8% to about 11%, about 9% to about 10 %, or about 9.7% w/w) of TURSO and about 15% to about 45% w/w (e.g., about 20% to about 40%, about 25% to about 35%, about 27% to about 32%, about 28% to about 32%, or about 29% to about 30%, e.g., about 29.2% w/w) of sodium phenylbutyrate. In some embodiments, the composition includes about 9.7% w/w of TURSO and 29.2% w/w of sodium phenylbutyrate. In some embodiments, the composition comprises about 5% to about 15% w/w (e.g., about 6% to about 14%, about 7% to about 13 %, about 8% to about 12%, about 8% to about 11%, about 9% to about 10 %, or about 9.7% w/w) of TURSO. In some embodiments, the composition includes about 9.7% w/w of TURSO. In some embodiments, the composition comprises about 15% to about 45% w/w (e.g., about 20% to about 40%, about 25% to about 35%, about 27% to about 32%, about 28% to about 32%, or about 29% to about 30%, e.g., about 29.2% w/w) of sodium phenylbutyrate. In some embodiments, the composition includes about 29.2% w/w of sodium phenylbutyrate. The sodium phenylbutyrate and TURSO can be present in the composition at a ratio by weight of between about 1:1 to about 4:1 (e.g., about 2:1 or about 3:1). In some embodiments, the ratio between sodium phenylbutyrate and TURSO is about 3:1. The compositions described herein can include any pharmaceutically acceptable carrier, adjuvant, and/or vehicle. The term “pharmaceutically acceptable Attorney Docket No.38709-0035WO1 carrier or adjuvant” refers to a carrier or adjuvant that may be administered to a patient, together with a compound disclosed herein, and which does not destroy the pharmacological activity thereof and is nontoxic when administered in doses sufficient to deliver a therapeutic amount of the compound. As used herein the language “pharmaceutically acceptable carrier” includes saline, solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration. The pharmaceutical compositions may contain any conventional non-toxic pharmaceutically-acceptable carriers, adjuvants or vehicles. In some cases, the pH of the formulation may be adjusted with pharmaceutically acceptable acids, bases or buffers to enhance the stability of the formulated compound or its delivery form. Compositions of the present disclosure can include about 8% to about 24% w/w of dextrates (e.g., about 9% to about 23%, about 10% to about 22%, about 10% to about 20%, about 11% to about 21%, about 12% to about 20%, about 13% to about 19%, about 14% to about 18%, about 14% to about 17%, about 15% to about 16%, or about 15.6% w/w of dextrates). Both anhydrous and hydrated dextrates are contemplated herein. The dextrates of the present disclosure can include a mixture of saccharides developed from controlled enzymatic hydrolysis of starch. Some embodiments of any of the compositions described herein include hydrated dextrates (e.g., NF grade, obtained from JRS Pharma, Colonial Scientific, or Quadra). Compositions of the present disclosure can include about 1% to about 6% w/w of sugar alcohol (e.g., about 2% to about 5%, about 3% to about 4%, or about 3.9% w/w of sugar alcohol). Sugar alcohols can be derived from sugars and contain one hydroxyl group (-OH) attached to each carbon atom. Both disaccharides and monosaccharides can form sugar alcohols. Sugar alcohols can be natural or produced by hydrogenation of sugars. Exemplary sugar alcohols include but are not limited to, sorbitol, xylitol, and mannitol. In some embodiments, the composition comprises about 1% to about 6% w/w (e.g., about 2% to about 5%, about 3% to about 4%, about 3.5% to about 4.5%, or about 3.9% w/w) of sorbitol. Compositions of the present disclosure can include about 22% to about 35% w/w of maltodextrin (e.g., about 22% to about 33%, about 24% to about 31%, about 25% to about 32%, about 26% to about 30%, or about 28% to about 29% w/w, e.g., about 28.3% w/w of maltodextrin). Maltodextrin can form a flexible helix enabling Attorney Docket No.38709-0035WO1 the entrapment of the active ingredients (e.g., any of the phenylbutyrate compounds and bile acids described herein) when solubilized into solution, thereby masking the taste of the active ingredients. Maltodextrin produced from any suitable sources are contemplated herein, including but not limited to, pea, rice, tapioca, corn, and potato. In some embodiments, the maltodextrin is pea maltodextrin. In some embodiments, the composition includes about 28.3% w/w of pea maltodextrin. For example, pea maltodextrin obtained from Roquette (KLEPTOSE® LINECAPS) can be used. The compositions described herein can further include sugar substitutes (e.g. sucralose). For example, the compositions can include about 0.5% to about 5% w/w of sucralose (e.g., about 1% to about 4%, about 1% to about 3%, or about 1% to about 2%, e.g., about 1.9% w/w of sucralose). Other sugar substitutes contemplated herein include but are not limited to aspartame, neotame, acesulfame potassium, saccharin, and advantame. In some embodiments, the compositions include one or more flavorants. The compositions can include about 2% to about 15% w/w of flavorants (e.g., about 3% to about 13%, about 3% to about 12%, about 4% to about 9%, about 5% to about 10%, or about 5% to about 8%, e.g., about 7.3% w/w). Flavorants can include substances that give another substance flavor, or alter the characteristics of a composition by affecting its taste. Flavorants can be used to mask unpleasant tastes without affecting physical and chemical stability, and can be selected based on the taste of the drug to be incorporated. Suitable flavorants include but are not limited to natural flavoring substances, artificial flavoring substances, and imitation flavors. Blends of flavorants can also be used. For example, the compositions described herein can include two or more (e.g., two, three, four, five or more) flavorants. Flavorants can be soluble and stable in water. Selection of suitable flavorants can be based on taste testing. For example, multiple different flavorants can be added to a composition separately, which are subjected to taste testing. Exemplary flavorants include any fruit flavor powder (e.g., peach, strawberry, mango, orange, apple, grape, raspberry, cherry or mixed berry flavor powder). The compositions described herein can include about 0.5% to about 1.5% w/w (e.g., about 1% w/w) of a mixed berry flavor powder and/or about 5% to about 7% w/w (e.g., about 6.3% w/w) of a masking flavor. Suitable masking flavors can be obtained from e.g., Firmenich. Attorney Docket No.38709-0035WO1 In some embodiments, the compositions include one or more flavor-masking agents (also referred to herein as “taste masking agents” and “masking flavor”). The compositions can include about 2% to about 15% w/w of flavor-masking agents (e.g., about 3% to about 13%, about 3% to about 12%, about 4% to about 9%, about 5% to about 10%, or about 5% to about 8%, e.g., about 7.3% w/w). Flavor masking agents attenuate undesirable flavors. Exemplary flavor-masking agents include saccharin, saccharin sodium, aspartame, sucrose, fructose, glucose, mannitol, sorbitol, xylitol, erythritol, maltitol, aspartame, sucralose, neotame, saccharine, trehalose, and tagatose. The compositions described herein can further include silicon dioxide (or silica). Addition of silica to the composition can prevent or reduce agglomeration of the components of the composition. Silica can serve as an anti-caking agent, adsorbent, disintegrant, or glidant. In some embodiments, the compositions described herein include about 0.05% to about 2% w/w of porous silica (e.g., about 0.1% to about 2%, about 0.3% to about 1.5%, about 0.5% to about 1.2%, or about 0.8% to about 1%, e.g., 0.9% w/w). Porous silica may have a higher H2O absorption capacity and/or a higher porosity as compared to fumed silica, at a relative humidity of about 20% or higher (e.g., about 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% or higher). The porous silica can have an H2O absorption capacity of about 5% to about 40% (e.g. about 20% to about 40%, or about 30% to about 40%) by weight at a relative humidity of about 50%. The porous silica can have a higher porosity at a relative humidity of about 20% or higher (e.g., about 30%, 40%, 50%, 60%, 70%, 80%, 90% or higher) as compared to that of fumed silica. In some embodiments, the porous silica have an average particle size of about 2 µm to about 10 µm (e.g. about 3 µm to about 9 µm, about 4 µm to about 8 µm, about 5 µm to about 8 µm, or about 7.5 µm). In some embodiments, the porous silica have an average pore volume of about 0.1 cc/gm to about 2.0 cc/gm (e.g., about 0.1 cc/gm to about 1.5 cc/gm, about 0.1 cc/gm to about 1 cc/gm, about 0.2 cc/gm to about 0.8 cc/gm, about 0.3 cc/gm to about 0.6 cc/gm, or about 0.4 cc/gm). In some embodiments, the porous silica have a bulk density of about 50 g/L to about 700 g/L (e.g. about 100 g/L to about 600 g/L, about 200 g/L to about 600 g/L, about 400 g/L to about 600 g/L, about 500 g/L to about 600 g/L, about 540 g/L to about 580 g/L, or about 560 g/L). In some embodiments, the compositions described herein include Attorney Docket No.38709-0035WO1 about 0.05% to about 2% w/w (e.g., any subranges of this range described herein) of Syloid® 63FP (WR Grace). The compositions described herein can further include one or more buffering agents. For example, the compositions can include about 0.5% to about 5% w/w of buffering agents (e.g., about 1% to about 4% w/w, about 1.5% to about 3.5% w/w, or about 2% to about 3% w/w, e.g. about 2.7% w/w of buffering agents). Buffering agents can include weak acid or base that maintain the acidity or pH of a composition near a chosen value after addition of another acid or base. Suitable buffering agents are known in the art. In some embodiments, the buffering agent in the composition provided herein is a phosphate, such as a sodium phosphate (e.g., sodium phosphate dibasic anhydrous). For example, the composition can include about 0.05% to about 5% (e.g., about 1% to about 4%, about 2% to about 3%, or about 2.7%) w/w of sodium phosphate (e.g., sodium phosphate dibasic). The compositions can also include one or more lubricants. For example, the compositions can include about 0.05% to about 1% w/w of lubricants (e.g., about 0.1% to about 0.9%, about 0.2% to about 0.8 %, about 0.3% to about 0.7%, or about 0.4% to about 0.6%, e.g. about 0.5% w/w of lubricants). Exemplary lubricants include, but are not limited to sodium stearyl fumarate, magnesium stearate, stearic acid, metallic stearates, talc, waxes and glycerides with high melting temperatures, colloidal silica, polyethylene glycols, alkyl sulphates, glyceryl behenate, and hydrogenated oil. Additional lubricants are known in the art. In some embodiments, the composition includes about 0.05% to about 1% w/w (e.g., any of the subranges of this range described herein) of sodium stearyl fumarate. For example, the composition can include about 0.5% w/w of sodium stearyl fumarate. In some embodiments, the composition include about 29.2% w/w of sodium phenylbutyrate, about 9.7% w/w of TURSO, about 15.6% w/w of dextrates, about 3.9% w/w of sorbitol, about 1.9% w/w of sucralose, about 28.3% w/w of maltodextrin, about 7.3% w/w of flavorants, about 0.9% w/w of silicon dioxide, about 2.7% w/w of sodium phosphate (e.g. sodium phosphate dibasic), and about 0.5% w/w of sodium stearyl fumerate. The composition can include about 3000 mg of sodium phenylbutyrate, about 1000 mg of TURSO, about 1600 mg of dextrates, about 400 mg of sorbitol, about 200 mg of sucralose, about 97.2 mg of silicon dioxide, about 2916 mg of maltodextrin, Attorney Docket No.38709-0035WO1 about 746 mg of flavorants (e.g. about 102 mg of mixed berry flavor and about 644 mg of masking flavor), about 280 mg of sodium phosphate (e.g. sodium phosphate dibasic), and about 48.6 mg of sodium stearyl fumerate. In some embodiments, the composition comprises: about 14% to about 17% w/w of dextrates; about 3.5% to about 4.5% w/w of sorbitol; about 25% to about 32% w/w of maltodextrin; and about 0.05% to about 1.5% w/w of porous silica. In some embodiments, the composition comprises: about 0.5% to about 5% w/w of sucralose; about 2% to about 15% w/w of flavorants; about 0.5% to about 5% w/w of a buffering agent; and about 0.05% to about 1% w/w of a lubricant. In some embodiments, the composition comprises: about 15.6% w/w of dextrates; about 3.9% w/w of sorbitol; about 1.9% w/w of sucralose; about 28.3% w/w of maltodextrin; about 7.3% w/w of flavorants; about 0.9% w/w of porous silica; about 2.7% w/w of sodium phosphate; and about 0.5% w/w of sodium stearyl fumarate. Additional suitable sweeteners or taste masking agents can also be included in the compositions, such as but not limited to, xylose, ribose, glucose, mannose, galactose, fructose, dextrose, sucrose, maltose, steviol glycosides, partially hydrolyzed starch, and corn syrup solid. Water soluble artificial sweeteners are contemplated herein, such as the soluble saccharin salts (e.g., sodium or calcium saccharin salts), cyclamate salts, acesulfam potassium (acesulfame K), and the free acid form of saccharin and aspartame based sweeteners such as L-aspartyl- phenylalanine methyl ester, Alitame® or Neotame®. The amount of sweetener or taste masking agents can vary with the desired amount of sweeteners or taste masking agents selected for a particular final composition. Attorney Docket No.38709-0035WO1 Pharmaceutically acceptable binders in addition to those described above are also contemplated. Examples include cellulose derivatives including microcrystalline cellulose, low-substituted hydroxypropyl cellulose (e.g. LH 22, LH 21, LH 20, LH 32, LH 31, LH30); starches, including potato starch; croscarmellose sodium (i.e. cross- linked carboxymethylcellulose sodium salt; e.g. Ac-Di-Sol®); alginic acid or alginates; insoluble polyvinylpyrrolidone (e.g. Polyvidon® CL, Polyvidon® CL-M, Kollidon® CL, Polyplasdone® XL, Polyplasdone® XL-10); and sodium carboxymethyl starch (e.g. Primogel® and Explotab®). Additional fillers, diluents or binders may be incorporated such as polyols, sucrose, sorbitol, mannitol, Erythritol®, Tagatose®, lactose (e.g., spray-dried lactose, α-lactose, β-lactose, Tabletose®, various grades of Pharmatose®, Microtose or Fast- Floc®), microcrystalline cellulose (e.g., various grades of Avicel®, such as Avicel® PH101, Avicel® PH102 or Avicel® PH105, Elcema® P100, Emcocel®, Vivacel®, Ming Tai® and Solka-Floc®), hydroxypropylcellulose, L-hydroxypropylcellulose (low-substituted) (e.g. L-HPC-CH31, L-HPC-LH11, LH 22, LH 21, LH 20, LH 32, LH 31, LH30), dextrins, maltodextrins (e.g. Lodex® 5 and Lodex® 10), starches or modified starches (including potato starch, maize starch and rice starch), sodium chloride, sodium phosphate, calcium sulfate, and calcium carbonate. The compositions described herein can be formulated or adapted for administration to a subject via any route (e.g. any route approved by the Food and Drug Administration (FDA)). Exemplary methods are described in the FDA's CDER Data Standards Manual, version number 004 (which is available at fda.give/cder/dsm/DRG/drg00301.html). Pharmaceutical compositions are typically formulated to be compatible with its intended route of administration. Examples of routes of administration include parenteral (subcutaneous, intracutaneous, intravenous, intradermal, intramuscular, intra-articular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques), oral (e.g., inhalation or through a feeding tube), transdermal (topical), transmucosal, and rectal administration. Pharmaceutical compositions can be in the form of a solution or powder for inhalation and/or nasal administration. In some embodiments, the pharmaceutical composition is formulated as a powder filled sachet. Suitable powders may include those that are substantially soluble in water. Pharmaceutical compositions may be Attorney Docket No.38709-0035WO1 formulated according to techniques known in the art using suitable dispersing or wetting agents (such as, for example, Tween 80) and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non- toxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3- butanediol. Among the acceptable vehicles and solvents that may be employed are mannitol, water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, or carboxymethyl cellulose or similar dispersing agents which are commonly used in the formulation of pharmaceutically acceptable dosage forms such as emulsions and or suspensions. Other commonly used surfactants such as Tweens or Spans and/or other similar emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation. The compositions can be orally administered in any orally acceptable dosage form including, but not limited to, powders, capsules, tablets, emulsions and aqueous suspensions, dispersions and solutions. In the case of powders for oral administration, the powders can be substantially dissolved in water prior to administration. In the case of tablets for oral use, carriers which are commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, may be added. For oral administration in a capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions and/or emulsions are administered orally, the active ingredient may be suspended or dissolved in an oily phase is combined with emulsifying and/or suspending agents. If desired, certain sweetening and/or flavoring and/or coloring agents may be added. Alternatively or in addition, the compositions can be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well- known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters Attorney Docket No.38709-0035WO1 to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents known in the art. In some embodiments, therapeutic compositions disclosed herein can be formulated for sale in the US, imported into the US, and/or exported from the US. The pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration. In some embodiments, the disclosure provides kits that include the bile acid and phenylbutyrate compounds. The kit may also include instructions for the physician and/or patient, syringes, needles, box, bottles, vials, etc. Some embodiments provide a sachet containing a compound disclosed herein. In some embodiments, the composition is vacuum-packed in the sachet. In some embodiments, the composition is packed under an inert atmosphere (e.g, under nitrogen) in the sachet. In some embodiments, the sachet contains a desiccant. In some embodiments, the desiccant is selected from silica gel, activated alumina, aerogel, bentonite clay, anhydrous magnesium sulfate, and anhydrous calcium sulfate (i.e., drierite). In some embodiments, the sachet comprises two or more layers. In some embodiments, the sachet comprises two layers. In some embodiments, the sachet comprises three layers. In some embodiments, the sachet comprises four layers. In some embodiments at least one (e.g., one) of the layers comprises aluminum. In some embodiments, the layer comprising aluminum has a surface facing the inside of the sachet. Some embodiments provide a package comprising two or more sachets, wherein each sachet contains a composition disclosed herein. In some embodiments, the package contains three sachets. In some embodiments, the package contains four sachets. In some embodiments, the package contains five sachets. In some embodiments, the package contains six sachets. In some embodiments, the package contains eight sachets. In some embodiments, the package contains ten sachets. In some embodiments, the package contains twelve sachets. In some embodiments, the package contains an even number of sachets. In some embodiments, the package contains an odd number of sachets. In some embodiments, the package contains a number of sachets, wherein the number is a multiple of five. In some embodiments, the package contains a number of sachets, wherein the number is a multiple of ten. In Attorney Docket No.38709-0035WO1 some embodiments, the package is a box. In some embodiments, the package is a box comprising cardboard. Some embodiments provide a kit, wherein the kit comprises one or more sachets, wherein each sachet contains a composition described herein; and instructions for preparing and/or administering the composition to a subject. Methods of Detecting Impurities Some embodiments provide a method of detecting one or more impurities in a composition comprising about 8% to about 12% w/w of taurursodiol (TURSO); about 27% to about 32% w/w of sodium phenylbutyrate; and one or more impurities, the method comprising: (a) dissolving the composition in a solvent comprising about 5% (v/v) acetonitrile in deionized water to form a mixture; (b) contacting a stationary phase of a C-18 reverse phase chromatography column with the mixture; (c) eluting the mixture with a mobile phase to separate out one or more of the one or more impurities, wherein the mobile phase comprises about 5% to about 95% of 0.5% (v/v) aqueous phosphoric acid and about 5% to about 95% of acetonitrile; and (d) optionally quantifying the amount of the one or more impurities in the composition. In some embodiments, the composition has one or more characteristics described previously herein. In some embodiments, the composition was obtained from a single sachet. In some embodiments, the solvent comprising about 5% (v/v) acetonitrile in deionized water is about 5% (v/v) acetonitrile in deionized water. In some embodiments, the method comprises contacting a solvent comprising about 5% (v/v) acetonitrile in deionized water with the stationary phase before step (b); and eluting the solvent comprising about 5% (v/v) acetonitrile in deionized water with a mobile phase, wherein the mobile phase comprises about 5% to about 95% of 0.5% (v/v) aqueous phosphoric acid and about 5% to about 95% of acetonitrile. In some embodiments, the method comprises contacting and eluting the solvent comprising about 5% (v/v) acetonitrile in deionized water with the stationary phase before step (b). In some embodiments, the method comprises contacting and eluting the solvent Attorney Docket No.38709-0035WO1 comprising about 5% (v/v) acetonitrile in deionized water with the stationary phase before contacting the QL solution with the stationary phase. In some embodiments, the method comprises contacting a quantitation limit (QL) solution comprising about 2 to about 5 mg/mL TURSO and about 0.25 to about 3 mg/mL sodium phenylbutyrate dissolved in a solvent comprising about 5% (v/v) acetonitrile in deionized water with the stationary phase; and eluting the QL solution with a mobile phase, wherein the mobile phase comprises about 5% to about 95% of 0.5% (v/v) aqueous phosphoric acid and about 5% to about 95% of acetonitrile. In some embodiments, the method comprises contacting a quantitation limit (QL) solution comprising about 2.25 mg/mL TURSO and about 0.75 mg/mL sodium phenylbutyrate dissolved in a solvent comprising about 5% (v/v) acetonitrile in deionized water with the stationary phase; and eluting the QL solution with a mobile phase, wherein the mobile phase comprises about 5% to about 95% of 0.5% (v/v) aqueous phosphoric acid and about 5% to about 95% of acetonitrile. In some embodiments, the method comprises contacting and eluting the QL solution with the stationary phase before step (b). In some embodiments, the method comprises contacting and eluting the QL solution with the stationary phase before contacting the resolution solution with the stationary phase. In some embodiments, the method comprises contacting a resolution solution comprising one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, or 9) impurities selected from the group consisting of: an impurity having a RRT of about 0.76, an impurity having a RRT of about 0.79 (4-oxo-4-phenylbutanoic acid), an impurity having a RRT of about 0.83, an impurity having a RRT of about 0.85, an impurity having a RRT of about 0.90, an impurity having a RRT of about 0.92, an impurity having a RRT of about 0.86, an impurity having a RRT of about 1.04 (3,4-dihydronaphthalen-1(2H)-one), and glucosylisomaltol dissolved in a solvent comprising about 5% (v/v) acetonitrile in deionized water with the stationary phase; and eluting the resolution solution with a mobile phase, wherein the mobile phase comprises about 5% to about 95% of 0.5% (v/v) aqueous phosphoric acid and about 5% to about 95% of acetonitrile. In some embodiments, the method comprises an impurity having a RRT of about 0.76, an impurity having a RRT of about 0.79 (4-oxo-4-phenylbutanoic acid), an impurity having a RRT of about 0.83, an impurity having a RRT of about 0.85, an impurity having a RRT of about 0.90, an impurity having a RRT of about 0.92, an impurity Attorney Docket No.38709-0035WO1 having a RRT of about 0.86, an impurity having a RRT of about 1.04 (3,4- dihydronaphthalen-1(2H)-one), and glucosylisomaltol dissolved in a solvent comprising about 5% (v/v) acetonitrile in deionized water. In some embodiments, the method comprises contacting and eluting the resolution solution with the stationary phase before step (b). In some embodiments, the method comprises contacting and eluting the resolution solution with the stationary phase before contacting the marker solution with the stationary phase. In some embodiments, the method comprises contacting a marker solution comprising about 0.5 to 2.5 mg/mL (e.g., about 1 mg/mL to about 2 mg/mL, or about 1.5 mg/mL) TURSO and about 2.5 to 6.5 mg/mL (e.g., about 3.5 mg/mL to about 5.5 mg/mL, or about 4.5 mg/mL) sodium phenylbutyrate dissolved in a solvent comprising about 5% (v/v) acetonitrile in deionized water with the stationary phase before step (b); and eluting the QL solution with a mobile phase, wherein the mobile phase comprises about 5% to about 95% of 0.5% (v/v) aqueous phosphoric acid and about 5% to about 95% of acetonitrile. In some embodiments, the method comprises contacting a marker solution comprising about 1.5 mg/mL TURSO and about 4.5 mg/mL sodium phenylbutyrate dissolved in a solvent comprising about 5% (v/v) acetonitrile in deionized water with the stationary phase before step (b); and eluting the QL solution with a mobile phase, wherein the mobile phase comprises about 5% to about 95% of 0.5% (v/v) aqueous phosphoric acid and about 5% to about 95% of acetonitrile. In some embodiments, the method comprises contacting and eluting the marker solution with the stationary phase before step (b). In some embodiments, the method comprises contacting and eluting the marker solution with the stationary phase before contacting the flavor masking sample solution with the stationary phase. In some embodiments, the method comprises adding flavor-masking agent, sodium phenylbutyrate, and TURSO to a methanolic solution of taurochenodeoxycholic acid (TCDC) to form a flavor-masking agent mixture; adding a solvent comprising about 5% (v/v) acetonitrile in deionized water to the flavor-masking agent mixture to form a diluted flavor-masking agent mixture; agitating the diluted flavor-masking agent mixture; diluting the diluted flavor-masking agent mixture with about 5 mL to about 25 mL (e.g., about 7 mL, about 9 mL, about 11 mL, about 13 mL, about 15 mL, about 17 mL, about 19 mL, about 21 mL, about 23 mL, or about 25 mL) additional 5% (v/v) acetonitrile in deionized water; and filtering through a 0.45 um pore Attorney Docket No.38709-0035WO1 size polytetrafluoroethylene (PTFE) filter to provide a flavor masking sample solution. In some embodiments, the weight ratio of flavor-masking agent to sodium phenyl butyrate added to the methanolic solution of TCDC is about 6:90 to about 2:1 (e.g., about 7:45, about 8:45, about 9:45, about 9.6:45, about 10:45, about 11:45, about 12:45). In some embodiments, the weight ratio of sodium phenyl butyrate to TURSO added to the methanolic solution of TCDC is about 10:1 to about 1:1 (e.g., about 45:10, about 45:11, about 45:12, about 45:13, about 45:14, about 45:15, about 45:16, about 45:17, about 45:18, about 45:19, about 45:20). In some embodiments, the weight ratio of flavor-masking agent, sodium phenylbutyrate, and TURSO added to the methanolic solution is about 9.6:45:15. In some embodiments, the w/v ratio of the flavor-masking agent to the methanolic solution is about 50:1 to about 1:2 (e.g., about 1:1 to about 50:1, about 2:1 to about 40:1, about 5:1 to about 40:1, about 10:1 to about 40:1, about 15:1 to about 25:1, about 17:1, about 18:1, about 19:1, about 19.3:1, about 20:1, about 21:1, about 22:1, or about 23:1). In some embodiments, the w/v ratio of flavor-masking agent to the solvent comprising about 5% (v/v) acetonitrile in deionized water is about 10:1 to about 1:2 (e.g., about 5:1 to about 1:1, about 4:1 to about 1:1, about 4:1 to about 1:1, about 3:1 to about 1:1, about 2:1 to about 1:1, about 1.5:1 to about 1:1, about 2:1, about 1.38:1, about 1:1). In some embodiments, the method comprises adding flavor-masking agent, sodium phenylbutyrate, and TURSO in an about 9.6:45:15 weight ratio to a methanolic solution of 300 mg/mL taurochenodeoxycholic acid (TCDC) to form a flavor-masking agent mixture, wherein the w/v ratio of the flavor-masking agent to the methanolic solution is about 19.3:1; adding a solvent comprising about 5% (v/v) acetonitrile in deionized water to the flavor-masking agent mixture to form a diluted flavor-masking agent mixture, wherein the w/v ratio of flavor-masking agent to the solvent comprising about 5% (v/v) acetonitrile in deionized water is about 1.38:1; agitating the diluted flavor-masking agent mixture; diluting the diluted flavor-masking agent mixture with about 5 mL to about 25 mL (e.g., about 7 mL, about 9 mL, about 11 mL, about 13 mL, about 15 mL, about 17 mL, about 19 mL, about 21 mL, about 23 mL, or about 25 mL) additional 5% (v/v) acetonitrile in deionized water; and filtering through a 0.45 mm pore size polytetrafluoroethylene (PTFE) filter to provide a flavor masking sample solution. In some embodiments, the method comprises contacting the flavor masking sample solution with the stationary phase; and eluting the flavor masking sample solution with Attorney Docket No.38709-0035WO1 a mobile phase, wherein the mobile phase comprises about 5% to about 95% of 0.5% (v/v) aqueous phosphoric acid and about 5% to about 95% of acetonitrile. In some embodiments, the method comprises contacting and eluting the flavor masking sample solution with the stationary phase before step (b). In some embodiments, the method comprises contacting and eluting the flavor masking sample solution with the stationary phase before contacting the working standard solution with the stationary phase. In some embodiments, the method comprises dissolving TURSO and sodium phenylbutyrate in a solvent comprising about 5% (v/v) acetonitrile in deionized water to provide a working standard solution, wherein the concentration of TURSO in the working standard solution is about 10 mg/mL to about 1500 mg/mL (e.g., about 10 mg/mL to about 1000 mg/mL, about 10 mg/mL to about 750 mg/mL, about 10 mg/mL to about 500 mg/mL, about 10 mg/mL to about 250 mg/mL, about 10 mg/mL to about 150 mg/mL, about 40 mg/mL to about 110 mg/mL, about 50 mg/mL to about 100 mg/mL, about 60 mg/mL to about 90 mg/mL, about 65 mg/mL to about 85 mg/mL, or about 75 mg/mL) and the concentration of sodium phenylbutyrate in the working standard solution is about 225 mg/mL. In some embodiments, the method comprises dissolving TURSO and sodium phenylbutyrate in a solvent comprising about 5% (v/v) acetonitrile in deionized water to provide a working standard solution, wherein the concentration of TURSO in the working standard solution is about 75 mg/mL and the concentration of sodium phenylbutyrate in the working standard solution is about 225 mg/mL. In some embodiments, the method comprises contacting the working standard solution with the stationary phase; and eluting the working standard solution with a mobile phase, wherein the mobile phase comprises about 5% to about 95% of 0.5% (v/v) aqueous phosphoric acid and about 5% to about 95% of acetonitrile. In some embodiments, the method comprises contacting and eluting the working standard solution with the stationary phase before step (b). In some embodiments, the method comprises contacting and eluting the working standard solution with the stationary phase before contacting the placebo sample solution with the stationary phase. In some embodiments, the contacting and eluting is performed at least two consecutive times (e.g., three consecutive times, four consecutive times, five consecutive times, or six consecutive times). In some embodiments, the contacting and eluting is performed six consecutive times. In some embodiments, when the contacting and eluting is performed Attorney Docket No.38709-0035WO1 at leas two consecutive times, the at least two consecutive times are performed before contacting the placebo sample solution with the stationary phase. In some embodiments, the method comprises adding one or more of hydrated dextrates, sorbitol, sucralose, silicon dioxide, maltodextrin, sodium phosphate dibasic anhydrous, sodium stearyl fumarate, a flavorant, and a flavor-masking agent to about 5% (v/v) acetonitrile in deionized water to form a placebo mixture; agitating the placebo mixture; diluting the placebo mixture with about 5 mL to about 25 mL (e.g., about 7 mL, about 9 mL, about 11 mL, about 13 mL, about 15 mL, about 17 mL, about 19 mL, about 21 mL, about 23 mL, or about 25 mL) additional 5% (v/v) acetonitrile in deionized water; and filtering to provide a placebo sample solution. In some embodiments, the method comprises adding hydrated dextrates, sorbitol, sucralose, silicon dioxide, maltodextrin, sodium phosphate dibasic anhydrous, sodium stearyl fumarate, a flavorant, and a flavor-masking agent to about 5% (v/v) acetonitrile in deionized water to form a placebo mixture; agitating the placebo mixture; diluting the placebo mixture with about 5 mL to about 25 mL (e.g., about 7 mL, about 9 mL, about 11 mL, about 13 mL, about 15 mL, about 17 mL, about 19 mL, about 21 mL, about 23 mL, or about 25 mL) additional 5% (v/v) acetonitrile in deionized water; and filtering to provide a placebo sample solution. In some embodiments, the ratio of sorbitol to 5% (v/v) acetonitrile in deionized water is about 0.1:1 to about 10:1 (e.g., about 0.4:1 to about 3:1, about 0.5:1 to about 2:1, about 0.6:1 to about 1.5:1, about 0.7:1 to about 1:1, about 0.8:1 to about 0.9:1, or about 0.85:1). In some embodiments, the placebo mixture is filtered through a 0.45 mm pore size polytetrafluoroethylene (PTFE) filter. In some embodiments, the method comprises adding hydrated dextrates, sorbitol, sucralose, silicon dioxide, maltodextrin, sodium phosphate dibasic anhydrous, sodium stearyl fumarate, a flavorant, and a flavor-masking agent in an about 1600:400:200:97:2916:280:49:644:102 weight ratio to about 5% (v/v) acetonitrile in deionized water, wherein the ratio of sorbitol to 5% (v/v) acetonitrile in deionized water is about 0.85:1, to form a placebo mixture; agitating the placebo mixture; diluting the placebo mixture with about 5 mL to about 25 mL (e.g., about 7 mL, about 9 mL, about 11 mL, about 13 mL, about 15 mL, about 17 mL, about 19 mL, about 21 mL, about 23 mL, or about 25 mL) additional 5% (v/v) acetonitrile in deionized water; and filtering through a 0.45 mm pore size polytetrafluoroethylene (PTFE) filter to provide a placebo sample solution. In some embodiments, the method comprises contacting the placebo Attorney Docket No.38709-0035WO1 sample solution with the stationary phase; and eluting the working standard solution with a mobile phase, wherein the mobile phase comprises about 5% to about 95% of 0.5% (v/v) aqueous phosphoric acid and about 5% to about 95% of acetonitrile; wherein the contacting and eluting are performed before step (b). In some embodiments, the column has a diameter of about 4.6 mm. In some embodiments, the column has a length of about 150 mm. In some embodiments, the phosphoric acid is o-phosphoric acid. In some embodiments, the volume of mixture contacted with the column in step (b) is about 5 mL to about 35 mL (e.g., about 10 mL to about 30 mL, about 15 mL to about 25 mL, about 17 mL to about 23 mL). In some embodiments, the volume of mixture contacted in step (b) is about 20 mL. In some embodiments, the contacting of step (b) comprises injecting the mixture into the column. In some embodiments, the mobile phase comprises a gradient that starts at about 95% of 0.5% (v/v) aqueous phosphoric acid and about 5% of acetonitrile and over a time period of 2-30 minutes changes to about 5% of 0.5% (v/v) aqueous phosphoric acid and about 95% of acetonitrile. In some embodiments, the mobile phase comprises a gradient that starts at about 95% of 0.5% (v/v) aqueous phosphoric acid and about 5% of acetonitrile and over a time period of 10-25 minutes changes to about 5% of 0.5% (v/v) aqueous phosphoric acid and about 95% of acetonitrile. In some embodiments, the mobile phase comprises a gradient that starts at about 95% of 0.5% (v/v) aqueous phosphoric acid and about 5% of acetonitrile and over a time period of 13-23 minutes changes to about 5% of 0.5% (v/v) aqueous phosphoric acid and about 95% of acetonitrile. In some embodiments, the time period is about 5 minutes to about 30 minutes (e.g., about 10 minutes to about 25 minutes, about 15 minutes to about 21 minutes, about 20 minutes to about 30 minutes, about 23 minutes to about 27 minutes, about 18 minutes, or about 25 minutes). In some embodiments, the time period is about 18 minutes. In some embodiments, the time period is about 25 minutes. In some embodiments, the mobile phase comprises a gradient that starts at about 95% of 0.5% (v/v) aqueous phosphoric acid and about 5% of acetonitrile and over a Attorney Docket No.38709-0035WO1 time period of about 15 minutes to about 21 minutes changes to about 5% of 0.5% (v/v) aqueous phosphoric acid and about 95% of acetonitrile. In some embodiments, the mobile phase comprises a gradient that starts at about 95% of 0.5% (v/v) aqueous phosphoric acid and about 5% of acetonitrile and over a time period of about 18 minutes changes to about 5% of 0.5% (v/v) aqueous phosphoric acid and about 95% of acetonitrile. In some embodiments, the mobile phase comprises a gradient that starts at about 95% of 0.5% (v/v) aqueous phosphoric acid and about 5% of acetonitrile and over a time period of 25 minutes changes to about 5% of 0.5% (v/v) aqueous phosphoric acid and about 95% of acetonitrile. In some embodiments, the mobile phase comprises a gradient that starts at about 95% of 0.5% (v/v) aqueous phosphoric acid and about 5% of acetonitrile; over a time period of about 18 minutes changes to about 5% of 0.5% (v/v) aqueous phosphoric acid and about 95% of acetonitrile; and over a time period of about 7 minutes changes to about 95% of 0.5% (v/v) aqueous phosphoric acid and about 5% of acetonitrile. In some embodiments, the mobile phase comprises: a gradient that starts at about 95% of 0.5% (v/v) aqueous phosphoric acid and about 5% of acetonitrile, and over a time period of about 7 minutes to about 11 minutes changes to about 55% of 0.5% (v/v) aqueous phosphoric acid and about 45% of acetonitrile; an isocratic elution of about 55% of 0.5% (v/v) aqueous phosphoric acid and about 45% of acetonitrile over a time period of about 3 minutes to about 7 minutes; a gradient that changes over a time period of about 2 minutes to about 6 minutes to about 5% of 0.5% (v/v) aqueous phosphoric acid and about 95% of acetonitrile; an isocratic elution of about 5% of 0.5% (v/v) aqueous phosphoric acid and about 95% of acetonitrile over a time period of about 1 minute to about 3 minutes; and an isocratic elution of about 95% of 0.5% (v/v) aqueous phosphoric acid and about 5% of acetonitrile over a time period of about 3 minutes to about 7 minutes. In some embodiments, the mobile phase comprises: a gradient that starts at about 95% of 0.5% (v/v) aqueous phosphoric acid and about 5% of acetonitrile, and over a time period of about 9 minutes changes to about 55% of 0.5% (v/v) aqueous phosphoric acid and about 45% of acetonitrile; Attorney Docket No.38709-0035WO1 an isocratic elution of about 55% of 0.5% (v/v) aqueous phosphoric acid and about 45% of acetonitrile over a time period of about 5 minutes; a gradient that changes over a time period of about 4 minutes to about 5% of 0.5% (v/v) aqueous phosphoric acid and about 95% of acetonitrile; an isocratic elution of about 5% of 0.5% (v/v) aqueous phosphoric acid and about 95% of acetonitrile over a time period of about 2 minutes; and an isocratic elution of about 95% of 0.5% (v/v) aqueous phosphoric acid and about 5% of acetonitrile over a time period of about 5 minutes. In some embodiments, the flow rate of the mobile phase is about 50 µL/minute to about 2 mL/minute. In some embodiments, the flow rate of a mobile phase of step (c) is about 0.5 mL/minute to about 1.5 mL/minute. In some embodiments, the flow rate of a mobile phase of step (c) is about 1 mL/minute. In some embodiments, the contacting of step (b) and the eluting of step (c) are performed at about 20 oC to about 30 oC (e.g., about 22 oC to about 28 oC, about 24 oC to about 26 oC, or about 25 oC). In some embodiments, the contacting of step (c) and the eluting of step (b) are performed at about 25 oC. In some embodiments, the method comprises detecting one or more impurities by collecting UV spectral data. In some embodiments, the method comprises detecting one or more impurities by collecting UV spectral data, wherein the UV spectral data is collected at 203 nM (± 1 nM) or 260 nM (± 1 nM). In some embodiments, the UV spectral data is collected at 203 nM (± 1 nM). In some embodiments, the UV spectral data is collected at 260 nM (± 1 nM). In some embodiments, the UV spectral data is collected at 203 nM (± 1 nM) and 260 nM (± 1 nM). In some embodiments, the method comprises quantifying the amount of the one or more impurities in the composition. In some embodiments, quantifying the amount of each of the one or more impurities in the composition comprises: generating a first chromatogram from eluting the mixture in step (b); measuring a peak area of each impurity from the first chromatogram; and determining the amount of each impurity. In some embodiments, quantifying the amount of each of the one or more impurities in the composition comprises: generating a first chromatogram from eluting the mixture in step (b); Attorney Docket No.38709-0035WO1 measuring a peak area of each impurity from the first chromatogram; and determining the amount of each impurity as a percentage of the composition. In some embodiments, determining the amount of each impurity as a percentage of the composition comprises determining the amount of each impurity as a molar percentage of the composition. In some embodiments, determining the amount of each impurity as a percentage of the composition comprises determining the amount of each impurity as a weight percentage of the composition. In some embodiments, the quantifying further comprises: generating one or more second chromatograms from eluting the working standard solution; and measuring the peak areas of TURSO or sodium phenylbutyrate from the second chromatograms. In some embodiments, measuring the peak areas of TURSO or sodium phenylbutyrate from the second chromatograms comprises measuring the peak areas of TURSO from the second chromatograms. In some embodiments, measuring the peak areas of TURSO or sodium phenylbutyrate from the second chromatograms comprises measuring the peak areas of sodium phenylbutyrate from the second chromatograms. In some embodiments, determining the amount of the impurity as a percentage of the composition comprises: calculating the amount of the impurity using the equation %RS = (ARS/AWSTD) x WSTD x PSTD x (DFSPL/DFSTD) x (Wavg / (WSPL x LC)) x RRF x 100; wherein: %RS is the amount of the impurity as a percentage of the composition; ARS is the peak area of the impurity from the first chromatogram; AWSTD is an average of the peak areas of TURSO or sodium phenylbutyrate from the second chromatograms; WSTD is the weight of TURSO or sodium phenylbutyrate dissolved to provide the working standard solution; PSTD is the potency of the reference standard; DFSPL is the volume of TURSO dissolved in the solvent comprising about 5% (v/v) acetonitrile in deionized water in step (a) divided by the volume of the mixture formed in step (a); or DFSPL is the volume of sodium phenylbutyrate dissolved in the Attorney Docket No.38709-0035WO1 solvent comprising about 5% (v/v) acetonitrile in deionized water in step (a) divided by the volume of the mixture formed in step (a); DFSTD is the volume of TURSO dissolved in the working standard solution divided by the volume of the working standard solution; or the volume of sodium phenylbutyrate dissolved in the working standard solution divided by the volume of the working standard solution; Wavg is an average of the weights of the composition in two or more sachets that contain the composition; WSPL is the weight of the composition dissolved in the solvent comprising about 5% (v/v) acetonitrile in deionized water in step (a); LC is the label claim of TURSO or sodium phenylbutyrate in the single sachet; and RRF is the relative response factor of the impurity. In some embodiments, the potency of the reference standard is 1. In some embodiments, AWSTD is an average of the peak areas of TURSO from the second chromatograms; WSTD is the weight of TURSO dissolved to provide the working standard solution; PSTD is the potency of the reference standard; DFSPL is the volume of TURSO dissolved in the solvent comprising about 5% (v/v) acetonitrile in deionized water in step (a) divided by the volume of the mixture formed in step (a); DFSTD is the volume of TURSO dissolved in the working standard solution divided by the volume of the working standard solution; Wavg is the average of the weights of the composition in two or more sachets that contain the composition; WSPL is the weight of the composition dissolved in the solvent comprising about 5% (v/v) acetonitrile in deionized water in step (a); LC is the label claim of TURSO; and RRF is the relative response factor of the impurity. In some embodiments, Attorney Docket No.38709-0035WO1 AWSTD is an average of the peak areas of sodium phenylbutyrate from the second chromatograms; WSTD is the weight of sodium phenylbutyrate dissolved to provide the working standard solution; PSTD is the potency of the reference standard; DFSPL is the volume of sodium phenylbutyrate dissolved in the solvent comprising about 5% (v/v) acetonitrile in deionized water in step (a) divided by the volume of the mixture formed in step (a); DFSTD is the volume of sodium phenylbutyrate dissolved in the working standard solution divided by the volume of the working standard solution; Wavg is the average of the weights of the composition in two or more sachets that contain the composition; WSPL is the weight of the composition dissolved in the solvent comprising about 5% (v/v) acetonitrile in deionized water in step (a); LC is the label claim of sodium phenylbutyrate in the single sachet; and RRF is the relative response factor of the impurity. In some embodiments, the label claim of TURSO is 1000 mg. In some embodiments, the label claim of sodium phenylbutyrate is 3000 mg. In some embodiments, when the impurity is TCDC, the relative response factor is 1.157. In some embodiments, when the impurity is glucosylisomaltol, the relative response factor is 0.044. In some embodiments, when the impurity is not known, the relative response factor is 1. Methods of Treatment Some embodiments provide a method of treating or preventing a neurodegenerative disease in a subject in need thereof, comprising administering a therapeutically effective amount of a composition described herein to the subject. In some embodiments, the neurodegenerative disease is selected from the group consisting of: amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), Multiple Sclerosis (MS), Parkinson's disease, Huntington’s disease, Pick’s Disease, Multi-Infarct Dementia, Creutzfeldt-Jakob’s Disease, Dementia with Lewy bodies, Mixed dementia, Wolfram syndrome, progressive supranuclear palsy, and frontotemporal dementia (e.g., amyotrophic lateral sclerosis (ALS) or Alzheimer's disease (AD)). In some Attorney Docket No.38709-0035WO1 embodiments, the neurodegenerative disease is amyotrophic lateral sclerosis (ALS). In some embodiments, the neurodegenerative disease is Alzheimer's disease (AD). In some embodiments, the neurodegenerative disease is Alzheimer's disease (AD). In some embodiments, the neurodegenerative disease is Multiple Sclerosis (MS). In some embodiments, the neurodegenerative disease is Parkinson's disease. In some embodiments, the neurodegenerative disease is Huntington’s disease. In some embodiments, the neurodegenerative disease is Pick’s Disease. In some embodiments, the neurodegenerative disease is Multi-Infarct Dementia. In some embodiments, the neurodegenerative disease is Creutzfeldt-Jakob’s Disease. In some embodiments, the neurodegenerative disease is Dementia with Lewy bodies. In some embodiments, the neurodegenerative disease is Mixed dementia. In some embodiments, the neurodegenerative disease is Wolfram syndrome. In some embodiments, the neurodegenerative disease is progressive supranuclear palsy (PSP). In some embodiments, the neurodegenerative disease is frontotemporal dementia (e.g. amyotrophic lateral sclerosis (ALS) or Alzheimer's disease (AD)). In some embodiments, the neurodegenerative disease is amyotrophic lateral sclerosis (ALS). In some embodiments, the neurodegenerative disease is Alzheimer's disease (AD). In some instances, methods can include selection of a human subject who has or had a condition or disease (e.g., a neurodegenerative condition or disease, e.g., ALS). In some instances, suitable subjects include, for example, subjects who have or had a condition or disease but that resolved the disease or an aspect thereof, present reduced symptoms of disease (e.g., relative to other subjects (e.g., the majority of subjects) with the same condition or disease), and/or that survive for extended periods of time with the condition or disease (e.g., relative to other subjects (e.g., the majority of subjects) with the same condition or disease), e.g., in an asymptomatic state (e.g., relative to other subjects (e.g., the majority of subjects) with the same condition or disease). Attorney Docket No.38709-0035WO1 In some instances, subject selection can include obtaining a sample from a subject (e.g., a candidate subject) and testing the sample for an indication that the subject is suitable for selection. In some instances, the subject can be confirmed or identified, e.g. by a health care professional, as having had or having a condition or disease. In some instances, exhibition of a positive immune response towards a condition or disease can be made from patient records, family history, and/or detecting an indication of a positive immune response. In some instances multiple parties can be included in subject selection. For example, a first party can obtain a sample from a candidate subject and a second party can test the sample. In some instances, subjects can be selected and/or referred by a medical practitioner (e.g., a general practitioner). In some instances, subject selection can include obtaining a sample from a selected subject and storing the sample and/or using the in the methods disclosed herein. Samples can include, for example, cells or populations of cells. The methods disclosed herein can be applied to a wide range of species, e.g., humans, non-human primates (e.g., monkeys), horses, cattle, pigs, sheep, deer, elk, goats, dogs, cats, rabbits, guinea pigs, hamsters, rats, and mice. Methods described in the present disclosure can include treatment of a neurodegenerative disease per se, as well as treatment for one or more symptoms of a neurodegenerative disease. Treating a neurodegenerative disease does not require 100% abolition of the disease or disease symptoms in the subject. Any relief or reduction in the severity of symptoms or features of the disease is contemplated. Treating a neurodegenerative disease also refers to a delay in onset of symptoms (e.g., in prophylaxis treatment) or delay in progression of symptoms or the loss of function associated with the disease. Treating a neurodegenerative disease also refers to eliminating or reducing one or more side effects of a treatment (e.g. those caused by any of the therapeutic agents for treating a neurodegenerative disease disclosed herein or known in the art). “Treating” a neurodegenerative disease also refers to eliminating or reducing one or more direct or indirect effects of a neurodegenerative disease progression. The subject may not exhibit signs of a neurodegenerative disease but may be at risk for a neurodegenerative disease. For instance, the subject may carry mutations in genes associated with a neurodegenerative disease, have elevated biomarker levels suggesting a risk of developing a neurodegenerative disease (e.g., but not limited to, total tau, phospho-tau, or YKL-40). The subject may exhibit early signs of the disease Attorney Docket No.38709-0035WO1 or display symptoms of established or progressive disease. The disclosure contemplates any degree of delay in the onset of symptoms, alleviation of one or more symptoms of the disease, or delay in the progression of any one or more disease symptoms. The treatment provided in the present disclosure can be initiated at any stage during disease progression. For example, treatment can be initiated prior to onset (e.g., for subjects at risk for developing a neurodegenerative disease, for instance, those with elevated total tau or phospho-tau), at symptom onset or immediately following detection of a neurodegenerative disease (e.g., a tauopathy like PSP) symptoms, upon observation of any one or more symptoms (e.g., decline in cognitive functions) that would lead a skilled practitioner to suspect that the subject may be developing a neurodegenerative disease (e.g., a tauopathy like PSP). Treatment can also be initiated at later stages. In some instances, treatments methods can include a single administration, multiple administrations, and repeating administration as required for the prophylaxis or treatment of the disease or condition from which the subject is suffering. In some instances treatment methods can include assessing a level of disease in the subject prior to treatment, during treatment, and/or after treatment. In some instances, treatment can continue until a decrease in the level of disease in the subject is detected. The terms “administer,” “administering,” or “administration,” as used herein refers to ingesting, implanting, absorbing, injecting, or inhaling, the composition, regardless of form. In some instances, the compositions described herein can be administered to a subject orally. For example, the methods herein include administration of an effective amount of a composition described herein to achieve the desired or stated effect. Specific dosage and treatment regimens for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health status, sex, diet, time of administration, rate of excretion, drug combination, the severity and course of the disease, condition or symptoms, the patient’s disposition to the disease, condition or symptoms, and the judgment of the treating physician. Following administration, the subject can be evaluated to detect, assess, or determine their level of disease. In some instances, treatment can continue until a change (e.g., reduction) in the level of disease in the subject is detected. Attorney Docket No.38709-0035WO1 Upon improvement of a patient’s condition (e.g., a change (e.g., decrease) in the level of disease in the subject), a maintenance dose of a compound, composition or combination of this invention may be administered, if necessary. Subsequently, the dosage or frequency of administration, or both, may be reduced, as a function of the symptoms, to a level at which the improved condition is retained. Patients may, however, require intermittent treatment on a long-term basis upon any recurrence of disease symptoms. The compositions described herein can be administered daily (e.g. once a day, twice a day, or three times a day or more), weekly, monthly, or quarterly. The compositions described herein can be administered over a period of weeks, months, or years. For example, the compositions can be administered over a period of at least or about 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 1 year, 2 years, 3 years, 4 years, or at least or about 5 years, or more. The compositions described herein can be administered once a day or twice a day for 60 days or less (e.g., 55 days, 50 days, 45 days, 40 days, 35 days, 30 days or less). Alternatively, compositions described herein can be administered once a day or twice a day for more than 60 days (e.g., more than 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 130, 140, 150, 160, 180, 200, 250, 300, 400, 500, 600 days). In some embodiments, the methods described herein include administering to a subject about 5 mg/kg to about 100 mg/kg of body weight of TURSO (e.g. about 10 to about 50, about 5 to about 10, about 10 to about 15, about 15 to about 20, about 20 to about 25, about 25 to about 30, about 30 to about 35, about 35 to about 40, about 40 to about 45, about 45 to about 50, about 50 to about 55, about 55 to about 60, about 60 to about 65, about 65 to about 70, about 70 to about 75, about 75 to about 80, about 80 to about 85, about 85 to about 90, about 90 to about 95, or about 95 to about 100 mg/kg). In some embodiments, the methods described herein include administering to a subject about 10 mg/kg to about 400 mg/kg of body weight of sodium phenylbutyrate (e.g., about 10 to about 15, about 15 to about 20, about 20 to about 25, about 25 to about 30, about 30 to about 35, about 35 to about 40, about 40 to about 45, about 45 to about 50, about 50 to about 55, about 55 to about 60, about 60 to Attorney Docket No.38709-0035WO1 about 65, about 65 to about 70, about 70 to about 100, about 100 to about 150, about 150 to about 200, about 200 to about 300, or about 300 to about 400 mg/kg). In some embodiments, TURSO is administered in an amount of about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 mg/kg of body weight. In some embodiments, sodium phenylbutyrate is administered in an amount of about 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 100, or 150 mg/kg of body weight. Skilled practitioners will appreciate that certain factors can affect the bioavailability and metabolism of the administered compounds for a subject, and can make adjustments accordingly. These include but are not limited to liver function (e.g. levels of liver enzymes), renal function, and gallbladder function (e.g., ion absorption and secretion, levels of cholesterol transport proteins). There can be variability in the levels of exposure each subject has for the administered compounds (e.g., TURSO and PB), differences in the levels of excretion, and in the pharmacokinetics of the compounds in the subjects being treated. Any of the factors described herein may affect drug exposure by the subject. For instance, decreased clearance of the compounds can result in increased drug exposure, while improved renal function can reduce the actual drug exposure. The extent of drug exposure may be correlated with the subject’s response to the administered compounds and the outcome of the treatment. In some instances, the subject has been diagnosed with a neurodegenerative disease. For example, the subject may have been diagnosed with a neurodegenerative disease for about 24 months or less (e.g., about 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 month or less). For example, the subject may have been diagnosed with a neurodegenerative disease for 1 week or less, or on the same day that the presently disclosed treatments are administered. The subject may have been diagnosed with the neurodegenerative disease for more than about 24 months (e.g., more than about 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 76, or 80 months). The compositions described herein can be administered shortly after a meal (e.g., within two hours of a meal) or under fasting conditions. The subject may have consumed food items (e.g., solid foods or liquid foods) less than 2 hours before administration of the compositions described herein. Food items may affect the rate and extent of absorption of the TURSO and/or the PB. For instance, food can change the bioavailability of the compounds by delaying gastric emptying, stimulating bile flow, Attorney Docket No.38709-0035WO1 changing gastrointestinal pH, increasing splanchnic blood flow, changing luminal metabolism of the substance, or physically or chemically interacting with a dosage form or the substance. The nutrient and caloric contents of the meal, the meal volume, and the meal temperature can cause physiological changes in the GI tract in a way that affects drug transit time, luminal dissolution, drug permeability, and systemic availability. In general, meals that are high in total calories and fat content are more likely to affect the GI physiology and thereby result in a larger effect on the bioavailability of a drug. The methods provided herein can further include administering to the subject a plurality of food items, for example, less than 2 hours (e.g., less than 1.5 hour, 1 hour, or 0.5 hour) before or after administering (i) or (ii). The subject can be e.g., older than about 18 years of age (e.g., between 18-100, 18-90, 18-80, 18-70, 18-60, 18-50, 18-40, 18-30, 18-25, 25-100, 25-90, 25-80, 25-70, 25-60, 25-50, 25-40, 25-30, 30-100, 30-90, 30-80, 30-70, 30-60, 30-50, 30-40, 40-100, 40-90, 40-80, 40-70, 40-60, 40-50, 50-100, 50-90, 50-80, 50-70, 50-60, 60-100, 60-90, 60-80, 60-70, 70-100, 70-90, 70-80, 80-100, 80-90, or 90-100 years of age). The subject can have a BMI of between about 18.5-30 kg/m2 (e.g., between 18.5-28, 18.5-26, 18.5- 24, 18.5-22, 18.5-20, 20-30, 20-28, 20-26, 20-24, 20-22, 22-30, 22-28, 22-26, 22-24, 24-30, 24-28, 24-26, 26-30, 26-28, or 28-30 kg/m2). Some embodiments provide a method of treating or preventing amyotrophic lateral sclerosis (ALS) in a subject in need thereof, comprising administering a composition described herein to the subject. The terms “amyotrophic lateral sclerosis” and “ALS” are used interchangeably herein, and include all of the classifications of ALS known in the art, including, but not limited to classical ALS (e.g., ALS that affects both lower and upper motor neurons), Primary Lateral Sclerosis (PLS, e.g., those that affect only the upper motor neurons), Progressive Bulbar Palsy (PBP or Bulbar Onset, a version of ALS that typically begins with difficulties swallowing, chewing and speaking) and Progressive Muscular Atrophy (PMA, typically affecting only the lower motor neurons). The terms include sporadic and familial (hereditary) ALS, ALS at any rate of progression (e.g., rapid, non-slow or slow progression) and ALS at any stage (e.g., prior to onset, at onset and late stages of ALS). The subjects in the methods described herein may exhibit one or more symptoms associated with ALS, or have been diagnosed with ALS. In some Attorney Docket No.38709-0035WO1 embodiments, the subjects may be suspected as having ALS, and/or at risk for developing ALS. The subjects in the methods described herein may exhibit one or more symptoms associated with benign fasciculation syndrome (BFS) or cramp-fasciculation syndrome (CFS). Some embodiments of any of the methods described herein can further include determining that a subject has or is at risk for developing ALS, diagnosing a subject as having or at risk for developing ALS, or selecting a subject having or at risk for developing ALS. Likewise, some embodiments of any of the methods described herein can further include determining that a subject has or is at risk for developing benign fasciculation syndrome or cramp fasciculation syndrome, diagnosing a subject as having or at risk for developing BFS or CFS , or selecting a subject having or at risk for developing BFS or CFS. In some embodiments of any of the methods described herein, the subject has shown one or more symptoms of ALS for about 24 months or less (e.g., about 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1 month, or 1 week or less). In some embodiments, the subject has shown one or more symptoms of ALS for about 36 months or less (e.g., about 35, 34, 33, 32, 31, 30, 29, 28, 27, 26, or 25 months or less). The order and type of ALS symptoms displayed by a subject may depend on which motor neurons in the body are damaged first, and consequently which muscles in the body are damaged first. For example, bulbar onset, limb onset, or respiratory onset ALS may present with similar or different symptoms. In general, ALS symptoms may include muscle weakness or atrophy (e.g., affecting upper body, lower body, and/or speech), muscle fasciculation (twitching), cramping, or stiffness of affected muscles. Early symptoms of ALS may include those of the arms or legs, difficulty in speaking clearly or swallowing (e.g., in bulbar onset ALS). Other symptoms include loss of tongue mobility, respiratory difficulties, difficulty breathing or abnormal pulmonary function, difficulty chewing, and/or difficulty walking (e.g., resulting in stumbling). Subjects may have respiratory muscle weakness as the initial manifestation of ALS symptoms. Such subjects may have very poor prognosis and in some instances have a median survival time of about two months from diagnosis. In some subjects, the time of onset of respiratory muscle weakness can be used as a prognostic factor. Attorney Docket No.38709-0035WO1 ALS symptoms can also be classified by the part of the neuronal system that is degenerated, namely, upper motor neurons or lower motor neurons. Lower motor neuron degeneration manifests, for instance, as weakness or wasting in one or more of the bulbar, cervical, thoracic, and/or lumbosacral regions. Upper motor neuron degeneration can include increased tendon reflexes, spasticity, pseudo bulbar features, Hoffmann reflex, extensor plantar response, and exaggerated reflexes (hyperreflexia) including an overactive gag reflex. Progression of neuronal degeneration or muscle weakness is a hallmark of the disease. Accordingly, some embodiments of the present disclosure provide a method of ameliorating at least one symptom of lower motor neuron degeneration, at least one symptom of upper motor neuron degeneration, or at least one symptom from each of lower motor neuron degeneration and upper motor neuron degeneration. In some embodiments of any of the methods described herein, symptom onset can be determined based on information from subject and/or subject’s family members. In some embodiments, the median time from symptom onset to diagnosis is about 12 months. In some instances, the subject has been diagnosed with ALS. For example, the subject may have been diagnosed with ALS for about 24 months or less (e.g., about 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 month or less). For example, the subject may have been diagnosed with ALS for 1 week or less, or on the same day that the presently disclosed treatments are administered. The subject may have been diagnosed with ALS for more than about 24 months (e.g., more than about 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 76, or 80 months). Methods of diagnosing ALS are known in the art. For example, the subject can be diagnosed based on clinical history, family history, physical or neurological examinations (e.g., signs of lower motor neuron or upper motor neuron degeneration). The subject can be confirmed or identified, e.g. by a healthcare professional, as having ALS. Multiple parties may be included in the process of diagnosis. For example, where samples are obtained from a subject as part of a diagnosis, a first party can obtain a sample from a subject and a second party can test the sample. In some embodiments of any of the human subjects described herein, the subject is diagnosed, selected, or referred by a medical practitioner (e.g., a general practitioner). In some embodiments, the subject fulfills the El Escorial criteria for probable or definite ALS, i.e. the subject presents: Attorney Docket No.38709-0035WO1 1. Signs of lower motor neuron (LMN) degeneration by clinical, electrophysiological or neuropathologic examination; 2. Signs of upper motor neuron (UMN) degeneration by clinical examination; and 3. Progressive spread of signs within a region or to other regions, together with the absence of: Electrophysiological evidence of other disease processes that might explain the signs of LMN and/or UMN degenerations; and Neuroimaging evidence of other disease processes that might explain the observed clinical and electrophysiological signs. Under the El Escorial criteria, signs of LMN and UMN degeneration in four regions are evaluated, including brainstem, cervical, thoracic, and lumbrasacral spinal cord of the central nervous system. The subject may be determined to be one of the following categories: A. Clinically Definite ALS, defined on clinical evidence alone by the presence of UMN, as well as LMN signs, in three regions. B. Clinically Probable ALS, defined on clinical evidence alone by UMN and LMN signs in at least two regions with some UMN signs necessarily rostral to (above) the LMN signs. C. Clinically Probable ALS - Laboratory-supported, defined when clinical signs of UMN and LMN dysfunction are in only one region, or when UMN signs alone are present in one region, and LMN signs defined by EMG criteria are present in at least two limbs, with proper application of neuroimaging and clinical laboratory protocols to exclude other causes. D. Clinically Possible ALS, defined when clinical signs of UMN and LMN dysfunction are found together in only one region or UMN signs are found alone in two or more regions; or LMN signs are found rostral to UMN signs and the diagnosis of Clinically Probable - Laboratory-supported. In some embodiments, the subject has clinically definite ALS (e.g., based on the El Escorial criteria). The subject can be evaluated and/or diagnosed using the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R). The ALSFRS-R is an ordinal rating scale (ratings 0-4) used to determine subjects' assessment of their capability and Attorney Docket No.38709-0035WO1 independence in 12 functional activities relevant in ALS. ALSFRS-R scores calculated at diagnosis can be compared to scores throughout time to determine the speed of progression. Change in ALSFRS-R scores can be correlated with change in strength over time, and can be associated with quality of life measures and predicted survival. ALSFRS-R demonstrates a linear mean slope and can be used as a prognostic indicator (See e.g., Berry et al. Amyotroph Lateral Scler Frontotemporal Degener 15:1–8, 2014; Traynor et al., Neurology 63:1933–1935, 2004; Simon et al., Ann Neurol 76:643–657, 2014; and Moore et al. Amyotroph Lateral Scler Other Motor Neuron Disord 4:42, 2003). In the ALSFRS-R, functions mediated by cervical, trunk, lumbosacral, and respiratory muscles are each assessed by 3 items. Each item is scored from 0-4, with 4 reflecting no involvement by the disease and 0 reflecting maximal involvement. The item scores are added to give a total. Total scores reflect the impact of ALS, with the following exemplary categorization: >40 (minimal to mild); 39-30 (mild to moderate); < 30 (moderate to severe); < 20 (advanced disease). For example, a subject can have an ALSFRS-R score (e.g., a baseline ALSFRS- R score) of 40 or more (e.g., at least 41, 42, 43, 44, 45, 46, 47, or 48), between 30 and 39, inclusive (e.g., 31, 32, 33, 34, 35, 36, 37, or 38), or 30 or less (e.g., 21, 22, 23, 24, 25, 26, 27, 28, or 29). In some embodiments of any of the methods described herein, the subject has an ALSFRS-R score (e.g., a baseline ALSFRS-R score) of 40 or less (e.g., 39, 38, 37, 36, 35, 34, 33, 32, 31, 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10 or less). In some embodiments, the subject has an ALSFRS-R score (e.g., a baseline ALSFRS-R score) of 20 or less (e.g., 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5 or less). As ALS is a progressive disease, all patients generally will progress over time. However, a large degree of inter-subject variability exists in the rate of progression, as some subjects die or require respiratory support within months while others have relatively prolonged survival. The subjects described herein may have rapid progression ALS or slow progression ALS. The rate of functional decline in a subject with ALS can be measured by the change in ALSFRS-R score per month. For example, the score can decrease by about 1.02 (±2.3) points per month. One predictor of patient progression is the patient’s previous rate of disease Attorney Docket No.38709-0035WO1 progression (ΔFS), which can be calculated as: ΔFS = (48 – ALSFRS-R score at the time of evaluation)/duration from onset to time of evaluation (month). The ΔFS score represents the number of ALSFRS-R points lost per month since symptom onset, and can be a significant predictor of progression and/or survival in subjects with ALS (See e.g., Labra et al. J Neurol Neurosurg Psychiatry 87:628–632, 2016 and Kimura et al. Neurology 66:265-267, 2006). The subject may have a disease progression rate (ΔFS) of about 0.50 or less (e.g., about 0.45, 0.40, 0.35, 0.30, 0.25, 0.20, 0.15, or 0.10 or less); between about 0.50 and about 1.20 inclusive (e.g., about 0.55, 0.60, 0.65, 0.70, 0.75, 0.80, 0.85, 0.90, 0.95, 1.00, 1.05, 1.10, or 1.15); or about 1.20 or greater (e.g., about 1.25, 1.30, 1.35, 1.40, 1.45, 1.50, 1.55, 1.60, 1.75, 1.80, 1.85, 1.90, 1.95, or 2.00 or greater). In some embodiments of any of the methods described herein, the subject can have an ALS disease progression rate (ΔFS) of about 0.50 or greater (e.g., about 0.55, 0.60, 0.65, 0.70, 0.75, 0.80, 0.85, 0.90, 0.95, 1.00, 1.05, 1.10, 1.15, 1.20, 1.25, 1.30, 1.35, 1.40, 1.45, 1.50, 1.55, 1.60, 1.75, 1.80, 1.85, 1.90, 1.95, or 2.00 or greater). However, it should be noted that the ΔFS score is a predictor of patient progression, and may under or overestimate a patient’s progression once under evaluation. In some embodiments, since initial evaluation, the subject has lost on average about 0.8 to about 2 (e.g., about 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, or 1.9) ALSFRS-R points per month over 3-12 months. In some embodiments, the subject has lost on average more than about 1.2 ALSFRS-R points per month over 3-12 months since initial evaluation. The subject may have had a decline of at least 3 points (e.g., at least 4, 6, 8, 10, 12, 14, 16, 20, 24, 28, or 32 points) in ALSFRS-R score over 3-12 months since initial evaluation. In some embodiments, the subject has lost on average about 0.8 to about 2 (e.g., about 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, or 1.9) ALSFRS-R points per month over the previous 3-12 months. In some embodiments, the subject has lost on average more than about 1.2 (e.g., more than about 1.5, 1.8, 2.0, 2.5, or 3) ALSFRS-R points per month over the previous 3-12 months. In some embodiments of any of the methods described herein, the presence or level of a marker in a sample obtained from the subject may be used for ALS diagnosis or prognosis, or to track disease activity and treatment responses. Suitable samples include, for example, cells, tissues, or body fluids (e.g. blood, urine, or cerebral spinal fluid (CSF) samples). For instance, levels of phosphorylated neurofilament heavy subunit (pNF-H) or neurofilament light chain (NfL) in the CSF and/or blood can be Attorney Docket No.38709-0035WO1 used as a biomarker for ALS diagnosis, prognosis, or to track disease activity or treatment outcomes. pNF-H is a main component of the neuronal cytoskeleton and is released into the CSF and the bloodstream with neuronal damage. Levels of pNF-H may correlate with the level of axonal loss and/or burden of motor neuron dysfunction (See, e.g., De Schaepdryver et al. Journal of Neurology, Neurosurgery & Psychiatry 89:367-373, 2018). The concentration of pNF-H in the CSF and/or blood of a subject with ALS may significantly increase in the early disease stage. Higher levels of pNF-H in the plasma, serum and/or CSF may be associated with faster ALS progression (e.g., faster decline in ALSFRS-R), and/or shorter survival. pNF-H concentration in plasma may be higher in ALS subjects with bulbar onset than those with spinal onset. In some cases, an imbalance between the relative expression levels of the neurofilament heavy and light chain subunits can be used for ALS diagnosis, prognosis, or tracking disease progression. Methods of detecting pNF-H and NfL (for example, in the cerebrospinal fluid, plasma, or serum) are known in the art and include but are not limited to, ELISA and Simoa assays (See e.g., Shaw et al. Biochemical and Biophysical Research Communications 336:1268–1277, 2005; Ganesalingam et al. Amyotroph Lateral Scler Frontotemporal Degener 14(2):146-9, 2013; De Schaepdryver et al. Annals of Clinical and Translational Neurology 6(10): 1971–1979, 2019; Wilke et al. Clin Chem Lab Med 57(10):1556-1564, 2019; Poesen et al. Front Neurol 9:1167, 2018; Pawlitzki et al. Front. Neurol. 9:1037, 2018; Gille et al. Neuropathol Appl Neurobiol 45(3):291-304, 2019). Commercialized pNF-H detection assays can also be used, such as those developed by EnCor Biotechnology, BioVendor, and Millipore-EMD. Commercial NfL assay kits based on the Simoa technology, such as those produced by Quanterix can also be used (See, e.g., Thouvenot et al. European Journal of Neurology 27:251- 257, 2020). Factors affecting pNF-H and NfL levels or their detection in serum or plasma in relation to disease course may differ from those in CSF. The levels of neurofilament (e.g. pNF-H and/or NfL) in the CSF and serum may be correlated (See, e.g., Wilke et al. Clin Chem Lab Med 57(10):1556-1564, 2019). Subjects described herein may have a CSF or blood pNF-H level of about 300 pg/mL or higher (e.g., about 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1050, 1100, 1150, 1200, 1250, 1300, 1350, 1400, 1450, 1500, 1550, 1600, Attorney Docket No.38709-0035WO1 1650, 1700, 1750, 1800, 1850, 1900, 1950, 2000, 2050, 2100, 2150, 2200, 2250, 2300, 2350, 2400, 2450, 2500, 2550, 2600, 2650, 2700, 2750, 2800, 2850, 2900, 3000, 3200, 3500, 3800, or 4000 pg/mL or higher). In some embodiments, the serum pNF-H level can be about 70 to about 1200 pg/mL (e.g., about 70 to about 1000, about 70 to about 800, about 80 to about 600, or about 90 to about 400 pg/mL). In some embodiments, the CSF pNF-H level can be about 1000 to about 5000 pg/mL (e.g., about 1500 to about 4000, or about 2000 to about 3000 pg/mL). The subjects may have a CSF or blood level of NfL of about 50 pg/mL or higher (e.g., about 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, or 250 pg/mL or higher). In some embodiments, the serum NfL level can be about 50 to about 300 pg/mL (e.g., about 50 to about 280, about 50 to about 250, about 50 to about 200, about 50 to about 150, about 50 to about 100, about 100 to about 300, about 100 to about 250, about 100 to about 200, about 100 to about 150, about 150 to about 300, about 150 to about 250, about 150 to about 200, about 200 to about 300, about 200 to about 250, or about 250 to about 300 pg/mL). In some embodiments, the CSF NfL level can be about 2000 to about 40,000 pg/mL (e.g., about 2000 to about 35,000, about 2000 to about 30,000, about 2000 to about 25,000, about 2000 to about 20,000, about 2000 to about 15,000, about 2000 to about 10,000, about 2000 to about 8000, about 2000 to about 6000, about 2000 to about 4000, about 4000 to about 40,000, about 4000 to about 35,000, about 4000 to about 30,000, about 4000 to about 25,000, about 4000 to about 20,000, about 4000 to about 15,000, about 4000 to about 10,000, about 4000 to about 8000, about 4000 to about 6000, about 6000 to about 40,000, about 6000 to about 35,000, about 6000 to about 30,000, about 6000 to about 25,000, about 6000 to about 20,000, about 6000 to about 15,000, about 6000 to about 10,000, about 6000 to about 8000, about 8000 to about 40,000, about 8000 to about 35,000, about 8000 to about 30,000, about 8000 to about 25,000, about 8000 to about 20,000, about 8000 to about 15,000, about 8000 to about 10,000, about 10,000 to about 40,000, about 10,000 to about 35,000, about 10,000 to about 30,000, about 10,000 to about 25,000, about 10,000 to about 20,000, about 10,000 to about 15,000, about 15,000 to about 40,000, about 15,000 to about 35,000, about 15,000 to about 30,000, about 15,000 to about 25,000, about 15,000 to about 20,000, about 20,000 to about 40,000, about 20,000 to about 35,000, about 20,000 to about 30,000, about 20,000 to about 25,000, about 25,000 to about 40,000, about 25,000 to about 35,000, about 25,000 to about 30,000, Attorney Docket No.38709-0035WO1 about 30,000 to about 40,000, about 30,000 to about 35,000, or about 35,000 to about 40,000 pg/mL). Additional biomarkers useful for ALS diagnosis, prognosis, and disease progression monitoring are contemplated herein, including but are not limited to, CSF levels of S100-β, cystatin C, and chitotriosidase (CHIT) (See e.g., Chen et al. BMC Neurol 16:173, 2016). Serum levels of uric acid can be used as a biomarker for prognosing ALS (See e.g., Atassi et al. Neurology 83(19):1719-1725, 2014). Akt phosphorylation can also be used as a biomarker for prognosing ALS (See e.g., WO2012/160563). Urine levels of p75ECD and ketones can be used as a biomarker for ALS diagnosis (See e.g., Shepheard et al. Neurology 88:1137-1143, 2017). Serum and urine levels of creatinine can also be used as a biomarker. Other useful blood, CSF, neurophysiological, and neuroradiological biomarkers for ALS are described in e.g., Turner et al. Lancet Neurol 8:94-109, 2009. Any of the markers described herein can be used for diagnosing a subject as having ALS, or determining that a subject is at risk for developing ALS. A subject may also be identified as having ALS, or at risk for developing ALS, based on genetic analysis. Genetic variants associated with ALS are known in the art (See, e.g., Taylor et al. Nature 539:197-206, 2016; Brown and Al-Chalabi N Engl J Med 377:162-72, 2017; and http://alsod.iop.kcl.ac.uk). Subjects described herein can carry mutations in one or more genes associated with familial and/or sporadic ALS. Exemplary genes associated with ALS include but are not limited to: ANG, TARDBP, VCP, VAPB, SQSTM1, DCTN1, FUS, UNC13A, ATXN2, HNRNPA1, CHCHD10, MOBP, C21ORF2, NEK1, TUBA4A, TBK1, MATR3, PFN1, UBQLN2, TAF15, OPTN, TDP-43, and DAO. Additional description of genes associated with ALS can be found at Therrien et al. Curr Neurol Neurosci Rep 16:59-71, 2016; Peters et al. J Clin Invest 125:2548, 2015, and Pottier et al. J Neurochem, 138:Suppl 1:32-53, 2016. Genetic variants associated with ALS can affect the ALS progression rate in a subject, the pharmacokinetics of the administered compounds in a subject, and/or the efficacy of the administered compounds for a subject. The subjects may have a mutation in the gene encoding CuZn-Superoxide Dismutase (SOD1). Mutation causes the SOD1 protein to be more prone to aggregation, resulting in the deposition of cellular inclusions that contain misfolded SOD1 aggregates (See e.g., Andersen et al., Nature Reviews Neurology 7:603-615, 2011). Attorney Docket No.38709-0035WO1 Over 100 different mutations in SOD1 have been linked to inherited ALS, many of which result in a single amino acid substitution in the protein. In some embodiments, the SOD1 mutation is A4V (i.e., a substitution of valine for alanine at position 4). SOD1 mutations are further described in, e.g., Rosen et al. Hum. Mol. Genet.3, 981-987, 1994 and Rosen et al. Nature 362:59-62, 1993. In some embodiments, the subject has a mutation in the C9ORF72 gene. Repeat expansions in the C9ORF72 gene are a frequent cause of ALS, with both loss of function of C9ORF72 and gain of toxic function of the repeats being implicated in ALS (See e.g., Balendra and Isaacs, Nature Reviews Neurology 14:544-558, 2018). The methods described herein can include, prior to administration of a bile acid and a phenylbutyrate compound, detecting a SOD1 mutations and/or a C9ORF72 mutation in the subject. Methods for screening for mutations are well known in the art. Suitable methods include, but are not limited to, genetic sequencing. See, e.g., Hou et al. Scientific Reports 6:32478, 2016; and Vajda et al. Neurology 88:1-9, 2017. Skilled practitioners will appreciate that certain factors can affect the bioavailability and metabolism of the administered compounds for a subject, and can make adjustments accordingly. These include but are not limited to liver function (e.g. levels of liver enzymes), renal function, and gallbladder function (e.g., ion absorption and secretion, levels of cholesterol transport proteins). There can be variability in the levels of exposure each subject has for the administered compounds (e.g., bile acid and a phenylbutyrate compound), differences in the levels of excretion, and in the pharmacokinetics of the compounds in the subjects being treated. Any of the factors described herein may affect drug exposure by the subject. For instance, decreased clearance of the compounds can result in increased drug exposure, while improved renal function can reduce the actual drug exposure. The extent of drug exposure may be correlated with the subject’s response to the administered compounds and the outcome of the treatment. The subject can be e.g., older than about 18 years of age (e.g., between 18-100, 18-90, 18-80, 18-70, 18-60, 18-50, 18-40, 18-30, 18-25, 25-100, 25-90, 25-80, 25-70, 25-60, 25-50, 25-40, 25-30, 30-100, 30-90, 30-80, 30-70, 30-60, 30-50, 30-40, 40-100, 40-90, 40-80, 40-70, 40-60, 40-50, 50-100, 50-90, 50-80, 50-70, 50-60, 60-100, 60-90, 60-80, 60-70, 70-100, 70-90, 70-80, 80-100, 80-90, or 90-100 years of age). The subject can have a BMI of between about 18.5-30 kg/m2 (e.g., between 18.5-28, 18.5-26, 18.5- Attorney Docket No.38709-0035WO1 24, 18.5-22, 18.5-20, 20-30, 20-28, 20-26, 20-24, 20-22, 22-30, 22-28, 22-26, 22-24, 24-30, 24-28, 24-26, 26-30, 26-28, or 28-30 kg/m2). Having a mutation in any of the ALS-associated genes described herein or presenting with any of the biomarkers described herein may suggest that a subject is at risk for developing ALS. Such subjects can be treated with the methods provided herein for preventative and prophylaxis purposes. In some embodiments, the subjects have one or more symptoms of benign fasciculation syndrome (BFS) or cramp-fasciculation syndrome (CFS). BFS and CFS are peripheral nerve hyperexcitability disorders, and can cause fasciculation, cramps, pain, fatigue, muscle stiffness, and paresthesia. Methods of identifying subjects with these disorders are known in the art, such as by clinical examination and electromyography. Some embodiments provide a method of treating or preventing Wolfram syndrome in a subject in need thereof, comprising administering a therapeutically effective amount of a composition described herein to the subject. The methods described herein can be used for treating or ameliorating at least one symptom of Wolfram syndrome. The methods can also be used for prophylactically treating a subject at risk for developing Wolfram syndrome. The methods can be used to treat subjects who display one or more conditions including, e.g., diabetes insipidus, diabetes mellitus (e.g. juvenile-onset diabetes), optic nerve atrophy, progressive neurodegeneration, hearing loss, endocrine deficiencies and neurological and psychiatric conditions, cerebellar ataxia, autonomic dysfunction, dementia or intellectual disability, psychiatric disease, seizures, neurogenic bladder or bladder dyssynergia, bowel dysfunction, delayed/absent puberty, hypogonadism in males, non- autoimmune hypothyroidism, growth retardation, cardiomyopathy or structural congenital heart defects. In some embodiments, the subject has or is at risk for developing diabetes, for example, insulin-dependent diabetes or juvenile onset diabetes. In some embodiments, the subject has or is at risk for developing optic nerve atrophy or a hearing impairment. In some embodiments, the subject has one or more mutations in the WFS1 gene. For example, the subject may have the c.1672C>T, p.R558C mutation in the WFS1 gene or the c.2654C>T, p.P885L mutation in the WFS1 gene. In some embodiments, Attorney Docket No.38709-0035WO1 the subject has one or more mutations in the CDGSH iron sulfur domain protein 2 (CISD2) gene. In some embodiments, administration of the combination of TURSO and sodium phenylbutyrate results in improved treatment of one or more symptoms of Wolfram syndrome as compared to each compound alone. For example, treatment with a combination of TURSO and sodium phenylbutyrate can lead to symptom reduction for the subjects described herein to a greater extent or at a faster rate than each compound alone. Methods described in the present disclosure can include treatment of Wolfram syndrome per se, as well as treatment for one or more symptoms of Wolfram syndrome. “Treating” Wolfram syndrome does not require 100% abolition of the disease or disease symptoms in the subject. Any relief or reduction in the severity, duration, and/or frequency of symptoms or features of the disease is contemplated. “Treating” Wolfram syndrome also refers to a delay in onset of symptoms (e.g., in prophylaxis treatment) or delay in progression of symptoms or the loss of function associated with the disease. “Treating” Wolfram syndrome also refers to eliminating or reducing one or more side effects of a treatment (e.g. those caused by any of the therapeutic agents for treating Wolfram syndrome disclosed herein or known in the art). “Treating” Wolfram syndrome also refers to eliminating or reducing one or more direct or indirect effects of Wolfram syndrome disease progression. The subject may not exhibit signs of Wolfram syndrome but may be at risk for Wolfram syndrome. For instance, the subject may carry mutations in genes associated with Wolfram syndrome, have family history of having Wolfram syndrome. The subject may exhibit early signs of the disease or display symptoms of established or progressive disease. The disclosure contemplates any degree of delay in the onset of symptoms, alleviation of one or more symptoms of the disease, or delay in the progression of any one or more disease symptoms. The treatment provided in the present disclosure can be initiated at any stage during disease progression. For example, treatment can be initiated prior to onset (e.g., for subjects at risk for developing Wolfram syndrome), at symptom onset or immediately following detection of Wolfram syndrome symptoms, upon observation of any one or more symptoms that would lead a skilled practitioner to suspect that the subject may be developing Wolfram syndrome. Treatment can also be initiated at later stages. For example, treatment may be initiated at progressive stages of the disease. Attorney Docket No.38709-0035WO1 Treatment methods can include a single administration, multiple administrations, and repeating administration as required for the prophylaxis or treatment of Wolfram syndrome, or at least one symptom of Wolfram syndrome. The duration of prophylaxis treatment can be a single dosage or the treatment may continue (e.g., multiple dosages), e.g., for years or indefinitely for the lifespan of the subject. For example, a subject at risk for Wolfram syndrome may be treated with the methods provided herein for days, weeks, months, or even years so as to prevent the disease from occurring or fulminating. In some embodiments treatment methods can include assessing a level of disease in the subject prior to treatment, during treatment, and/or after treatment. The treatment provided herein can be administered one or more times daily, or it can be administered weekly or monthly. In some embodiments, treatment can continue until a decrease in the level of disease in the subject is detected. Following administration of the compositions described herein, the subject can be evaluated to detect, assess, or determine their level of Wolfram syndrome disease. In some embodiments, treatment can continue until a change (e.g., reduction) in the level of disease in the subject is detected. Upon improvement of a patient's condition (e.g., a change (e.g., decrease) in the level of disease in the subject), a maintenance dose of a compound, composition or combination of this disclosure may be administered, if necessary. Subsequently, the dosage or frequency of administration, or both, may be reduced, as a function of the symptoms, to a level at which the improved condition is retained. Patients may, however, require intermittent treatment on a long-term basis upon any recurrence of disease symptoms. The methods described herein can further include administering to the subject one or more additional therapeutic agents, e.g. in amounts effective for treating or achieving a modulation of at least one symptom of Wolfram syndrome. Any Wolfram syndrome therapeutic agents known in the art can be used as an additional therapeutic agent. Exemplary therapeutic agents include valproic acid, glucagon-like peptide (GLP)-1 receptor agonists, dantrolene sodium, and ER Ca2+ stabilizer. Some embodiments provide a method of treating or preventing progressive supranuclear palsy (PSP) in a subject in need thereof, comprising administering a composition described herein to the subject. Attorney Docket No.38709-0035WO1 Some embodiments provides methods of treating at least one symptom of PSP in a human subject. Also contemplated are methods of slowing PSP disease progression (e.g., reducing the PSP disease progression rate); and methods of reducing the progressive decline of cognitive functions, including loss of declarative and procedural memory, decreased learning ability, reduced attention span, and severe impairment in thinking ability, judgment, and decision making. Also provided are methods of increasing survival time of a human subject having one or more symptoms of PSP. Also provided are methods of ameliorating one or more biomarkers that is affected in a human subject with PSP (for example, lowering the levels of total tau and phospho-tau, both may be elevated in PSP or lowering the levels of YKL-40, which may also be elevated in PSP). Any of the methods described herein can include administering to the subject a composition described herein. Any of the human subjects in the methods described herein may exhibit one or more symptoms associated with PSP, or have been diagnosed with PSP. In some embodiments, the subjects may be suspected as having PSP, and/or at risk for developing PSP. Some embodiments of any of the methods described herein can further include determining that a human subject has or is at risk for developing PSP, diagnosing a human subject as having or at risk for developing PSP, or selecting a human subject having or at risk for developing PSP. In some embodiments of any of the methods described herein, the human subject has shown one or more symptoms of PSP for about 24 months or less (e.g., about 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1 month, or 1 week or less). In some embodiments, the subject has shown one or more symptoms of PSP for about 36 months or less (e.g., about 35, 34, 33, 32, 31, 30, 29, 28, 27, 26, or 25 months or less). In some instances, the human subject has been diagnosed with PSP. For example, the subject may have been diagnosed with PSP for about 24 months or less (e.g., about 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 month or less). For example, the subject may have been diagnosed with PSP for 1 week or less, or on the same day that the presently disclosed treatments are administered. The subject may have been diagnosed with PSP for longer than about 24 months (e.g., longer than about 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 76, or 80 Attorney Docket No.38709-0035WO1 months). Methods of diagnosing PSP are known in the art. For example, the subject can be diagnosed based on clinical history, family history, physical or neurological examinations. The subject can be confirmed or identified, e.g. by a healthcare professional, as having PSP. Multiple parties may be included in the process of diagnosis. For example, where samples are obtained from a subject as part of a diagnosis, a first party can obtain a sample from a subject and a second party can test the sample. In some embodiments of any of the human subjects described herein, the subject is diagnosed, selected, or referred by a medical practitioner (e.g., a general practitioner). Generally, diagnosis of PSP is known in the art. Symptoms of PSP usually first appear at the age of 60 and worsen until death. People with PSP commonly die from pneumonia, choking or other complications caused by the loss of functional brain cells, resulting in loss of autonomic and motor function (e.g. the ability to swallow). Signs and symptoms of PSP include movement, cognitive and psychiatric disorders. Voluntary movement can be impaired in PSP and include pseudobulbar palsy (i.e. inability to control facial movements), bradykinesia (i.e. slow or abnormal muscle movement), neck and trunk rigidity, impaired gait, impaired balance, posture instability and difficulty with speech and swallowing. Individuals who become unable to swallow food can be fitted with a feeding tube to provide nutrition. A most obvious, outward sign of the disease is an inability to coordinate and move the eyes normally, resulting in a vertical gaze palsy. Cognitive impairments include loss of executive functions (e.g. attention control, inhibitory control, working memory, cognitive flexibility, reasoning, problem solving and planning) and diminished fluency. Associated psychiatric symptoms include depression, feelings of irritability, sadness or apathy, insomnia, fatigue and loss of energy. Progressive supranuclear palsy can be difficult to diagnose because signs and symptoms are similar to those of Parkinson's disease. Those of skill in the art may distinguish PSP from Parkinson’s based on the lack of tremors, a lot of unexplained falls, little to no response to Parkinson's medications, and/or difficulty moving eyes, particularly downward. In some embodiments, a subject can be identified as having PSP using the MDS PSP Diagnostic Criteria (as described in, e.g., Hoglinger et al., Mov. Disord. 31:644- 652, 2016). The diagnostic criteria addresses four functional domains (ocular motor Attorney Docket No.38709-0035WO1 dysfunction, postural instability, akinesia, and cognitive dysfunction) as clinical predictors of PSP. Some embodiments of any of the methods described herein can include monitoring the progression of PSP in the subject, e.g., by assessing the severity of PSP in the subject over time, e.g., using the Progressive Supranuclear Palsy Rating Scale (PSPRS) (e.g., as described in Golbe et al., Brain 130(6):1552-1565, 2007). The PSPRS evaluates subjects according to their ability to perform daily activities, behavior, bulbar function, ocular motor function, limb motor function, and gait. The full PSPRS includes 28 items in six areas. The available total score ranges from 0 (normal) to 100 (maximally disabled). Six items are rated on a 3-point scale (0 to 2) and 22 items are rated on a 5-point scale (0 to 4). The History/Daily Activities area includes seven items with a total maximum of 24 points, the Mentation area four items with 16 points, the Bulbar area two items with 8 points, the Ocular Motor area four items with 16 points, the Limb Motor area six items with 16 points, and the Gait area five items with 20 points. In some embodiments, a subject can be identified as being at increased risk of developing PSP or identified as having PSP (e.g., any of the types of PSP described herein), e.g., at least in part, by detecting a genetic alteration in a gene encoding the microtubule-associated protein tau (MAPT) (e.g., any of the inversion polymorphisms in the MAPT gene, any of the haplotype-specific polymorphisms in the MAPT gene, the rare-coding MAPT variant (A152T), or mutations that enhance splicing of exon 10 in the MAPT gene described, e.g., in Hoglinger et al., Nature Genet.43:699-705, 2011, and Hinz et al., Cold Spring Harb. Perspect Biol.). Non-limiting examples of genetic alterations in a gene encoding MAPT include mutations that result in the production of MAPT protein that include one or more point mutations of: S285R, L284R, P301L, and G303V. Additional specific genetic mutations in a gene encoding MAPT protein that can be used to identify a subject as having an increased risk of developing PSP or can be used to identify a subject as having PSP (e.g., any of the types of PSP described herein) are described in, e.g., Boxer et al., Lancet 16:552-563, 2017. In some embodiments, a subject can be identified as having an increased risk of developing PSP or identified as having PSP (e.g., any of the types of PSP described herein), e.g., at least in part, by detecting tau protein deposits (e.g., 4-repeat tau protein deposits), detecting of atrophy of the midbrain and/or superior cerebellar peduncles Attorney Docket No.38709-0035WO1 (e.g., using any of the imaging techniques described herein or known in the art, e.g., magnetic resonance imaging (MRI) or positron emission tomography (PET) scans), and/or detecting of hypometabolism in the frontal cortex, caudate, and/or thalamus in the subject (e.g., using any of the imaging techniques described herein or known in the art, e.g., MRI, CT scan, or PET scan). For example, in some embodiments a subject can be identified or diagnosed as having PSP (e.g., any of the types of PSP described herein), e.g., at least in part, by using MRI to detect brain atrophy (Min et al., Nat. Med. 21:1154-1162, 2015; Yanamandra et al., Ann. Clin. Transl. Neurol. 2:278-288, 2015), changes in regional gray and white matter volume to detect atrophy (see, e.g., Josephs et al., Brain 137:2783-2795, 2014; Santos-Santos et al., JAMA Neurol. 73:733-742, 2016), and midbrain atrophy by detecting midbrain area and volume in the subject (Josephs et al., Neurobiol. Aging 29:280-289, 2008; Whitwell et al., Eur. J. Neurol. 20:1417-1422, 2013). In some embodiments, a subject can be identified or diagnosed as having PSP (e.g., any of the types of PSP described herein), e.g., at least in part, by administering to a subject a tau protein tracer (e.g., AV1451 or PBB3) and detecting tau protein in the subject's brain using a PET scan (see, e.g., Marquie et al., Ann. Neurol. 78:787-800, 2015; Cho et al., Mov. Disord.32:134-140, 2017; Whitwell et al., Mov. Disord.32:124- 133, 2017; and Smith et al., Mov. Disord. 32:108-114, 2017). In some embodiments, a subject can be diagnosed or identified as having PSP (e.g., any of the types of PSP described herein), e.g., at least in part, by detecting the difference in binaural masking level in the subject using a PET scan (see, e.g., Hughes et al., J. Neurophysiol. 112:3086-3094, 2014). In some embodiments, a subject can be identified as being at increased risk of developing PSP or identified as having PSP (e.g., any of the types of PSP described herein), e.g., at least in part, by detecting the presence of, or an elevated level (e.g., as compared to a level in a healthy control subject) of, one or more biomarkers in a subject. In some embodiments, a subject can be identified as being at increased risk of developing PSP or identified as having PSP by having plasma or CSF total tau level that is elevated as compared to a healthy subject. For example, the subject may have plasma or CSF total tau level of about 100 pg/mL or higher. In some embodiments, the subjects have plasma or CSF total tau level of about 300 pg/mL or higher (e.g., about 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1050, 1100, Attorney Docket No.38709-0035WO1 1150, 1200, 1250, 1300, 1350, 1400, 1450, 1500, 1550, 1600, 1650, 1700, 1750, 1800, 1850, 1900, 1950, 2000, 2050, 2100, 2150, 2200, 2250, 2300, 2350, 2400, 2450, 2500, 2550, 2600, 2650, 2700, 2750, 2800, 2850, 2900, 3000, 3200, 3500, 3800, or 4000 pg/mL or higher). In some embodiments, a subject can be identified as being at increased risk of developing PSP or identified as having PSP by having plasma or CSF phospho-tau (e.g. phospho-tau 181, phospho-tau 199, and/or phosphor-tau 231) that is elevated as compared to a healthy subject. For example, the subject may have plasma or CSF phospho-tau level of about 30 pg/mL or higher. In some embodiments, the subjects have plasma or CSF phospho-Tau (e.g. phosphor-tau 181) level about 70 pg/mL or higher (e.g., about 75, 100, 125, 150, 175, or 200 pg/mL or higher). In some embodiments, a subject can be identified or diagnosed as having PSP (e.g., any of the types of PSP described herein), e.g., at least in part, by detecting the presence of, or detection of an elevated level (e.g., as compared to a level in a healthy control subject) of, neurofilament light (NfL) chain in the blood and/or cerebrospinal fluid in a subject (e.g., using any of the immunoassays described in Scherling et al., Ann. Neurol. 75:116-126, 2014; Bacioglu et al., Neuron 91:56-66, 2016; and Rojas et al., Ann. Clin. Transl. Neurol. 3:216-255, 2016). Methods of NfL (for example, in the cerebrospinal fluid, plasma, or serum) are known in the art and include but are not limited to, ELISA and Simoa assays (See e.g., Shaw et al. Biochemical and Biophysical Research Communications 336:1268–1277, 2005; Ganesalingam et al. Amyotroph Lateral Scler Frontotemporal Degener 14(2):146-9, 2013; De Schaepdryver et al. Annals of Clinical and Translational Neurology 6(10): 1971–1979, 2019; Wilke et al. Clin Chem Lab Med 57(10):1556- 1564, 2019; Poesen et al. Front Neurol 9:1167, 2018; Pawlitzki et al. Front. Neurol. 9:1037, 2018; Gille et al. Neuropathol Appl Neurobiol 45(3):291-304, 2019). Commercial NfL assay kits based on the Simoa technology, such as those produced by Quanterix can also be used (See, e.g., Thouvenot et al. European Journal of Neurology 27:251-257, 2020). Factors affecting NfL levels or their detection in serum or plasma in relation to disease course may differ from those in CSF. The levels of neurofilament (e.g. pNF-H and/or NfL) in the CSF and serum may be correlated (See, e.g., Wilke et al. Clin Chem Lab Med 57(10):1556-1564, 2019). Attorney Docket No.38709-0035WO1 In some embodiments, a subject can be identified or diagnosed as having PSP (e.g., any of the types of PSP described herein), e.g., at least in part, by detecting the presence of, or detection of an elevated level (e.g., as compared to a level in a healthy control subject) of, YKL-40 in plasma or cerebrospinal fluid from the subject (see, e.g., Magdalinou et al., J. Neurol. Neurosurg. Psychiatry 2014 October; 85(10): 1065-1075; and Magdalinou et al., J. Neurol. Neurosurg. Psychiatry 86:1240-1247, 2015). In some embodiments, a subject can be identified or diagnosed as having PSP (e.g., any of the types of PSP described herein), e.g., at least in part, by detecting a decreased ratio of 33 kDa tau to 55 kDa tau in the plasma or CSF of a subject (e.g., as compared to the ratio of 33 kDa tau to 55 kDa tau in a healthy subject). In some embodiments, a subject can be identified or diagnosed as having PSP (e.g., any of the types of PSP described herein), e.g., at least in part, by detecting the presence of, or detecting an elevated level of protein tyrosine phosphatase 1 (Ptpn1) (e.g., as described in Santiago et al., Mov. Discord. 29(4):550-555, 2014). In some embodiments, a subject can be identified or diagnosed as having PSP (e.g., any of the types of PSP described herein), e.g., at least in part, by detecting the presence of, or detecting an elevated level of neurogranin (see, e.g., Xiang Y, Xin J, Le W, Yang Y. Neurogranin: A Potential Biomarker of Neurological and Mental Diseases. Front Aging Neurosci. 2020 Oct 6;12:584743. doi: 10.3389/fnagi.2020.584743.). In some embodiments, a subject can be identified or diagnosed as having PSP (e.g., any of the types of PSP described herein), e.g., at least in part, by detecting decreased saccade velocity and gain in the subject using infrared oculography (see, e.g., Boxer et al., Arch. Neurol. 69:509-517, 2012; Boxer et al., Lancet Neurol. 132:676- 685, 2014). In some embodiments, a subject can be identified or diagnosed as having PSP (e.g., any of the types of PSP described herein), e.g., at least in part, by detecting a spontaneous and evoked blink rate associated with PSP in the subject (see, e.g., Bologna et al., Brain 132:502-510, 2009). In some embodiments, a subject can be identified or diagnosed as having PSP (e.g., any of the types of PSP described herein), e.g., at least in part, by detecting decreased retinal thickness in a subject's eye using optical coherence tomography (see, e.g., Schneider et al., J. Neural Transm.121:41-47, 2014). In some embodiments, a subject can be identified or diagnosed as having PSP (e.g., any of the types of PSP described herein), e.g., at least in part, by detecting Attorney Docket No.38709-0035WO1 disrupted circadian rhythms and sleep in the subject (see, e.g., Walsh et al., Sleep Med. 22; 50-56, 2016). In some embodiments, the subjects described herein have an “elevated level” of a biomarker (e.g., tau, phospho-tau, NfL, YKL-40, Ptpn1, or neurogranin) in the CSF or blood as compared to a healthy subject who does not have PSP. In some embodiments, an elevated level of a PSP subject can be an elevation or an increase of about 1% to about 500%, about 1% to about 450%, about 1% to about 400%, about 1% to about 350%, about 1% to about 300%, about 1% to about 250%, about 1% to about 200%, about 1% to about 150%, about 1% to about 100%, about 1% to about 50%, about 1% to about 25%, about 1% to about 20%, about 1% to about 15%, about 1% to about 10%, about 1% to about 5%, about 2% to about 500%, about 2% to about 450%, about 2% to about 400%, about 2% to about 350%, about 2% to about 300%, about 2% to about 250%, about 2% to about 200%, about 2% to about 150%, about 2% to about 100%, about 2% to about 50%, about 2% to about 25%, about 2% to about 20%, about 2% to about 15%, about 2% to about 10%, about 5% to about 500%, about 5% to about 450%, about 5% to about 400%, about 5% to about 350%, about 5% to about 300%, about 5% to about 250%, about 5% to about 200%, about 5% to about 150%, about 5% to about 100%, about 5% to about 50%, about 5% to about 25%, about 5% to about 20%, about 5% to about 15%, about 5% to about 10%, about 10% to about 500%, about 10% to about 450%, about 10% to about 400%, about 10% to about 350%, about 10% to about 300%, about 10% to about 250%, about 10% to about 200%, about 10% to about 150%, about 10% to about 100%, about 10% to about 50%, about 10% to about 25%, about 10% to about 20%, about 10% to about 15%, about 15% to about 500%, about 15% to about 450%, about 15% to about 400%, about 15% to about 350%, about 15% to about 300%, about 15% to about 250%, about 15% to about 200%, about 15% to about 150%, about 15% to about 100%, about 15% to about 50%, about 15% to about 25%, about 15% to about 20%, about 20% to about 500%, about 20% to about 450%, about 20% to about 400%, about 20% to about 350%, about 20% to about 300%, about 20% to about 250%, about 20% to about 200%, about 20% to about 150%, about 20% to about 100%, about 20% to about 50%, about 20% to about 25%, about 25% to about 500%, about 25% to about 450%, about 25% to about 400%, about 25% to about 350%, about 25% to about 300%, about 25% to about 250%, about 25% to about 200%, about 25% to about 150%, about 25% to about 100%, about 25% to about 50%, about 50% Attorney Docket No.38709-0035WO1 to about 500%, about 50% to about 450%, about 50% to about 400%, about 50% to about 350%, about 50% to about 300%, about 50% to about 250%, about 50% to about 200%, about 50% to about 150%, about 50% to about 100%, about 100% to about 500%, about 100% to about 450%, about 100% to about 400%, about 100% to about 350%, about 100% to about 300%, about 100% to about 250%, about 100% to about 200%, about 100% to about 150%, about 150% to about 500%, about 150% to about 450%, about 150% to about 400%, about 150% to about 350%, about 150% to about 300%, about 150% to about 250%, about 150% to about 200%, about 200% to about 500%, about 200% to about 450%, about 200% to about 400%, about 200% to about 350%, about 200% to about 300%, about 200% to about 250%, about 250% to about 500%, about 250% to about 450%, about 250% to about 400%, about 250% to about 350%, about 250% to about 300%, about 300% to about 500%, about 300% to about 450%, about 300% to about 400%, about 300% to about 350%, about 350% to about 500%, about 350% to about 450%, about 350% to about 400%, about 400% to about 500%, about 400% to about 450%, or about 450% to about 500%, e.g., as compared to a healthy subject who does not have PSP. In some embodiments, after administration with any of the compositions described herein, the subjects have a reduction in the level (plasma or CSF) of a biomarker (e.g., tau, phospho-tau, NfL, YKL-40, or Ptpn1). For example, a 1% to about 99% reduction, a 1% to about 95% reduction, a 1% to about 90% reduction, a 1% to about 85% reduction, a 1% to about 80% reduction, a 1% to about 75% reduction, a 1% to about 70% reduction, a 1% to about 65% reduction, a 1% to about 60% reduction, a 1% to about 55% reduction, a 1% to about 50% reduction, a 1% to about 45% reduction, a 1% to about 40% reduction, a 1% to about 35% reduction, a 1% to about 30% reduction, a 1% to about 25% reduction, a 1% to about 20% reduction, a 1% to about 15% reduction, a 1% to about 10% reduction, a 1% to about 5% reduction, an about 5% to about 99% reduction, an about 5% to about 95% reduction, an about 5% to about 90% reduction, an about 5% to about 85% reduction, an about 5% to about 80% reduction, an about 5% to about 75% reduction, an about 5% to about 70% reduction, an about 5% to about 65% reduction, an about 5% to about 60% reduction, an about 5% to about 55% reduction, an about 5% to about 50% reduction, an about 5% to about 45% reduction, an about 5% to about 40% reduction, an about 5% to about 35% reduction, an about 5% to about 30% reduction, an about 5% to about 25% reduction, Attorney Docket No.38709-0035WO1 an about 5% to about 20% reduction, an about 5% to about 15% reduction, an about 5% to about 10% reduction, an about 10% to about 99% reduction, an about 10% to about 95% reduction, an about 10% to about 90% reduction, an about 10% to about 85% reduction, an about 10% to about 80% reduction, an about 10% to about 75% reduction, an about 10% to about 70% reduction, an about 10% to about 65% reduction, an about 10% to about 60% reduction, an about 10% to about 55% reduction, an about 10% to about 50% reduction, an about 10% to about 45% reduction, an about 10% to about 40% reduction, an about 10% to about 35% reduction, an about 10% to about 30% reduction, an about 10% to about 25% reduction, an about 10% to about 20% reduction, an about 10% to about 15% reduction, an about 15% to about 99% reduction, an about 15% to about 95% reduction, an about 15% to about 90% reduction, an about 15% to about 85% reduction, an about 15% to about 80% reduction, an about 15% to about 75% reduction, an about 15% to about 70% reduction, an about 15% to about 65% reduction, an about 15% to about 60% reduction, an about 15% to about 55% reduction, an about 15% to about 50% reduction, an about 15% to about 45% reduction, an about 15% to about 40% reduction, an about 15% to about 35% reduction, an about 15% to about 30% reduction, an about 15% to about 25% reduction, an about 15% to about 20% reduction, an about 20% to about 99% reduction, an about 20% to about 95% reduction, an about 20% to about 90% reduction, an about 20% to about 85% reduction, an about 20% to about 80% reduction, an about 20% to about 75% reduction, an about 20% to about 70% reduction, an about 20% to about 65% reduction, an about 20% to about 60% reduction, an about 20% to about 55% reduction, an about 20% to about 50% reduction, an about 20% to about 45% reduction, an about 20% to about 40% reduction, an about 20% to about 35% reduction, an about 20% to about 30% reduction, an about 20% to about 25% reduction, an about 25% to about 99% reduction, an about 25% to about 95% reduction, an about 25% to about 90% reduction, an about 25% to about 85% reduction, an about 25% to about 80% reduction, an about 25% to about 75% reduction, an about 25% to about 70% reduction, an about 25% to about 65% reduction, an about 25% to about 60% reduction, an about 25% to about 55% reduction, an about 25% to about 50% reduction, an about 25% to about 45% reduction, an about 25% to about 40% reduction, an about 25% to about 35% reduction, an about 25% to about 30% reduction, an about 30% to about 99% reduction, an about 30% to about 95% reduction, an about 30% to about 90% reduction, an about 30% to about Attorney Docket No.38709-0035WO1 85% reduction, an about 30% to about 80% reduction, an about 30% to about 75% reduction, an about 30% to about 70% reduction, an about 30% to about 65% reduction, an about 30% to about 60% reduction, an about 30% to about 55% reduction, an about 30% to about 50% reduction, an about 30% to about 45% reduction, an about 30% to about 40% reduction, an about 30% to about 35% reduction, an about 35% to about 99% reduction, an about 35% to about 95% reduction, an about 35% to about 90% reduction, an about 35% to about 85% reduction, an about 35% to about 80% reduction, an about 35% to about 75% reduction, an about 35% to about 70% reduction, an about 35% to about 65% reduction, an about 35% to about 60% reduction, an about 35% to about 55% reduction, an about 35% to about 50% reduction, an about 35% to about 45% reduction, an about 35% to about 40% reduction, an about 40% to about 99% reduction, an about 40% to about 95% reduction, an about 40% to about 90% reduction, an about 40% to about 85% reduction, an about 40% to about 80% reduction, an about 40% to about 75% reduction, an about 40% to about 70% reduction, an about 40% to about 65% reduction, an about 40% to about 60% reduction, an about 40% to about 55% reduction, an about 40% to about 50% reduction, an about 40% to about 45% reduction, an about 45% to about 99% reduction, an about 45% to about 95% reduction, an about 45% to about 90% reduction, an about 45% to about 85% reduction, an about 45% to about 80% reduction, an about 45% to about 75% reduction, an about 45% to about 70% reduction, an about 45% to about 65% reduction, an about 45% to about 60% reduction, an about 45% to about 55% reduction, an about 45% to about 50% reduction, an about 50% to about 99% reduction, an about 50% to about 95% reduction, an about 50% to about 90% reduction, an about 50% to about 85% reduction, an about 50% to about 80% reduction, an about 50% to about 75% reduction, an about 50% to about 70% reduction, an about 50% to about 65% reduction, an about 50% to about 60% reduction, an about 50% to about 55% reduction, an about 55% to about 99% reduction, an about 55% to about 95% reduction, an about 55% to about 90% reduction, an about 55% to about 85% reduction, an about 55% to about 80% reduction, an about 55% to about 75% reduction, an about 55% to about 70% reduction, an about 55% to about 65% reduction, an about 55% to about 60% reduction, an about 60% to about 99% reduction, an about 60% to about 95% reduction, an about 60% to about 90% reduction, an about 60% to about 85% reduction, an about 60% to about 80% reduction, an about 60% to about 75% reduction, an about 60% to about 70% reduction, an about Attorney Docket No.38709-0035WO1 60% to about 65% reduction, an about 65% to about 99% reduction, an about 65% to about 95% reduction, an about 65% to about 90% reduction, an about 65% to about 85% reduction, an about 65% to about 80% reduction, an about 65% to about 75% reduction, an about 65% to about 70% reduction, an about 70% to about 99% reduction, an about 70% to about 95% reduction, an about 70% to about 90% reduction, an about 70% to about 85% reduction, an about 70% to about 80% reduction, an about 70% to about 75% reduction, an about 75% to about 99% reduction, an about 75% to about 95% reduction, an about 75% to about 90% reduction, an about 75% to about 85% reduction, an about 75% to about 80% reduction, an about 80% to about 99% reduction, an about 80% to about 95% reduction, an about 80% to about 90% reduction, an about 80% to about 85% reduction, an about 85% to about 99% reduction, an about 85% to about 95% reduction, an about 85% to about 90% reduction, an about 90% to about 99% reduction, an about 90% to about 95% reduction, or an about 95% to about 99% reduction, e.g., in a second level (i.e., after treatment with the compositions described herein) of a biomarker (e.g., tau, phospho-tau, NfL, YKL-40, or Ptpn1) as compared to a first level (i.e., prior to treatment with the compositions described herein) of the biomarker (e.g., tau, phospho-tau, NfL, YKL-40, or Ptpn1). The disclosures of all publications cited herein are expressly incorporated herein by reference, each in its entirety, to the same extent as if each were incorporated by reference individually. It is to be understood that while the disclosure has been described in conjunction with the detailed description thereof, the foregoing description is intended to illustrate and not limit the scope of the disclosure, which is defined by the scope of the appended claims. The following are numbered embodiments intended to further illustrate, but not limit, the scope of the disclosure. EXAMPLES Example 1. Determination of taurourdeoxycholic acid (TUDCA) and sodium phenylbutyrate (PB) in AMX-0035 powder in sachet by HPLC Herein describes a fully validated analytical method applicable for analysis of samples from batches required for regulatory studies. The compounds to be determined by this HPLC method are list in Table 1. Attorney Docket No.38709-0035WO1 Table 1. Compounds to be quantitated
Figure imgf000083_0001
Materials: Taurourdeoxycholic acid (TUDCA) Sodium phenylbutrate (PB) Taurochenodeoxycholic acid (TCDC, TUDCA impurity) Glucosylisomaltol (PB impurity) 4,4’-(1,4-phenylene) dibutanoic acid (reference standard for RRT 0.90) 4,4’-(1,3-phenylene) dibutanoic acid (reference standard for RRT 0.92) XBridge C183.5 mm 4.6 x 150 mm column (PN186003034) Clean HPLC vials Acetonitrile (ACN), HPLC grade methanol (MeOH), HPLC grade 85% H2PO4, ACS grade or equivalent Miscellaneous glassware 0.45 mm PTFE syringe filters Deionized (D.I) water TC pipette Attorney Docket No.38709-0035WO1 Preparation of HPLC media: Diluent (5% ACN): combine 950 mL D.I water with 50 mL ACN and mix well. Representative chromatograms of the diluent are shown in FIG. 1. Needle wash: combine 30 mL ACN with 70 mL D.I water and mix well. Mobile phase A: Pipette 5.0 mL phosphoric acid into 1000 mL D.I water; mix well and degas before use. Mobile phase B: 100% CAN; degas before use Preparation of working standard solution: Accurately weigh and transfer 45 ± 4 mg PB and about 15 ± 2 mg TUDCA reference standard into a 200 mL volumetric flask. Add about 160 mL of diluent, then solicit for 5 min. Add diluent to the volume line and mix well. Note: the working standard solution is stable up to 14 days at room temperature and under storage at 2-8° C. Representative chromatograms of the working standard solution are shown in FIG. 2. Concentration of PB is about 225 mg/mL Concentration TUDCA is about 75 mg/mL Preparation of QL solution (0.05% level): Pipette 1.0 mL of working standard solution Into 100 mL volumetric flask; dilute to volume with diluent and mix well. Representative chromatograms of the QL solution are shown in FIG. 3. Concentration of PB is about 2.25 mg/mL Concentration TUDCA is about 0.75 mg/mL Preparation of resolution solution: A. Impurity RRT = 0.90 and impurity RRT = 0.92 stock solution Accurately weigh and transfer about 4.5 mg each of 4,4’-(1,4-phenylene) dibutanoic acid (reference standard for RRT 0.90) and 4,4’-(1,3-phenylene) dibutanoic acid (reference standard for RRT 0.92) into a 10 mL volumetric flask. Add 7 mL MeOH to dissolve, then dilute to volume with diluent and mix well. Concentration of RRT 0.90 and RRT 0.92 is about 450 mg/mL B. Glucosylisomaltol stock solution Attorney Docket No.38709-0035WO1 Accurately weigh and transfer about 4.5 mg glucosylisomaltol into a 50 mL volumetric flask. Add 35 mL MeOH to dissolve, then dilute to volume with diluent and mix well. Concentration of glucosylisomaltol is about 90 mg/mL C. TCDC stock solution Accurately weigh and transfer about 6 mg TCDC into a 20 mL volumetric flask. Add 14 mL MeOH to dissolve, then dilute to volume with diluent and mix well. Concentration of TCDC is about 300 mg/mL D. Resolution solution Accurately weigh and transfer about 90 ± 9 mg PB and about 30 ± 3 mg TUDCA 20 mL volumetric flask. Add about 10 mL of diluent and sonicate until all solids are dissolved (about 5 min). Pipette 2.0 mL of impurity RRT = 0.90 and impurity RRT = 0.92 stock solution, 1.0 mL glucosylisomaltol stock solution, and 1.0 mL TCDC stock solution into the same 20 mL volumetric flask. Dilute to volume with diluent. Approximate concentrations (mg/mL) are as follows: PB: 4.5 TUDCA: 1.5 RRT 0.90: 45 RRT 0.92: 45 Glucosylisomaltol: 4.5 TCDC: 15 Resolution solution can be stored under refrigeration and used as long as all known peaks can be accurately identified. Representative chromatograms are shown in FIG. 4 - FIG. 8. Preparation of marker solution: Sample lot 1524711, stored at 40° C/ 75% relative humidity from stability studies is used to confirm that peak for impurity TCDC and peak of PB-related impurity at RRT 0.96 (RRT 1.17 at 203 nm based on TUDCA) are well separated. The preparation of this solution is disclosed herein. Accurately weigh and transfer 309 mg AMX-0035 sachet powder equivalent to 90 mg PB and 30 mg TUDCA into a 20 mL volumetric flask. Add about 14 mL of diluent and sonicate until all solids are dissolved (about 10 min, with intermittent Attorney Docket No.38709-0035WO1 swirling). Shake sample solution at 200 rpm for 30 min, then dilute to volume with diluent and mix well. Filter a portion through 0.45 mm PTFE filter and discard the first 2-3 mL of filtrate. Approximate concentrations: PB is about 4.5 mg/mL TUDCA is about 1.5 mg/mL Marker solution can be stored under refrigeration and used as long as the two peaks can be accurately identified. Representative chromatograms are shown in FIG.9 - FIG. 10. Preparation of flavor masking sample solution spiked with TCDC at 1% level: Accurately weigh and transfer 96.6 mg flavour masking excipient equivalent to 450 mg PB and 150 mg TUDCA into a 100 mL volumetric flask. Pipette 5.0 mL TCDC stock standard solution into the same volumetric flask. Add about 70 mL diluent and sonicate for 10 min with intermittent swirling. Shake the sample solution at 200 rpm for 30 min, then dilute to volume with diluent and mix well. Filter a portion through 0.45 mm PTFE filter and discard the first 2-3 mL of filtrate. The flavor masking sample solution can be stored under refrigeration and used as long as the TCDC and excipient peak (before TCDC) peaks can be separated and identified. Representative chromatograms are shown in FIG. 11 - FIG. 12. Preparation of placebo sample solution: The purpose of the placebo solution is to identify excipient peaks, which are excluded from the results. Preparation is described herein. Prepare excipient mixture according to the formulation shown in Table 2, excluding PB and TUDCA. Accurately weigh 943.2 mg AMX-0035 excipient powder equivalent to 450 mg PB and 150 mg TUDCA and transfer to 100 mL volumetric flask. Add about 70 mL diluent and sonicate for 10 minutes with intermittent swirling. Shake sample solution at 200 rpm for 30 minutes, then dilute to volume with diluent. Mix well. Filter a portion through 0.45 mm PTFE filter and discard the first 2-3 mL of filtrate. Table 2. Formulation for AMX-0035 powder in sachet
Figure imgf000086_0001
Attorney Docket No.38709-0035WO1
Figure imgf000087_0001
Preparation of AMX-0035 sample solution: Record total weight of ten (10) AMX-0035 sachets, and transfer into a suitable container. Mix the dry blend well. Completely empty each sachet by blowing air. Record total weight of all ten emptied sachets to calculate total content mass. Calculate average fill weight per sachet. Accurately weigh 15,432 mg AMX-0035 sachet powder equivalent to 4500 mg PB and 1500 mg TUDCA and transfer into a 1000 mL volumetric flask. Add about 700 mL diluent and solicate for 10 minutes with intermittent swirling. Shake the sample solution at 200 rpm for 30 minutes and dilute to volume with diluent. Mix well. Filter a portion through 0.45 mm PTFE filter and discard the first 2-3 mL of filtrate. Note: the AMX-0035 sample solution is stable up to 3 days at room temperature and under storage at 2-8° C. Representative chromatograms and UV spectra of impurities observed in AMX-0035 sample solutions are shown in Figs 15-28. Approximate concentrations: PB is about 4.5 mg/mL TUDCA is about 1.5 mg/mL Instrument parameters: Column: XBridge C183.5 mm, 4.6 X 150 mm Column Temperature: 25° C Detection: TUDCA at 203 nm (bandwidth 1 nm); PB at 260 nm (bandwidth 1 nm); collect DAD (200-400 nm) Injection volume: 20 mL Needle wash 30% CAN Flow rate: 1.0 mL/min Run time: 25 min Mobile phase A: 0.5% H3PO4 in water solution Mobile phase B: 100% CAN Table 3. HPLC run Gradient Attorney Docket No.38709-0035WO1
Figure imgf000088_0002
Injection procedure: 1. make two injections of the diluent 2. make one injection of the QL solution 3. make one injection of the resolution solution 4. make one injection of the marker solution 5. make one injection of the flavor masking sample solution 6. make 6 consecutive injections of the working standard solution 7. make one injection of the placebo sample solution 8. make one injection of each sample solution 9. make one injection of the working standard solution after every six sample solution injections and at the end of the sequence. System suitability: The following system suitability must be met: No interfering peak area QL ≥ area should be observed at the retention times of PB related substances RRT 0.18/0.19, RRT 0.31/0.32, glucosylisomaltol, TCDC (RRT 1.15) in the diluent injection. Injection reproducibility: The working standard solution will be consecutively injected 6 times. The RSD of the TUDCA and PB peak areas from the 6 consecutive injections of the working standard solution should be ≤5.0 %. Tailing factor: Calculate the USP tailing factor, T, using the following equation:
Figure imgf000088_0001
Where W0.05 is the peak width of the TUDCA and PB peak at 5% of the peak height from the baseline and is the distance from the peak maximum to the leading edge of the peak. The USP tailing factor of the TUDCA and PB peak in the first injection of the working standard solution should be ≤ 2.0. Number of theoretical plates: Attorney Docket No.38709-0035WO1 The number of theoretical plates per column, N, is calculated using the following equation:
Figure imgf000089_0001
Where t is the retention time of the TUDCA and PB peak and W is the peak width of TUDCA and PB peak, obtained the extrapolating the relatively straight sides of the peak to the base line. The number of theoretical places per column for TUDCA and PB peaks in the first injection of the working standard solution should be ≥40000. QL solution: The signal –to-noise ratio (s/n) of the TUDCA and PB peaks from the injection of the QL solution should not be less than 10. Resolution: From the injection of the resolution solution, calculate the resolution factor, R, between adjacent known related substances and actives using the following equation:
Figure imgf000089_0003
The resolution between impurity RRT 0.90 and RRT 0.92 at 260 for PB related substances should be NLT 1.5 in resolution solution. The resolution between impurity TUDCA and TCDC at 203 nm should be NLT 2.0 in resolution solution. The resolution between impurity TCDC (RRT 1.15) and peak (RRT 1.17) should be NLT 1.5 in marker solution. For the flavour masking sample solution spiked with TCDC at 1% level, the excipient peak (before TCDC) can be separated with TCDC peak identified. System Drift: Make one injection of the working standard solution after injection of every six sample injections, and again at the end of the sequence run. Calculate % recovery using
Figure imgf000089_0002
Where ASKC is the peak area of TUDCA or PB from the system drift injection of the working standard solution and AWSTD is the average peak area of the TUDCA or PB from the first 6 system suitability injections of the working standard solution. Attorney Docket No.38709-0035WO1 Calculations: Exclude any peaks in the injections of diluent and placebo solution from calculations. Refer to the spectra of the respective solutions and the RRT value to identify specified impurities RRT 0.18/0.19, RRT 0.31/0.32, RRT 0.76, RRT 0.83, RRT 0.85, RRT 0.90, RRT 0.92 and RRT 0.96. Ensure not to report any impurity peak twice (i.e., under both wavelength). Based on the DAD spectra of the unknown peak and active peaks, determine if the unknown peak is related to PB and TUDCA and report the highest % RS to represent worst case scenario. Calculate PB impurities using PB in the working standard solution and the TUDCA impurities using the TUDCA in the working solution. The % related substances can be calculated as follows: For Sachet sample: %RS = (ARS/AWSTD) x WSTD x PSTD x (DFSPL/DFSTD) x (Wavg / (WSPL x LC)) x RRF x 100 For blend sample: %RS = (ARS/AWSTD) x WSTD x PSTD x (DFSPL/DFSTD) x (1/ (WSPL x %w/w)) x RRF x 100 Where
Attorney Docket No.38709-0035WO1 Reporting results: A. Individual Impurity 1. Identify and quantitate PB impurity glucosylisomaltol (GSM) at 260 nm, TUDCA impurity TCDC at 203, report result 2. PB related impurity RRT 0.76, impurity A (RRT 0.79), impurity RRT 0.83, Impurity 0.85, impurity 0.90, impurity 0.92, impurity 0.96, impurity B (RRT 1.04) are process impurities; identify these peaks, do not report results. 3. Identify ursodeoxycholic acid (UDCA peak) when existing in sample, but do not quantitate using this method. 4. Each individual related substance equal to or above QL is reported by name or by RRT for unknown related substances. Report to two decimal places. 5. If any individual related substance is detected below QL but is greater than or equal to DL, report a value <QL. 6. If any individual related substance is detected below DL, report as ND (not detected). PB and TUDCA related known and unknown impurities are listed in Tables 4 and 5. Table 4. PB related known and unknown impurities
Figure imgf000091_0001
GSM is glucosylisomaltol Table 5. TUDCA related known and unknown impurities
Figure imgf000091_0002
GSM is glucosylisomaltol B. Total related substances: Sum all peaks ≥ QL, report to one decimal place. For PB related substances, do not include impurity RRT 0.76, impurity A (RRT 0.79), impurity RRT 0.83, Impurity Attorney Docket No.38709-0035WO1 0.85, impurity 0.90, impurity 0.92, impurity 0.96, impurity B (RRT 1.04) in total related substance calculation, these are process impurities. Table 6 lists the PB related impurities not required to report in this method. Table 6. PB related impurities not required to report in this method
Figure imgf000092_0001
Example 2. Stability testing of batch 1592787 ICH Q1A stability testing of new drug substances and drug products defines the stability data package for a new drug substance or drug product that is sufficient for a registration application within the ICH regions. The example herein discloses stability testing of batch 1592787 using the HPLC method of Example 1. The stability of AMX0035 Packaged Batch (3 g Sodium phenylbutyrate + 1 g TUDCA) were evaluated for 24-months storage at 25°C ±2°C/60% RH ±5%, 12- months at 30°C±2°C/65% RH ±5%, and 6-months at 40°C ±2°C/75% RH ±5%. The results of these studies are summarized the following tables. Attorney Docket No.38709-0035WO1 Table 7. AMX0035 Packaged Batch 1592787 (Bulk Batch CBTDN) Stored at 25°C ±2°C/60% RH ±5%
Figure imgf000093_0001
Attorney Docket No.38709-0035WO1
Figure imgf000094_0001
aconforms as white fine to large granule with absence of clumping; boff-white fine to large granules with absence of clumping; cslightly yellow fine to large granules, clumping absent; doff-white cloudy solution with particles on surface and bottom; eslightly yellow cloudy solution with particle on surface and bottom; fNMT = not more than; gaverage of two measurements; hND = not detected; iQL = quantitation limit; jRRT = 1.15; k “-“means not required by protocol; GSM = glucosylisomaltol; TCDC = taurochenodeoxycholic acid; Ab = absent Table 8. AMX0035 Packaged Batch 1592787 (Bulk Batch CBTDN) Stored at 30°C ±2°C/65% RH ±5% Attorney Docket No.38709-0035WO1
Figure imgf000095_0001
Attorney Docket No.38709-0035WO1
Figure imgf000096_0001
aconforms as white fine to large granule with absence of clumping; boff-white fine to large granules with absence of clumping; cslightly yellow fine to large granules, clumping absent; doff-white cloudy solution with particles on surface and bottom; eslightly yellow cloudy solution with particle on surface and bottom; fNMT = not more than; gaverage of two measurements; hND = not detected; iQL = quantitation limit; jout of specification result; kRRT = 1.15; l “-“means not required by protocol; GSM = glucosylisomaltol; TCDC = taurochenodeoxycholic acid; Ab = absent Table 9. AMX0035 Packaged Batch 1592787 (Bulk Batch CBTDN) Stored at 40°C ±2°C/75% RH ±5%
Figure imgf000096_0002
Attorney Docket No.38709-0035WO1
Figure imgf000097_0001
aconforms as white fine to large granule with absence of clumping; boff-white fine to large granules with absence of clumping; cslightly yellow fine to large granules, clumping absent; doff-white cloudy solution with particles on surface and bottom; e,fslightly yellow cloudy solution with particle on surface and bottom; gyellow large granules, very large clumps present; hout of specification result; iNMT = not more than; javerage of two measurements; kND = not detected; lQL = quantitation limit; mRRT = 1.15; l “-“means not required by protocol; GSM = glucosylisomaltol; TCDC = taurochenodeoxycholic acid; Ab = absent; DNC = does not conform Example 3. Stability testing of batch 1631705. ICH Q1A stability testing of new drug substances and drug products defines the stability data package for a new drug substance or drug product that is sufficient for a registration application within the ICH regions. The example herein discloses stability testing of batch 1631705 using the HPLC method of Example 1. Attorney Docket No.38709-0035WO1 The stability of AMX0035 Packaged Batch (3 g Sodium phenylbutyrate + 1 g TUDCA) were evaluated for 18-months storage at 25°C ±2°C/60% RH ±5%, 12- months at 30°C±2°C/65% RH ±5%, and 6-months at 40°C ±2°C/75% RH ±5%. The results of these studies are summarized the following tables. Table 10. AMX0035 Packaged Batch 1631705 (Bulk Batch CBXHX) Stored at 25°C ±2°C/60% RH ±5%
Figure imgf000098_0001
Attorney Docket No.38709-0035WO1
Figure imgf000099_0001
aconforms as white fine to large granule with absence of clumping; boff-white fine to large granules with absence of clumping; cslightly yellow fine to large granules, clumping absent; doff-white cloudy solution with particles on surface and bottom; ewhite cloudy solution with particles on the surface and bottom; fYellowish cloudy solution with particles on surface and bottom; gslightly yellow cloudy solution with particle on surface and bottom; hNMT = not more Attorney Docket No.38709-0035WO1 than; iaverage of two measurements; jND = not detected; kQL = quantitation limit; lRRT = 1.15; maverage of three measurements; n “-“means not required by protocol; GSM = glucosylisomaltol; TCDC = taurochenodeoxycholic acid; Ab = absent Table 11. AMX0035 Packaged Batch 1631705 (Bulk Batch CBXHX) Stored at 30°C ±2°C/65% RH ±5%
Figure imgf000100_0001
Attorney Docket No.38709-0035WO1
Figure imgf000101_0001
aconforms as white fine to large granule with absence of clumping; boff-white fine to large granules with absence of clumping; cslightly yellow fine to large granules, clumping absent; dlight yellow fine to large particle, clumping absent; eYellow fine to large granules, clumping present; foff-white cloudy solution with particles on surface and bottom; gslightly yellow cloudy solution with particles on surface and bottom; hyellow cloudy solution with particles on surface and bottom; iNMT = not more than; javerage of two measurements; kND = not detected; lQL = quantitation limit; mout of specification result; nRRT = 1.15; o “-“means not required by protocol; GSM = glucosylisomaltol; TCDC = taurochenodeoxycholic acid; Ab = absent Table 12. AMX0035 Packaged Batch 1631705 (Bulk Batch CBXHX) Stored at 40°C ±2°C/75% RH ±5%
Figure imgf000101_0002
Attorney Docket No.38709-0035WO1
Figure imgf000102_0001
aconforms as white fine to large granule with absence of clumping; byellow fine to large granules, very large clumps present; cyellow fine to large granules, clumping present; dbrown fine to large granules, clumping present; eout of specification result;f off-white cloudy solution with particles on surface and bottom; gyellowish cloudy solution with particles on the surface and bottom; hyellow cloudy solution with particles on surface and bottom; iNMT = not more than; javerage of two measurements; kND = not detected; lQL = quantitation limit; mRRT = 1.15; n “-“means not required by protocol; GSM = glucosylisomaltol; TCDC = taurochenodeoxycholic Acid; Ab = absent; DNC = does not conform Attorney Docket No.38709-0035WO1 Example 4. Stability testing of batch 1660499 ICH Q1A stability testing of new drug substances and drug products defines the stability data package for a new drug substance or drug product that is sufficient for a registration application within the ICH regions. The example herein discloses stability testing of batch 1631705 using the HPLC method of Example 1. The stability of AMX0035 Packaged Batch (3 g Sodium phenylbutyrate + 1 g TUDCA) were evaluated for 18-months storage at 25°C ±2°C/60% RH ±5%, 12- months at 30°C±2°C/65% RH ±5%, and 6-months at 40°C ±2°C/75% RH ±5%. The results of these studies are summarized the following tables. Table 13. AMX0035 Packaged Batch 1660499 (Bulk Batch CBXHY) Stored at 25°C ±2°C/60% RH ±5%
Figure imgf000103_0001
Attorney Docket No.38709-0035WO1
Figure imgf000104_0001
Attorney Docket No.38709-0035WO1
Figure imgf000105_0001
aconforms as off-white fine to large granules, clumping absent; boff-white cloudy solution with particles on surface and bottom; cNMT = not more than; daverage of two measurements; eQL = quantitation limit; fND = not detected; g~RRT 1.15; h - = testing not required by protocol Table 14. AMX0035 Packaged Batch 1660499 (Bulk Batch CBXHY) Stored at 30°C ±2°C/65% RH ±5%
Figure imgf000105_0002
Attorney Docket No.38709-0035WO1
Figure imgf000106_0001
aconforms as off-white fine to large granules, clumping absent; bslightly yellow fine to large granules, clumping absent; cslightly yellowish fine to large granules, clumping absent; dyellowish fine to large granules, clumping absent; eoff-white cloudy solution with particles on surface and bottom; fyellowish cloudy solution with particles on surface and bottom; gyellow cloudy solution with particles on the surface and bottom; hNMT = not more than; iaverage of two measurements; jQL = quantitation limit; kND = not detected; l~RRT 1.15; m - = testing not required by protocol Table 15. AMX0035 Packaged Batch 1660499 (Bulk Batch CBXHY) Stored at 40°C ±2°C/75% RH ±5%
Figure imgf000106_0002
Attorney Docket No.38709-0035WO1
Figure imgf000107_0001
Attorney Docket No.38709-0035WO1
Figure imgf000108_0001
aconforms as off-white fine to large granules, clumping absent; byellow fine to large granules, clumping present; cyellow fine to large granules, large clumps present; dout of specification result; eyellow fine to large granules, very large clumps present; foff-white cloudy solution with particles on surface and bottom; gyellowish cloudy solution with particles on the surface and bottom; hyellow cloudy solution with particles on the surface and bottom; iNMT = not more than; javerage of two measurements; kQL = limit of quantitation; lND = not detected; m~RRT 1.15; naverage of three measurements; o - = testing not required by protocol DNC = does not conform Example 5. Stability testing of batch 1660500. ICH Q1A stability testing of new drug substances and drug products defines the stability data package for a new drug substance or drug product that is sufficient for a registration application within the ICH regions. The example herein discloses stability testing of batch 1631705 using the HPLC method of Example 1. The stability of AMX0035 Packaged Batch (3 g Sodium phenylbutyrate + 1 g TUDCA) were evaluated for 18-months storage at 25°C ±2°C/60% RH ±5%, 12- months at 30°C±2°C/65% RH ±5%, and 6-months at 40°C ±2°C/75% RH ±5%. The results of these studies are summarized the following tables. Table 16. AMX0035 Packaged Batch 1660500 (Bulk Batch CCPKP) Stored at 25°C ±2°C/60% RH ±5% Attorney Docket No.38709-0035WO1
Figure imgf000109_0001
Attorney Docket No.38709-0035WO1
Figure imgf000110_0001
aoff-white fine to large granules, clumping absent; bslightly yellow fine to large granules, clumping absent; coff-white cloudy solution with particles on surface and bottom, dyellowish cloudy solution with particles on surface and bottom; eyellow cloudy solution with particles on the surface and bottom; fNMT = not more than; gaverage of two measurements; hQL = quantitation limit; iND = not detected; j~RRT 1.15; k - = testing not required by protocol; GSM = glucosylisomaltol;lUSP Method 1c Table 17. AMX0035 Packaged Batch 1660500 (Bulk Batch CCPKP) Stored at Stored at 30°C ±2°C/65% RH ±5%
Figure imgf000110_0002
Attorney Docket No.38709-0035WO1
Figure imgf000111_0001
Attorney Docket No.38709-0035WO1
Figure imgf000112_0001
aconforms as off-white fine to large granules, clumping absent; bslightly yellow fine to large granules, clumping present; cyellow fine to large granules, clumping present; doff- white cloudy solution with particles on surface and bottom; eyellowish cloudy solution with particles on surface and bottom; fyellow cloudy solution with particles on surface and bottom; gNMT = not more than; haverage of two measurements; iQL = quantitation limit; jND = not detected; kout of specification result; lRRT 1.15; m - = testing not required by protocol; n(USP Method 1c) Table 18. AMX0035 Packaged Batch 1660500 (Bulk Batch CCPKP) Stored at 40°C ±2°C/75% RH ±5%
Figure imgf000112_0002
Attorney Docket No.38709-0035WO1
Figure imgf000113_0001
aconforms as off-white fine to large granules, clumping absent; byellow fine to large granules, large clumping present; cout of specification result; dyellow fine to large granules, very large clumps present; eoff-white cloudy solution with particles on surface and bottom; fyellow cloudy solution with particles on the surface and bottom; gNMT = not more than; haverage of two Attorney Docket No.38709-0035WO1 measurements; iQL = quantitation limit; jND = not detected; k~RRT 1.15; l - = testing not required by protocol Example 6. Stability testing of batch 1697227 ICH Q1A stability testing of new drug substances and drug products defines the stability data package for a new drug substance or drug product that is sufficient for a registration application within the ICH regions. The example herein discloses stability testing of batch 1697227 using the HPLC method of Example 1. The stability of AMX0035 Packaged Batch (3 g Sodium phenylbutyrate + 1 g TUDCA) were evaluated for Data are provided for 6-months storage at 25°C ±2°C/60% RH ±5%, 30°C ±2°C/65% RH ±5%, and 40°C ±2°C/75% RH ±5% for stability batch 1697227 (bulk batch CFGGB) Table 19. AMX0035 Packaged Batch 1697227 (Bulk Batch CFGGB) Stored at 25°C ±2°C/60% RH ±5%
Figure imgf000114_0001
Attorney Docket No.38709-0035WO1
Figure imgf000115_0001
aoff-white fine to large granules, clumping absent; bwhite fine to large granules, clumping absent; coff-white cloudy solution with particles on surface and bottom; dNMT = not more than; eaverage of two measurements; fQL = quantitation limit; gND = not detected; hRRT 1.15; i- = testing not required by protocol Table 20. AMX0035 Packaged Batch 1697227 (Bulk Batch CFGGB) Stored at 30°C ±2°C/65% RH ±5%
Figure imgf000115_0002
Attorney Docket No.38709-0035WO1
Figure imgf000116_0001
Attorney Docket No.38709-0035WO1
Figure imgf000117_0002
Figure imgf000117_0001
clumping absent; clight yellow fine to large granules, clumping absent; doff-white cloudy solution with particles on surface and bottom; eslightly yellow cloudy solution with particles on the surface and bottom; fNMT = not more than; gaverage of two measurements; hQL = quantitation limit; iND = not detected; jout of specification result; kRRT 1.15; l- = testing not required by protocol Table 21. AMX0035 Packaged Batch 1697227 (Bulk Batch CFGGB) Stored at 40°C ±2°C/75% RH ±5%
Figure imgf000117_0003
Attorney Docket No.38709-0035WO1
Figure imgf000118_0001
Attorney Docket No.38709-0035WO1
Figure imgf000119_0001
aoff-white fine to large granules clumping absent; bslightly yellowish fine to large granules, clumping present; cyellow pellet; doff-white cloudy solution with particles on surface and bottom; eyellowish cloudy solution with particles on the surface and bottom; fyellow cloudy solution with particles on surface and bottom; gNMT = not more than; haverage of two measurements; iQL = quantitation limit; jND = not detected; kout of specification result; lRRT 1.15; m- = testing not required by protocol Example 7. Stability testing of batch 1697228 ICH Q1A stability testing of new drug substances and drug products defines the stability data package for a new drug substance or drug product that is sufficient for a registration application within the ICH regions. The example herein discloses stability testing of batch 1697227 using the HPLC method of Example 1. The stability of AMX0035 Packaged Batch (3 g Sodium phenylbutyrate + 1 g TUDCA) were evaluated for Data are provided for 6-months storage at 25°C ±2°C/60% RH ±5%, 30°C ±2°C/65% RH ±5%, and 40°C ±2°C/75% RH ±5% for stability batch 1697228 (Bulk Batch CGBSG) Attorney Docket No.38709-0035WO1 Table 22. AMX0035 Packaged Batch 1697228 (Bulk Batch CGBSG) Stored at 25°C ±2°C/60% RH ±5%
Figure imgf000120_0001
Attorney Docket No.38709-0035WO1
Figure imgf000121_0001
aoff-White fine to large granules clumping absent; boff-white cloudy solution with particles on surface and bottom; cNMT = not more than; daverage of two measurements; eND = not detected; fQL = quantitation limit; gRRT 1.15; h- = testing not required by protocol Table 23. AMX0035 Packaged Batch 1697228 (Bulk Batch CGBSG) Stored at 30°C ±2°C/65% RH ±5%
Figure imgf000121_0002
Attorney Docket No.38709-0035WO1
Figure imgf000122_0001
aoff-white fine to large granules, clumping absent; bslightly yellow fine to large granules, no clumping present; coff-white cloudy solution with particles on surface and bottom; dslightly yellow cloudy solution with particles on the surface and bottom; eNMT = not more than; faverage of two measurements; gND = not detected; hQL = quantitation limit; iout of specification result; jRRT 1.15; k- = testing not required by protocol Table 24. AMX0035 Packaged Batch 1697228 (Bulk Batch CGBSG) Stored at 40°C ±2°C/75% RH ±5%
Figure imgf000122_0002
Attorney Docket No.38709-0035WO1
Figure imgf000123_0001
Attorney Docket No.38709-0035WO1
Figure imgf000124_0001
awhite fine to large granules clumping absent; byellow fine to large granules, clumping present; cyellow fine to large granules. Large or very large clumping present (pellet); doff-white cloudy solution with particles on surface and bottom; eyellow cloudy solution with particles on the surface and bottom; fNMT = not more than; gaverage of two measurements; hND = not detected; iQL = quantitation limit; jout of specification result; kRRT 1.15; l- = testing not required by protocol Example 8. Summary of Stability testing Three primary stability batches manufactured using Uetikon PB have been placed on stability using the protocol provided in Table 26. Two of the batches were manufactured using the proposed commercial manufacturing process and Uetikon PB. Batch 1697227 was manufactured at 360 kg scale, batch 1697228 was manufactured at 900 kg scale (proposed commercial scale). The third batch (1660500) was manufactured at the 200 kg scale. Attorney Docket No.38709-0035WO1 Significant changes in appearance and other parameters were observed at the 40°C ± 2°C/ 75% RH ± 5% storage condition for all batches; therefore, the 30°C ± 2°C/ 65% RH ± 5% storage condition samples have been tested. There is no observed significant change for these batches at the 25°C ± 2°C/ 60% RH ± 5% storage condition. Detailed information regarding the primary stability batches is provided in Table 25. Table 25. Information Regarding Primary Stability Batches
Figure imgf000125_0001
The stability protocol for primary stability batches is provided in Table 26. Table 26. Stability Protocol for Primary and Supportive Stability Batches
Figure imgf000125_0002
A tabular summary of the available data for each batch is provided in Table 27. A detailed summary of the results of each test is also provided herein. Table 27. Summary of Results for Primary Stability Batches
Figure imgf000125_0003
Attorney Docket No.38709-0035WO1
Figure imgf000126_0001
As specified in ICH Q1A, data from additional stability studies are provided to support the proposed shelf life and the label storage conditions. Three batches manufactured using sodium phenylbutyrate manufactured at Sri Krishna Pharmaceuticals were stored using the protocol provided in Table 27. Significant changes in appearance and other parameters were observed at the Attorney Docket No.38709-0035WO1 40°C ± 2°C/ 75% RH ± 5% storage condition for all batches; therefore, the 30°C ± 2°C/ 65% RH ± 5% storage condition samples have been tested. There is no observed significant change for these batches at the 25°C ± 2°C/ 60% RH ± 5% storage condition. Detailed information regarding the supportive stability batches is shown in Table 28 Table 28. Information Regarding Supportive Stability Batches
Figure imgf000127_0001
The differences in the supportive stability batches and those intended for commercialization are provided in Table 29. Table 29. Overview of Supportive Stability Batches for NDA Submission
Figure imgf000127_0002
Figure imgf000127_0003
A tabular summary of the available data for each batch is shown in Table 30. A detailed summary of the results of each test is provided in Table 31. Table 30. Tabular Summary of Results for Supportive Stability Batches Attorney Docket No.38709-0035WO1
Figure imgf000128_0001
Summary of Primary and Supportive Stability Data Appearance of drug product: Results at the proposed storage condition (25°C ± 2°C/ 60% RH ± 5%) and the intermediate storage condition (30°C ± 2°C/ 65% RH ± 5%) for the primary and supportive stability batches meet the proposed specifications. The primary and supportive studies showed significant change to the appearance (outside of specifications, OOS) as early as 3 months on the accelerated storage condition (40°C ± 2°C/ 75% RH ± 5%). The drug product showed color changes (yellowing) and clumping. There are no significant differences between the results observed for the primary and supportive batches at the proposed storage conditions. Appearance of Reconstituted Solution: Attorney Docket No.38709-0035WO1 Results at all storage conditions for the primary and supportive stability batches met specifications for appearance of reconstituted solution. Reconstitution Time: Results at all storage conditions for the primary and supportive stability batches met specifications for reconstitution time. API assay: Results at all storage conditions for the primary and supportive stability batches met specifications for assay. FIG. 29 shows the PB assay values for the proposed storage condition stability data and FIG. 30 shows the taurursodiol assay values for the proposed storage condition stability data. All results were within the stability specification and do not show a degradation trend. There are no observable differences in the results obtained for the primary and supportive stability batches at the proposed storage conditions. 260 nm Degradation Products: Results for specified degradation products met specifications for the primary and supportive stability batches at all storage conditions. Results for unspecified degradation products were OOS for multiple studies on storage of as little as 3-months at the intermediate storage condition and as little as 1-month at the accelerated storage condition. Results for total 260 nm degradation products were within specifications at the proposed storage conditions and intermediate storage conditions for the primary and supportive stability batches. Out of specification results were obtained for the primary and supportive stability batches at the 6-month timepoint for stability studies at accelerated conditions. The RRT 0.18/0.19 degradation products at 260 nm are shown in FIG. 31, the RRT 0.31/0.32 degradation products at 260 nm are shown in FIG. 32, and the RRT 0.37 degradation product at 260 nm is shown in FIG. 32. The total degradation products at 260 nm at the proposed storage conditions are shown in Fig 33. All results are within the stability specification and do not show a clear degradation trend. There are no observable differences in the results obtained for the primary and supportive stability batches at the proposed storage conditions. 203 nm Degradation Products: Results for specified, unspecified, and total degradation products at 203 nm met Attorney Docket No.38709-0035WO1 specifications at all storage conditions for the primary and supportive stability batches. FIG.35 and FIG.36 show the TCDC results, and the total degradation products results at the proposed storage conditions, respectively. All results are within the stability specification and do not show a degradation trend. The results for TCDC and total impurities at 203 nm are lower in the primary stability batches vs. the levels in the supportive batches. All results meet specifications. Results for pH met specifications at the proposed and intermediate storage conditions for all timepoints for the primary and supportive stability batches. The pH results over storage at the proposed storage conditions are shown in FIG.36. All results were within the stability specification and do not show a degradation trend. The 9- month results for batch 1631705 were out of trend with a result of pH 7.2; however, the 12-month and subsequent results are within previous trends. There are no observable differences between the data for the primary and supportive stability batches at the proposed storage conditions. Moisture: Moisture results met specifications at all storage conditions for the primary and supportive stability batches. The water results over storage at the proposed storage conditions are shown in FIG.37. All results are within specifications and do not show a degradation trend. There are no observable differences between the data for the primary and supportive stability batches at the proposed storage conditions Microbial Limits: Microbial limits met specifications at all storage conditions for the primary and supportive stability batches. Justification for Container-Closure Pouch Size Change: All stability batches were filled into 3” x 5” pouches. Commercial batches will be filled into 2.5” x 5” pouches. From a performance viewpoint with considerations on the container closure functionality and drug delivery, the difference in changing to a 2.5” x 5” sachet is negligible. The main area of consideration would be the reduction in the volume and surface area. This reduction would not impact fill volume or dispensability of the powder. A description of the surface area (product contact area) and seal area for each size sachet is provided in Table 31. The potential impact of this change on the stability, quality, and safety of the drug product is expected to be Attorney Docket No.38709-0035WO1 minimal and reportable post-approval as described in 21 CFR 314.70(d)(2)(iv). Table 31. Surface Area (Product Contact Area) and Seal Area for Sachets
Figure imgf000131_0001
Bulk stability: A bulk stability study was performed using bulk feasibility batch YNHP, manufactured at Patheon Whitby to establish the stability of the drug product during storage and shipment prior to packaging. A summary of the differences in the manufacture of the feasibility batch and the most recent clinical batches are provided below. • The batch scale for batch 1523975 was 90 kg. • Batch 1523975 was manufactured using sodium phenylbutyrate Ph. Eur. • An additional 14-mesh screen was used for clinical materials. • Both active ingredients were screened through a 14-mesh screen instead of Comil 0.62R screen. • Additional Comil step after partial mixing. • Additional mixing step. Total mixing time remained the same. Performed as single step for clinical and commercial batches. Additional bulk drug product stability studies have been performed for batches CFGGB (360 kg) and CGBSG (900 kg) manufactured using the as proposed commercial manufacturing process. Six-months data at 22.5°C ±7.5°C/ Ambient RH are available for these batches. The batches were stored using the protocol provided in Table 32. All results are within specifications. Bulk drug product will be held for ≤ 6 months prior to packaging. Table 32. Bulk Stability Protocol
Figure imgf000131_0002
Attorney Docket No.38709-0035WO1
Figure imgf000132_0001
X indicates that the following testing was performed: appearance, appearance after reconstitution, pH, moisture, reconstitution time, assay, impurities, and dissolution; Y indicates that the following testing will be performed: microbial limits In-Use Stability: In-use stability studies were performed to establish the stability of the drug product when reconstituted as per patient instructions. Batch 1631705 was tested for in-use stability within 3-months of manufacture, 1-month of packaging. In addition, aged batch 1524711 was tested for in-use stability after storage in the stability chamber under long-term storage conditions (25°C/60% RH) for approximately 32 months. The commercial label instructs the patient to consume the solution within 60 minutes of reconstitution. The in-use stability data indicate that the reconstituted drug product remains within all stability specifications for at least 120 minutes both when batches are newly made and after ~32 months of storage. The aged sample would be considered stable up to 180 minutes. Forced Degradation: AMX0035 was subjected to forced degradation and the degradation products were determined by HPLC. Forced degradation studies show drug product is susceptible to oxidation as well as temperature and humidity, but stable under acidic or basic conditions, possibly due to the use of a buffered formulation. The following is observed for PB-related impurities • Known PB USP impurity A and Impurity B do not appear to be degradation-related products. • The impurity at ~RRT 0.31/0.32 appears to be a degradation product under thermal conditions. • 4-[4-(3-carboxypropyl)phenyl]4-oxobutanoic acid (~RRT 0.76, RRT 0.75 in this study) forms at thermal and thermal humidity conditions; however, the stability data for the formulation do not show an increase of this compound during storage at the proposed storage conditions. • 4-(4-Formylphenyl)butanoic acid (~RRT 0.83) was not detected during this study, indicating this compound is not a degradation product. • 4-(3-formylphenyl)butanoic acid (~RRT 0.85) does show some increase under thermal, acidic (3 days), and basic (3 days and 7 days) conditions; however, based on the response factor of this impurity the levels observed in this study Attorney Docket No.38709-0035WO1 and stability studies are not above the ICH identification/qualification thresholds. • 4,4’-(1,4-Phenylene) dibutanoic acid (~RRT 0.90), 4,4’(1,2- phenylene) dibutanoic acid (~RRT 0.92), and 4-(8-oxo-5,6,7,8-tetrahydronaphthalen- 2-yl) butanoic acid (~RRT 0.96) which are observed in drug product produced using Sri Krishna PB do not appear to be degradation-related products. • The taurursodiol related impurity TCDC, does not increase in forced degradation conditions; however, the drug product stability data shows an increase in this compound during storage. • UDCA and taurine increase under acidic and basic conditions; however, these are expected amide hydrolysis products. Neither taurine nor UDCA are observed at increased levels in the dosage form after storage for up to 8.5 months at 40°C/75% RH as described herein. Based on these data, it does not appear that either UDCA or taurine are degradation products under normal storage conditions. The specifications for taurine and UDCA in the drug substance are “not more than 0.2% and “not more than 0.5%,” respectively. A description of the study performed and the results are provided in Example 9. Storage conditions: The proposed storage conditions for AMX0035 Powder for Oral Suspension are described below. The storage statement appearing on cartons will be: Store at 20 to 25°C. Protect from moisture. The proposed expiry is based on the following available stability data and the principles of ICH Q1E: · Stability data from the primary batches: · 18-months on one pilot scale batch · 6-months data on one pilot scale batch · 6-months data on one full scale batch · Stability data from the supportive batches · 24 months data on one pilot scale batch · 18-months data on two pilot scale batches An expiry period of 24 months is proposed for AMX0035 Powder for Oral Suspension. As agreed in the CMC Pre-NDA Meeting, the expiration dating may be extended in an Annual Reports based on data from the primary stability batches. Example 9. Forced degradation study of AMX-0035 Powder in Sachet Attorney Docket No.38709-0035WO1 A forced degradation study for AMX-0035 Powder in Sachet (label claim: 3g Sodium Phenylbutyrate (PB) and 1g Tauroursodeoxycholic Acid (TUDCA) per sachet) was carried out according to the protocol described herein. The forced degradation study included stressing samples of PB API, TUDCA API, placebo, and AMX-0035 Powder in Sachet under Thermal, Thermal-Humidity, Light, Oxidation, Acid, and Base conditions. The control and stressed samples were assayed for potency using the HPLC method described in Example 1. The purpose of performing forced degradation study include: • To obtain information on degradation profile for APIs, product, and analytically prepared placebo powder under various forced degradation conditions. • To establish whether the HPLC procedure described in this protocol is stability-indicating. The compounds of interest in this example are shown in Table 33. Table 33. Substances of interest in the forced degradation study of AMX-0035
Figure imgf000134_0001
Attorney Docket No.38709-0035WO1
Figure imgf000135_0001
Standards and samples used: · AMX-0035 Powder in Sachets, 10 g, CTM, Lot 1631705 Sodium Phenylbutyrate drug substance, Lot 1075127. · Tauroursodeoxycholic Acid (TUDCA) drug substance, Lot 1081598 Sodium Phenylbutyrate Reference Standard, Lot F1M546. · Tauroursodeoxycholic Acid (TUDCA) Reference Standard, Lot 2014120413 Dextrates Hydrated, NF (Emdex), Lot 1079302. · Sorbitol, NF (Neosorb P110), Lot 1070429 Sucralose, NF/Ph. Eur., Lot 1079439. · Silicon Dioxide, NF (Syloid 63FP), Lot 1079403 Maltodextrin, NF/Ph. Eur. (Kleptose), Lot 1077438 Sodium Phosphate Dibasic Anhydrous, USP, Lot 1071325 Sodium Stearyl Fumarate, NF/ EP (PRUV), Lot 1082156 Flavour Masking, Lot 1083533. · Mixed Berry Flavour, Lot 1083531. See Table 2 (Example 1) for formulation of AMX-0035 Powder in Sachet. Attorney Docket No.38709-0035WO1 Accuracy for assay The forced degradation study required the use of same sample preparation for assay and related substances analysis to ensure the mass balance calculations can be performed accurately. Therefore, the sample solution from related substances analysis was used as the stock sample solution and diluted to match the concentration in the assay method (see Example 1) assay working sample solution. To ensure the above procedure is acceptable for assay analysis, placebo samples spiked TUDCA and PB at 100% level were prepared using the exact procedure as that used for forced degradation study assay samples and analyzed for % recovery. The accuracy study results are listed in Table 34. The results indicate that the sample preparation procedure used for assay of forced degradation study samples yield accurate results. Table 34. Accuracy Study Results for Assay Sample Preparation
Figure imgf000136_0001
Samples of PB API, TUDCA API, Placebo mixture, and AMX-0035 Powder in Sachet were stressed under the conditions listed in Table 35 for the duration specified. Table 35. Forced Degradation Conditions
Figure imgf000136_0002
Attorney Docket No.38709-0035WO1
Figure imgf000137_0001
Results and Discussion The assay results of the control and stress sample are summarized in Table 36. The results for related substances (RS) are summarized in Table 4 (TUDCA related substances) and Table 5 (PB related substances). The Relative Mass Balance Deficit values are listed in Table 6. The representative chromatograms of the control and stress samples are presented in section 7.0 (assay) and 8.0 (related substances). The PB API did not degrade in any of the forced degradation conditions studied. The TUDCA API also did not degrade in thermal and light conditions. It degraded slightly in acidic condition by Day 7 and in oxidation and base condition by Day 3. By Day 7, TUDCA API degraded by ~17% in base condition. The TUDCA API in Thermal-Humidity condition completely changed in nature or precipitated in solution as no TUDCA peak was detected in the assay sample solution. The exposure of placebo mixture to forced degradation conditions did not generate any peaks that interfered at the retention times of active peaks. The PB and TUDCA in AMX-0035 Powder in Sachet did not degrade in acid, base, and light conditions. PB in sachet did not degrade in oxidation condition, but degraded by approximately 8% and 4% in Thermal and Thermal-Humidity condition, respectively. TUDCA in sachet slightly degraded in oxidation condition and by 19% and 10% in Thermal and Thermal-Humidity condition, respectively. The extend of TUDCA degradation in Thermal-Humidity condition was much lower in sachet compared to full degradation in TUDCA API sample. Attorney Docket No.38709-0035WO1 The PB peaks (of PB API and AMX-0035 Powder in Sachet) were spectrally pure in all the assay sample solutions and in the RS solutions for Control, Oxidation, Acid, and Base conditions. The PB peaks (of PB API and AMX-0035 Powder in Sachet) were not pure in the RS sample solutions for Thermal, Thermal-Humidity, Light Control, and Light conditions. Since the UV absorbance values are very high in RS sample solutions (~ 1.0 AU), peak purity values are not very reliable. The UV absorbance values are not linear at high absorbance. The TUDCA peaks did not pass peak purity requirements in any of the samples (Assay and RS sample solutions). This may be due to baseline noise level as TUDCA is measured at low wavelength of 203 nm. Table 36. Assay Results for Forced Degradation of PB API
Figure imgf000138_0001
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Figure imgf000139_0001
Table 37. Assay Results for Forced Degradation of TUDCA API
Figure imgf000139_0002
Table 38. Assay Results for Forced Degradation of Placebo
Figure imgf000139_0003
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Figure imgf000140_0001
Table 39. Assay Results for Forced Degradation of AMX-0035 Powder in Sachet
Figure imgf000140_0002
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Figure imgf000141_0001
Table 40A. TUDCA Related Substances Resultsa for Forced Degradation Study Samples
Figure imgf000141_0002
a results in % w/w Table 40B. TUDCA Related Substances Resultsa for Forced Degradation Study Samples
Figure imgf000141_0003
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Figure imgf000142_0001
a results in % w/w Table 41A. PB Related Substances Results for Forced Degradation Study Samples.
Figure imgf000142_0002
Table 41B. PB Related Substances Results for Forced Degradation Study Samples. Attorney Docket No.38709-0035WO1
Figure imgf000143_0001
Table 41C. PB Related Substances Results for Forced Degradation Study Samples.
Figure imgf000143_0002
Table 41D. PB Related Substances Results for Forced Degradation Study Samples.
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Figure imgf000144_0001
Table 42. % RMBD (Relative Mass Balance Deficit) Results for Forced Degradation Study Samples.
Figure imgf000144_0002
This example summarizes the results for the forced degradation study of AMX- 0035 Powder in Sachet performed. The stress conditions studied include Thermal, Thermal-Humidity, Oxidation, Light, Acid, and Base. The product did not degrade under acid, base, and light conditions. Thermal condition showed the highest degradation of AMX-0035 powder in sachet followed by Thermal-Humidity and Oxidation. The mass balance values were close to 100% for PB and also for TUDCA except for TUDCA in AMX-0035 powder in sachet exposed to Thermal and Thermal- Attorney Docket No.38709-0035WO1 Humidity condition and TUDCA API exposed to base condition for 7 days at 50°C where the mass balance values ranged from 81– 90%. Lower mass balance values are expected for TUDCA since CTMLP-4073 does not detect TUDCA impurities Taurine and UDCA which are monitored by another laboratory using LC-MS. Example 10. Qualification of Impurity RRT 0.31/0.32 present in Batch CBTDN An orally administered drug candidate, AMX0035, consists of two active components: Tauroursodeoxycholic Acid (TUDCA) and Sodium Phenylbutyrate (PB), for the long-term treatment of amyotrophic lateral sclerosis (ALS). A combined oral clinical dosage form (a sachet) has been prepared. This sachet is to be given twice a day. Each dose contains 3 grams of sodium phenylbutyrate and 1 gram of TUDCA. RRT 0.31/0.32 has been detected in batch CBTDN of AMX0035 (see Table 43) and has substantially increased during stability. Impurity identification work is actively ongoing, but a definitive structure has not been identified to date. Table 43. Impurity Qualification RRT 0.31/0.32
Figure imgf000145_0001
Batch CBTDN has been used in a 9-month study in minipig and a 6-month study in Sprague- Dawley rats. In the 6-month study, rats (15-20/sex/dose) have been administered 0, 250, 420, or 840 mg/kg/day AMX0035 for 6 months. In-life data (clinical observations, body weights, body weight gains, food consumption, and clinical observations) through 6 months revealed that no treatment-related adverse effects have been seen during the study. Similarly, in the 9-month study, minipigs (4- 6/sex/dose) have been administered 0, 250, 423, or 845 mg/kg/day AMX0035 for over 8 months with no treatment-related effects seen. In embryofetal toxicity pilot studies in rats and mice, no test-article effects were seen in maternal or offspring rats or mice at up to 1500 mg/kg/day. RRT 0.31/0.32 has been present in nonclinical batch of AMX0035 at levels of 0.12% to 0.18%. Impurity identification work is actively ongoing, but a definitive structure has not been identified to date. In a different batch, impurity RRT 0.31/0.32 Attorney Docket No.38709-0035WO1 has been detected at .24% but has only been seen at 0.18% in clinical trials. A level of 0.3% is also assessed for safety. Table 44 presents a summary of the impurity present in the combined oral clinical dosage form. Table 44. AMX0035 Dosage Form PB Related Impurity RRT 0.31/0.32
Figure imgf000146_0001
a. Based on daily dose of 6000 mg sodium phenylbutyrate x 0.18% Impurity RRT 0.31/0.32 ÷ 60 kg default human b. Based on daily dose of 6000 mg sodium phenylbutyrate x 0.30% impurity RRT 0.31/0.32 ÷ 60 kg default human c. Margin of safety at potential max daily dose 5.07 For Impurity RRT 0.31/0.32, NOAEL levels in the rat (840 mg/kg/day) and the minipig (845 mg/kg/day) GLP toxicology studies resulted in respective Impurity RRT 0.31/0.32 levels of 1.008 mg/kg/day and 1.521 mg/kg/day. As these NOAEL dose levels in the toxicology studies were over 8X the current clinical dose (0.18 mg/kg/day) and over 5X the potential maximum daily dose of 0.3 mg/kg/day, the impurity should be considered qualified at 0.3%. Example 11. Safety Assessment of Four Impurities Present in Initial Clinical Batches Amylyx has developed an orally administered drug candidate for the long term treatment of amyotrophic lateral sclerosis (ALS) which consists of two active components: Tauroursodeoxycholic Acid (TUDCA) and Sodium Phenylbutyrate (PB). A combined oral clinical dosage form (a sachet) has been prepared. This 9.72 gram oral sachet is to be given twice a day. Each dose contains 3 grams of sodium phenylbutyrate and 1 gram of TUDCA. Table 45 below presents a summary of 4 impurities present in the combined oral clinical dosage form. In order to evaluate the safety of these impurities, a 14-day rat study was conducted using the ambient and accelerated drug product, which contained all of the impurities. Rats were administered 0, 1000 mg/kg (ambient), 1000 mg/kg Attorney Docket No.38709-0035WO1 (accelerated), or 2000 mg/kg (accelerated) AMX0035 orally by gavage once daily for 14 consecutive days. Daily doses of AMX 0035 at 1000 or 2000 mg/kg were well tolerated in both male and female Sprague Dawley Rats. All animals survived to the end of the study and no treatment-related adverse effects were seen. Based on the results of this study, a NOAEL of 2000 mg/kg is determined. Table 45. Amylyx Dosage Form Impurities
Figure imgf000147_0001
aFor high-dose group (2000 mg/kg) under accelerated conditions; bBased on daily dose of 6000 mg PB (PDE ÷ 6000 x 100) (mg); cBased on daily dose of 2000 mg TUDCA (PDE ÷ 2000 x 100) (mg) For each of the impurities a Permissible Daily Exposure (PDE) was calculated according to the risk assessment procedures specified in ICH Q3C. The permitted daily exposure (PDE) to the excipient is calculated as follows: PDE = Effect Level x Weight Adjustment F1 x F2 x F3 x F4 x F5 The factors in the denominator are defined in the guideline for residual solvents in ICH Q3C. The following factors were selected: F1 = A factor to account for extrapolation between species = 5 (rats) F2 = A factor to account for variability between individuals = 1 as sensitive populations are well characterized F3 = A factor to account for toxicity studies of short-term exposure = 1 (based on use as approved therapeutics) F4 = A factor that may be applied in cases of severe toxicity = 1 (no severe toxicity) F5 = A factor that may be applied if the no-effect level was not established = 1 (use of a NOAEL) Attorney Docket No.38709-0035WO1 Therfore: The safe levels of the four AMX0035 impurities discussed above have been evaluated against conservative PDE values based on systemic toxicity data. Upon consideration of all the available data summarized above, it is not expected that any components should pose a significant risk to the patient at the levels provided. Example 12. Qualification of Impurities Present in Initial Clinical Batches Amylyx is developing an orally administered drug candidate for the long term treatment of amyotrophic lateral sclerosis (ALS) which consists of two active components: Tauroursodeoxycholic Acid (TUDCA) and Sodium Phenylbutyrate (PB). A combined oral clinical dosage form (a sachet) has been prepared. This sachet is to be given twice a day. Each dose contains 3 grams of sodium phenylbutyrate and 1 gram of TUDCA. Table 46 below presents a summary of PB levels and Table 47 presents a summary of TUDCA levels observed. Table 46. Amylyx Dosage Form PB Impurities
Figure imgf000148_0001
** In the most sensitive species (the rat), the NOAEL (qualified) level would (8 x 0.19) =1.52% *** In the most sensitive species (the rat), the NOAEL (qualified) level would (8 x 0.62) =4.96% **** In the most sensitive species (the rat), the NOAEL (qualified) level would (8 x 0.11) =0.88% ***** Controlled as non-Qualified Impurity Attorney Docket No.38709-0035WO1 Table 47. Amylyx Dosage Form TUDCA Impurities
Figure imgf000149_0001
*In the most sensitive species (the rat), the NOAEL (qualified) level would (8 x 1) = 8% For systemic toxicity, in accordance with ICH Q3B, only Impurities (RRT) 0.90, 0.92, and 1.15 currently require qualification. As NOAEL dose levels in GLP toxicology studies were 8X the intended clinical dose in rats and 22X in pigs, these impurities should be considered qualified at stated specification levels. While not required by ICH Q3B, Impurities at (RRT) 0.83 and 0.96 should also be considered qualified by the systemic GLP toxicology studies. Chromosomal aberration studies, Ames Test and in vivo micronucleus testing were also conducted on the toxicology batches with no mutagenic findings. Identification of appropriate impurities is in progress. Example 13. Investigational medical Product Dossier Safety and Efficacy AMX0035 is a combination of two active pharmaceutical ingredients (API), sodium phenylbutyrate (PB) and ursodoxicoltaurine (TURSO), designed to block neuronal death and neuroinflammation through simultaneous inhibition of endoplasmic reticulum (ER) and mitochondrial stress. This drug is in a novel pharmacological class of dual ER stress and mitochondrial stress inhibitors. PB and TURSO have been evaluated individually in disease- specific models of Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS), and other neurodegenerative diseases, as well as in models of ER stress and mitochondrial dysfunction. AMX0035 is currently being developed for the treatment of AD, ALS, Wolfram syndrome, and progressive supranuclear palsy (PSP). AMX0035 is supplied as a powder filled sachet. Each sachet contains 3 g PB and 1 g taurursodiol. The drug product powder is blended and is filled under cGMP conditions in an aluminum foil lined sachet, then packaged into carton boxes. Attorney Docket No.38709-0035WO1 Nonclinical Pharmacology, Pharmacokinetics, and Toxicology: ~RRT 0.18/0.19 A summary of the impurity observed at ~RRT 0.18/0.19 present in the combined oral clinical dosage form is provided in Table 48. A definitive structure for this impurity could not be determined; therefore, it is controlled in drug product by relative retention time. A 14-day rat study was conducted using the ambient and accelerated drug product (batch 16M03), which contained this impurity. Rats were administered 0, 1,000 mg/kg (ambient), 1,000 mg/kg (accelerated), or 2,000 mg/kg (accelerated) AMX0035 orally by gavage once daily for 14 consecutive days. Daily doses of AMX 0035 at 1,000 or 2,000 mg/kg were well tolerated in both male and female Sprague Dawley Rats. All animals survived to the end of the study and no treatment-related adverse effects were seen. Based on the results of this study, a NOAEL of 2,000 mg/kg is determined. Table 48. Levels of Impurity RRT 0.18/0.19 in AMX0035 Batch CBTDN, Batch 16M03 (Used in Toxicology Studies)
Figure imgf000150_0001
a. For high-dose group (2000 mg/kg) under accelerated conditions; b. Based on daily dose of 6000 mg PB (PDE ÷ 6000 x 100) (mg) For impurity ~RRT 0.18/0.19 a Permissible Daily Exposure (PDE) was calculated according to the risk assessment procedures specified in ICH Q3C. The safe levels of the AMX0035 ~RRT 0.18/0.19 impurity discussed above have been evaluated against conservative PDE values based on systemic toxicity data. Upon consideration of all the available data summarized above, it is not expected that the impurity should pose a significant risk to the patient at the proposed specification (not more than 0.2%). ~RRT 0.30 Attorney Docket No.38709-0035WO1 An impurity of RRT 0.30 has been detected in multiple batches of AMX0035 and has shown levels close to the limit for unidentified degradation products (NMT 0.10%). A definitive structure for this impurity could not be determined; therefore, it is controlled in drug product by relative retention time. This impurity was studied in the same toxicological study as ~RRT 0.37, below. Information regarding the level of this impurity in the toxicological study is provided in Table 4. For the impurity a Permissible Daily Exposure (PDE) was calculated according to the risk assessment procedures specified in ICH Q3C. The safe levels of the AMX0035 impurity at RRT 0.30 (260 nm) has been evaluated against conservative PDE values based on systemic toxicity data. Upon consideration of all the available data summarized above, it is not expected that the component should pose a significant risk to the patient at the levels provided. The impurity should be considered qualified at 0.5%. ~RRT 0.31/0.32 An impurity at RRT 0.31/0.32 has been detected in batch CBTDN (packaged batch 1592787) of AMX0035 (Table 49) and has shown increase during packaged drug product stability. A definitive structure for this impurity could not be determined; therefore, it is controlled in drug product by relative retention time. Table 49. Levels of Impurity RRT 0.31/0.32 in AMX0035 Batch CBTDN, Packaged Batch 1592787 (Used in Toxicology Studies)
Figure imgf000151_0001
Batch CBTDN has been used in a 9-month study in minipig (S15821) and a 6-month study in Sprague Dawley Rats In the 6-month study, rats (15 – 20/sex/dose) have been administered 0, 250, 420, or 840 mg/kg/day of AMX0035 for 6 months. In-life data (clinical observations, body weights, body weight gains, food consumption, and clinical observations) through 6 months revealed that no treatment-related adverse effects have been seen during the study. Similarly, in the 9-month study, minipigs (4 – 6/sex/dose) have been administered 0, 250, 423, or 845 mg/kg/day of AMX0035 for 9 months with no Attorney Docket No.38709-0035WO1 treatment-related effects seen. In embryofetal toxicity pilot and GLP studies in rats and mice, no test-article effects were seen in maternal or offspring rats or mice at up to 1500 mg/kg/day. The impurity at RRT 0.31/0.32 has been present in this nonclinical batch on stability at levels of 0.12% to 0.18% (at 6-months timepoint). In a different batch, this impurity has been detected at 0.35% on stability but had only been seen at 0.18% in clinical trials at the time the toxicology study was performed. A level of 0.3% is also assessed for safety. A summary of the impurity present in the combined oral clinical dosage form is provided in Table 50. Table 50. AMX0035 Dosage Form PB Related Impurity at RRT 0.31/0.32
Figure imgf000152_0001
a. Based on a daily dose of 6000 mg sodium phenylbutyrate x 0.18% Impurity RRT 0.31/0.32 ÷ 60 kg default human; b. Based on a daily dose of 6000 mg sodium phenylbutyrate x 0.40% Impurity RRT 0.31/0.32 ÷ 60 kg default human For the impurity at RRT 0.31/0.32, NOAEL levels in the rat (840 mg/kg/day) and the minipig (845 mg/kg/day) GLP toxicology studies resulted in respective impurity RRT 0.31/0.32 levels of 1.008 mg/kg/day and 1.521 mg/kg/day. As these NOAEL dose levels in the toxicology studies were over 8 x the current clinical dose (0.18 mg/kg/day) and over 3 x the potential maximum daily dose of 0.4 mg/kg/day, the impurity should be considered qualified at 0.4%. ~RRT 0.37 A summary of the impurity observed at ~RRT 0.37 present in the combined oral clinical dosage form is provided in Table 4. A definitive structure for this impurity could not be determined; therefore, it is controlled in drug product by relative Attorney Docket No.38709-0035WO1 retention time. An additional toxicology study (14-day rat study) was performed using ambient and accelerated drug product. Rats were administered 0, 1000 mg/kg (ambient), 1000 mg/kg (accelerated), or 2000 mg/kg (accelerated AMX0035 by oral gavage once daily for 14 consecutive days). Based on the results of this study, a no observed adverse effect level (NOAEL) of 2000 mg/kg was determined. Information regarding the impurity at RRT 0.37 is provided in Table 51. Table 51. Levels of Impurities at RRT 0.30 and RRT 0.37 Used in 14-Day Rat Study
Figure imgf000153_0001
a. For high-dose group (2000 mg/kg) under accelerated conditions; b. Based on daily dose of 6000 mg sodium phenylbutyrate (PDE ÷ 6000 x 100) (mg) For the impurities a Permissible Daily Exposure (PDE) was calculated according to the risk assessment procedures specified in ICH Q3C. The safe levels of the AMX0035 impurity at RRT 0.37 (260 nm) has been evaluated against conservative PDE values based on systemic toxicity data. Upon consideration of all the available data summarized above, it is not expected that the component should pose a significant risk to the patient at the levels provided. The impurity should be considered qualified at 0.4%. Degradation Products Quantitated at 203 nm: Potential taurursodiol-related degradation products are taurochenodeoxycholic acid (TCDC) and other bile acids. The specification in the drug substance taurursodiol for TCDC is “not more than 1.0%” and the specification for other bile acids (total) is “not more than 0.5%.” The levels of TCDC observed in the toxicology batches are provided in Table 52. Attorney Docket No.38709-0035WO1 Table 52. TCDC Observed in API Toxicology Batches.
Figure imgf000154_0001
A summary of the taurursodiol impurities observed in the Formex and Patheon Whitby clinical batches (packaged powder) and the initial API toxicology batch is provided in Table 53. Table 53. TCDC Observed in the Formex and Patheon Whitby Clinical Batches (Bulk Powder) and the Toxicology Batch.
Figure imgf000154_0002
a. NMT = not more than; b. In the most sensitive species (the rat), the NOAEL (qualified) level would be (8 x q) = 8%. As NOAEL dose levels in GLP toxicity studies were 8-times the intended clinical dose in rats and 22-times in pigs, these impurities should be considered qualified. An in- silico evaluation was performed to determine the potential for mutagenicity of TCDC, in accordance with ICH M7 Guidelines using DEREK and were not found to have genotoxic potential. Based on the foregoing information, not more than 1.5% is recommended in the formulation. A summary of preclinical assessments is provided in Table 54 and Table 55. Nonclinical studies evaluating systemic toxicity, genotoxicity, embryo-fetal toxicity, fertility, and early embryonic development were GLP-compliant. Bioanalytical analyses for these studies were performed with validated methods and systems. Attorney Docket No.38709-0035WO1 Table 54A. Studies Investigating the In Vitro Pharmacology of AMX0035
Figure imgf000155_0001
* Report contains a GLP Compliance Statement; Abbreviations: ALS = amyotrophic lateral sclerosis; AMX0035 = combination of PB and TURSO; ER = endoplasmic reticulum; MPP+ = 1-methyl-4-phenylpyridinium; PB = sodium phenylbutyrate; TH = tyrosine hydroxylase; TURSO = ursodoxicoltaurine; UPR = unfolded protein response Table 54B. Studies Investigating the In Vitro Pharmacology of AMX0035
Figure imgf000155_0002
* Report contains a GLP Compliance Statement; Abbreviations: ALS = amyotrophic lateral sclerosis; AMX0035 = combination of PB and TURSO; ER = endoplasmic reticulum; MPP+ = 1-methyl-4-phenylpyridinium; PB = sodium phenylbutyrate; TH = tyrosine hydroxylase; TURSO = ursodoxicoltaurine; UPR = unfolded protein response Attorney Docket No.38709-0035WO1 Table 54C. Studies Investigating the In Vitro Pharmacology of AMX0035
Figure imgf000156_0001
* Report contains a GLP Compliance Statement; Abbreviations: ALS = amyotrophic lateral sclerosis; AMX0035 = combination of PB and TURSO; ER = endoplasmic reticulum; MPP+ = 1-methyl-4-phenylpyridinium; PB = sodium phenylbutyrate; TH = tyrosine hydroxylase; TURSO = ursodoxicoltaurine; UPR = unfolded protein response Table 55A. Toxicology Studies Investigating of AMX0035
Figure imgf000156_0002
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Figure imgf000157_0001
Table 55C. Toxicology Studies Investigating of AMX0035
Figure imgf000157_0002
Clinical Data: Clinical Pharmacokinetics The PK of AMX0035 in healthy subjects and the target patient population was evaluated after single and repeat doses given orally (or via feeding tube). Based on accumulated data, there appears to be no significant difference in PK be- tween healthy participants and participants living with ALS. PB plasma concentrations for the healthy subjects in A35-002 were substantially lower and profiles more prolonged following administration with a high fat meal com- pared to fasting administration. Food-related changes in the PAA plasma concentration-time data were comparable. The effect of food on the sparsely collected plasma concentrations from the ALS clinical trial, AMX3500, was less consistent than Attorney Docket No.38709-0035WO1 observed in the healthy subject study. The final population PK model estimated a 52.4% (95% confidence interval: 48.5%-56.3%) decrease in relative bioavailability and 60% (95% confidence interval: 56%-64%) decrease in the absorption rate constant when PB is administered under fed versus fasting conditions. The single-dose PK of ursodoxicoltaurine and its metabolites (UDCA, GUDCA) were characterized in Study A35-002 and steady-state plasma concentrations were obtained in Study AMX3500. Ursodoxicoltaurine is slowly absorbed with a median time to peak concentration of 4.5 hours. Ursodoxicoltaurine plasma concentration profiles in many subjects have 2 to 3 peaks, consistent with bile acid storage and release upon a meal/snack. Following oral administration of a single dose of AMX0035 in healthy subjects under fasting conditions (n=13), geometric mean (%CV) AUC0-last and Cmax were 4360 (71.6) ng-h/mL and 741 (71.6) ng/mL, respectively, for ursodoxicoltaurine; 5540 (72.5) ng-h/mL and 639 (73.0) ng/mL respectively for UDCA; and 4140 (70.4) ng- h/ml and 381 (76.5) ng/mL, respectively for GUDCA. Terminal half-life could not be reliably determined in most subjects due to the presence of enterohepatic circulation. A high-fat meal did not significantly affect the Cmax for ursodoxicoltaurine, but AUC was increased by 46%. Comparing across studies, there was little accumulation of ursodoxicoltaurine after twice daily dosing while there was substantial accumulation of UDCA and GUDCA. Human Exposure Table 56 summarizes the AMX0035 clinical program. The completed studies include a Phase 1 clinical study in healthy participants (A35-002), a Phase 2 clinical study in participants living with ALS (AMX3500, with a 24-week randomized phase and additional 24 weeks in an open-label extension [OLE]), and a Phase 2, 24-week, randomized clinical study in participants with Alzheimer’s disease (AMX8000). In addition, there is an ongoing Phase 3 study of AMX0035 for the treatment of ALS which includes participants from Europe and the US (A35-004). Table 56A. Clinical Studies Investigating AMX0035 Attorney Docket No.38709-0035WO1
Figure imgf000159_0001
Abbreviations: AD = Alzheimer’s disease; ALS = amyotrophic lateral sclerosis; ALSAQ-40 = ALS assessment questionnaire of 40-item; ALSFRS-R = Amyotrophic Lateral Sclerosis Functional Rating Scale – Revised; CSR = clinical study report; OLE = open-label extension; PK = pharmacokinetic; QOL = Quality of Life; SVC = Slow Vital Capacity Table 56B. Clinical Studies Investigating AMX0035
Figure imgf000159_0002
Abbreviations: AD = Alzheimer’s disease; ALS = amyotrophic lateral sclerosis; ALSAQ-40 = ALS assessment questionnaire of 40-item; ALSFRS-R = Amyotrophic Lateral Sclerosis Functional Rating Scale – Revised; CSR = clinical study report; OLE = open-label extension; PK = pharmacokinetic; QOL = Quality of Life; SVC = Slow Vital Capacity Attorney Docket No.38709-0035WO1 Overall Risk and Benefit Assessment Therapeutic Context With a median survival of approximately 2 years from diagnosis, ALS is a universally fatal neurodegenerative disease marked by rapid loss of motor function due to degeneration of motor neurons in the CNS. Most affected patients eventually require assistance with activities of daily living, with subsequent progression leading to respiratory compromise, complete paralysis, and respiratory failure, the leading cause of death in ALS. There is currently 1 approved product for treating ALS in Europe: riluzole (Riluek®), which blocks glutamatergic neurotransmission in the CNS. This product has only showed a modest benefit (approximately 3 to 6 months) for survival, but has not shown a slowing in physical decline. Therefore, despite the availability of riluzole, a high unmet medical need remains for patients with ALS who even with this therapy face rapid morbidity and mortality. Benefits Amylyx designed AMX0035, a combination of ursodoxicoltaurine (also known as TURSO) and sodium phenylbutyrate (PB), to simultaneously target the ER stress and mitochondrial dysfunction involved in ALS, thereby reducing or preventing downstream cell death. The administration of AMX0035 orally (or via feeding tube) allows for individuals to take the medicine themselves and avoid additional intravenous or other routes of administration that further impair their quality of life. Analyses of AMX0035’s efficacy over 24 weeks demonstrated clinically meaningful slowing of ALS (function, strength, and breathing) as well as statistically significant benefits in ALSFRS-R (primary efficacy endpoint) compared with placebo (and standard of care). Overall survival, ventilation, and hospitalization were assessed over long-term follow-up and demonstrated significant improvement in patients treated with AMX0035. Furthermore, the benefit of AMX0035 was maintained during a 48- week analysis of ALSFRS-R and additional secondary outcomes. These results demonstrated that earlier and longer-term treatment with AMX0035 maximized the benefits of AMX0035 administration. Importantly, the positive effect of AMX0035 on slowing disease progression and improving survival time was conserved in pre-planned sensitivity analyses that Attorney Docket No.38709-0035WO1 corrected for the effects of concomitant use of ALS standard of care (i.e., riluzole and/or edaravone) in which 77% of patients were taking riluzole and/or edaravone. Although population subgroups were small, no meaningful differences were noted in measures of efficacy based on demographic factors, weight, concomitant illness, or concomitant therapy use. Risks The main side effects noted with AMX0035 administration (compared with placebo) were gastrointestinal (e.g., nausea and diarrhea). After 2 to 3 weeks of AMX0035 administration, the gastrointestinal AEs generally subsided. Two additional imbalances were observed in the Phase 2 randomized phase: AEs of cardiac origin (7 cases with AMX0035 vs. none for placebo) and hypersalivation (9 cases with AMX0035 vs. 1 case with placebo). Both sets of events were reviewed, both in the context of the clinical study as well as within the expected events associated with ALS. Cardiac events, assessed by an independent cardiologist, were considered self- limiting, did not require treatment discontinuation, patients had no differences in ECG findings (vs placebo), and the events had no character of gravity per se. The review concluded that the incidence of cardiac events was low in the context of ALS and three cardiac events were assessed as possibly related to AMX0035 (first degree atrioventricular block, bundle branch block left, and atrial fibrillation). All other cardiac events were considered unlikely or not related to AMX0035. Overall, the risk of neurotoxicity related to AMX0035 therapy appears low based on available evidence and no excess neurotoxicity was identified in the Phase 2 study in ALS (AMX3500). Hypersalivation occurred more frequently in the AMX0035 treatment group, which correlates with the higher frequency of AMX0035-treated patients having bulbar onset ALS and in context of bulbar symptoms typical of ALS progression. None of these events resulted in study drug interruption and were considered as unlikely or not related to study drug. Therefore, it was determined that the imbalance was likely related to the progression of ALS and not AMX0035 treatment. Attorney Docket No.38709-0035WO1 Although population subgroups were small, no meaningful differences in rates of AEs were observed based on demographic factors, weight, concomitant illness, concomitant therapy, or polymorphic metabolism. Overall, there is no evidence that AMX0035 resulted in an increase in clinically significant safety events or increased safety risk in this patient population during the randomized phase of the study. Benefit-Risk Assessment In summary: • More effective therapies are needed for the treatment of ALS. AMX0035 offers a new treatment in the very limited armamentarium currently available to patients with ALS and their physicians • The totality of data demonstrates that AMX0035 has a favorable risk benefit profile which supports an NDA submission for a potential therapy for this debilitating and life-threatening disease. • In addition to statistically significant data on loss of function (ALSFRS- R), the results of long-term monitoring demonstrate a compelling, statistically significant, and clinically meaningful benefit on survival and key study events including hospitalizations and tracheostomies. AMX0035 is the first therapeutic to show a benefit on both survival and function in ALS. In the context of a rare, rapidly progressing and life-threatening disease with high unmet medical need, it is believed that the efficacy and safety demonstrated in clinical studies, along with numerous clinical studies of the individual components of AMX0035 (i.e., PB and TURSO) demonstrating an acceptable safety profile at doses multiple times that which is used in AMX0035, allows for a very positive benefit:risk profile for AMX0035 in ALS. Example 15. Assay of AMX-0035 for Taurine and Ursodeoxycholic Acid This example summarizes the assay results for seven lots of AMX-0035. The data and assays presented herein were obtained in compliance with the cGMP, as defined in 21 CFR 210, 211, and 820. Samples were assayed by the SOPs listed in Table 57. Abbreviations/ Acronyms Attorney Docket No.38709-0035WO1 LOD Limit of Detection LOQ Limit of Quantitation RH Relative Humidity UDCA Ursodeoxycholic Acid ULOQ Upper Limit of Quantitation Abbreviations not listed follow guidelines specified in The ACS Style Guide, 3rd Edition, 2006. Table 57. Methods and Instrumental Limits Table 58. Sample received for analysis Table 59. Sample Results for Taurine
Attorney Docket No.38709-0035WO1 Table 60. Sample Results for UDCA

Claims

Attorney Docket No.38709-0035WO1 WHAT IS CLAIMED IS: 1. A composition comprising about 8% to about 12% w/w of taurursodiol (TURSO); about 27% to about 32% w/w of sodium phenylbutyrate; wherein the composition comprises not more than (i) 0.2% of an impurity having a relative retention time (RRT) of about 0.18; (ii) 0.4% of an impurity having a RRT of about 0.31; and (iii) 0.4% of an impurity having a RRT of about 0.37; and wherein each RRT is determined relative to sodium phenylbutyrate. 2. The composition of Claim 1, comprising not more than 0.1% of an impurity having a relative retention time (RRT) of about 0.18. 3. The composition of Claim 1 or 2, comprising not more than 0.2% of an impurity having a RRT of about 0.31. 4. The composition of any one of Claims 1-3, comprising not more than 0.1% of an impurity having a RRT of about 0.37. 5. The composition of any one of Claims 1-4, wherein the composition further comprises not more than 0.1% of an impurity having a RRT of about 0.62. 6. The composition of any one of Claims 1-5, wherein the composition further comprises not more than 0.1% of an impurity having a RRT of about 0.64. 7. The composition of any one of Claims 1-6, wherein the composition further comprises not more than 0.1% of an impurity having a RRT of about 0.67. 8. The composition of any one of Claims 1-7, wherein the composition further comprises not more than 0.1% of an impurity having a RRT of about 0.68. 9. The composition of any one of Claims 1-8, wherein the composition further comprises not more than 0.1% of an impurity having a RRT of about 0.70. 10. The composition of any one of Claims 1-9, wherein the composition further comprises not more than 0.1% of an impurity having a RRT of about 0.71. 11. The composition of any one of Claims 1-10, wherein the composition further comprises not more than 0.1% of an impurity having a RRT of about 0.73. 12. The composition of any one of Claims 1-11, wherein the composition further comprises not more than 0.1% of an impurity having a RRT of about 0.74. 13. The composition of any one of Claims 1-12, wherein the composition further comprises not more than 0.1% of an impurity having a RRT of about 0.76. 14. The composition of any one of Claims 1-13, wherein the composition further comprises not more than 0.1% of an impurity having a RRT of about 0.79. Attorney Docket No.38709-0035WO1 15. The composition of any one of Claims 1-14, wherein the composition further comprises not more than 0.1% of an impurity having a RRT of about 0.80. 16. The composition of any one of Claims 1-15, wherein the composition further comprises not more than 0.1% of an impurity having a RRT of about 0.85. 17. The composition of any one of Claims 1-16, wherein the composition further comprises not more than 0.1% of an impurity having a RRT of about 0.86. 18. The composition of any one of Claims 1-17, wherein the composition further comprises not more than 0.1% of an impurity having a RRT of about 0.90. 19. The composition of any one of Claims 1-18, wherein the composition further comprises not more than 0.1% of an impurity having a RRT of about 0.92. 20. The composition of any one of Claims 1-19, wherein the composition further comprises not more than 0.1% of an impurity having a RRT of about 0.96. 21. The composition of any one of Claims 1-20, wherein the composition further comprises not more than 0.1% of an impurity having a RRT of about 0.98. 22. The composition of any one of Claims 1-21, wherein the composition further comprises not more than 0.1% of an impurity having a RRT of about 0.17. 23. The composition of any one of Claims 1-22, wherein the composition further comprises not more than 0.1% of an impurity having a RRT of about 0.22. 24. The composition of any one of Claims 1-23, wherein the composition further comprises not more than 0.1% of an impurity having a RRT of about 0.25. 25. The composition of any one of Claims 1-24, wherein the composition further comprises not more than 0.1% of an impurity having a RRT of about 0.27. 26. The composition of any one of Claims 1-25, wherein the composition further comprises not more than 0.1% of an impurity having a RRT of about 0.30. 27. The composition of any one of Claims 1-26, wherein the composition further comprises not more than 0.1% of an impurity having a RRT of about 0.34. 28. The composition of any one of Claims 1-27, wherein the composition further comprises not more than 0.1% of an impurity having a RRT of about 0.39. 29. The composition of any one of Claims 1-28, wherein the composition further comprises not more than 0.1% of an impurity having a RRT of about 0.43. 30. The composition of any one of Claims 1-29, wherein the composition further comprises not more than 0.1% of an impurity having a RRT of about 0.60. Attorney Docket No.38709-0035WO1 31. The composition of any one of Claims 1-30, wherein the composition further comprises not more than 0.1% of an impurity having a RRT of about 0.66. 32. The composition of any one of Claims 1-31, wherein the composition further comprises not more than 0.1% of an impurity having a RRT of about 0.83. 33. The composition of any one of Claims 1-32, wherein the composition further comprises not more than 0.1% of an impurity having a RRT of about 0.91. 34. The composition of any one of Claims 1-33, wherein the composition further comprises about 0% to about 0.125% w/w Ursodeoxycholic acid (UDCA). 35. The composition of any one of Claims 1-34, wherein the composition further comprises about 0% to about 0.08% w/w UDCA. 36. The composition of any one of Claims 1-35, wherein the composition comprises about 9.7% of TURSO. 37. The composition of any one of Claims 1-36, wherein the composition comprises about 29.2% of sodium phenylbutyrate. 38. The composition of any one of Claims 1-37, wherein the composition comprises: about 14% to about 17% w/w of dextrates; about 3.5% to about 4.5% w/w of sorbitol; about 25% to about 32% w/w of maltodextrin; and about 0.05% to about 1.5% w/w of porous silica. 39. The composition of any one of Claims 1-37, wherein the composition comprises: about 0.5% to about 5% w/w of sucralose; about 2% to about 15% w/w of flavorants; about 0.5% to about 5% w/w of a buffering agent; and about 0.05% to about 1% w/w of a lubricant. 40. The composition of any one of Claims 1-37, wherein the composition comprises: about 15.6% w/w of dextrates; about 3.9% w/w of sorbitol; about 1.9% w/w of sucralose; about 28.3% w/w of maltodextrin; about 7.3% w/w of flavorants; Attorney Docket No.38709-0035WO1 about 0.9% w/w of porous silica; about 2.7% w/w of sodium phosphate; and about 0.5% w/w of sodium stearyl fumarate. 41. The composition of any one of Claims 1-40, wherein the amount of each impurity is determined after 1 month of storage at about 25°C and about 60% relative humidity. 42. The composition of any one of Claims 1-40, wherein the amount of each impurity is determined after 3 months of storage at about 25°C and about 60% relative humidity. 43. The composition of any one of Claims 1-40, wherein the amount of each impurity is determined after 6 months of storage at about 25°C and about 60% relative humidity. 44. The composition of any one of Claims 1-40, wherein the amount of each impurity is determined after 9 months of storage at about 25°C and about 60% relative humidity. 45. The composition of any one of Claims 1-40, wherein the amount of each impurity is determined after 12 months of storage at about 25°C and about 60% relative humidity. 46. The composition of any one of Claims 1-40, wherein the amount of each impurity is determined after 15 months of storage at about 25°C and about 60% relative humidity. 47. The composition of any one of Claims 1-40, wherein the amount of each impurity is determined after 18 months of storage at about 25°C and about 60% relative humidity. 48. The composition of any one of Claims 1-40, wherein the amount of each impurity is determined after 24 months of storage at about 25°C and about 60% relative humidity. 49. The composition of any one of Claims 1-40, wherein the amount of each impurity is determined after 36 months of storage at about 25°C and about 60% relative humidity. 50. The composition of any one of Claims 1-49, wherein the composition is formulated as a unit dosage form. Attorney Docket No.38709-0035WO1 51. The composition of any one of Claims 1-50, wherein the unit dosage form is a sachet. 52. The composition of Claim 50 or 51, wherein the unit dosage form has substantially the same weight as the initial weight of the unit dosage form after about 1 month of storage at about 25°C and about 60% relative humidity. 53. The composition of Claim 50 or 51, wherein the unit dosage form has substantially the same weight as the initial weight of the unit dosage form after about 3 months of storage at about 25°C and about 60% relative humidity. 54. The composition of Claim 50 or 51, wherein the unit dosage form has substantially the same weight as the initial weight of the unit dosage form after about 6 months of storage at about 25°C and about 60% relative humidity. 55. The composition of Claim 50 or 51, wherein the unit dosage form has substantially the same weight as the initial weight of the unit dosage form after about 9 months of storage at about 25°C and about 60% relative humidity. 56. The composition of Claim 50 or 51, wherein the unit dosage form has substantially the same weight as the initial weight of the unit dosage form after about 12 months of storage at about 25°C and about 60% relative humidity. 57. The composition of Claim 50 or 51, wherein the unit dosage form has substantially the same weight as the initial weight of the unit dosage form after about 15 months of storage at about 25°C and about 60% relative humidity. 58. The composition of Claim 50 or 51, wherein the unit dosage form has substantially the same weight as the initial weight of the unit dosage form after about 18 months of storage at about 25°C and about 60% relative humidity. 59. The composition of Claim 50 or 51, wherein the unit dosage form has substantially the same weight as the initial weight of the unit dosage form after about 24 months of storage at about 25°C and about 60% relative humidity. 60. The composition of Claim 50 or 51, wherein the unit dosage form has substantially the same weight as the initial weight of the unit dosage form after about 36 months of storage at about 25°C and about 60% relative humidity. 61. The composition of any one of Claims 1-60, wherein the composition comprises not more than 1.2% (w/w) total degradation products characterized at 260 nm. Attorney Docket No.38709-0035WO1 62. The composition of any one of Claims 1-60, wherein the composition comprises not more than 0.1% total degradation products characterized at 260 nm after about 1 month of storage at about 25°C and about 60% relative humidity. 63. The composition of any one of Claims 1-60, wherein the composition comprises not more than 0.1% total degradation products characterized at 260 nm after about 3 months of storage at about 25°C and about 60% relative humidity. 64. The composition of any one of Claims 1-60, wherein the composition comprises not more than 0.2% total degradation products characterized at 260 nm after about 6 months of storage at about 25°C and about 60% relative humidity. 65. The composition of any one of Claims 1-60, wherein the composition comprises not more than 0.3% total degradation products characterized at 260 nm after about 9 months of storage at about 25°C and about 60% relative humidity. 66. The composition of any one of Claims 1-60, wherein the composition comprises not more than 0.3% total degradation products characterized at 260 nm after about 12 months of storage at about 25°C and about 60% relative humidity. 67. The composition of any one of Claims 1-60, wherein the composition comprises not more than 0.3% total degradation products characterized at 260 nm after about 15 months of storage at about 25°C and about 60% relative humidity. 68. The composition of any one of Claims 1-60, wherein the composition comprises not more than 0.4% total degradation products characterized at 260 nm after about 18 months of storage at about 25°C and about 60% relative humidity. 69. The composition of any one of Claims 1-60, wherein the composition comprises not more than 0.5% total degradation products characterized at 260 nm after about 24 months of storage at about 25°C and about 60% relative humidity. 70. The composition of any one of Claims 1-60, wherein the composition comprises not more than 0.5% total degradation products characterized at 260 nm after about 36 months of storage at about 25°C and about 60% relative humidity. 71. The composition of any one of Claims 1-70, wherein the composition comprises not more than 3.4% total degradation products characterized at 203 nm. 72. The composition of any one of Claims 1-71, wherein the composition comprises not more than 1.2% total degradation products characterized at 203 nm. 73. The composition of any one of Claims 1-72, wherein each RRT is determined relative to sodium phenylbutyrate using HPLC method in Example 1. Attorney Docket No.38709-0035WO1 74. A method of detecting one or more impurities in a composition comprising about 8% to about 12% w/w of taurursodiol (TURSO); about 27% to about 32% w/w of sodium phenylbutyrate; and one or more impurities, the method comprising: (a) dissolving the composition in a solvent comprising about 5% (v/v) acetonitrile in deionized water to form a mixture; (b) contacting a stationary phase of a C-18 reverse phase chromatography column with the mixture; (c) eluting the mixture with a mobile phase to separate out one or more of the one or more impurities, wherein the mobile phase comprises about 5% to about 95% of 0.5% (v/v) aqueous phosphoric acid and about 5% to about 95% of acetonitrile; and (d) optionally quantifying the amount of the one or more impurities in the composition. 75. The method of Claim 73, further comprising filtering a mixture of step (a) through a polytetrafluoroethylene filter of about 0.1 mm to about 0.5 mm pore size prior to contacting a stationary phase of step (b). 76. The method of any one of Claims 73-74, further comprising injection of about 0.1 mL to about 250 mL of a mixture of step (a) to a reverse phase chromatography column of step (b). 77. The method of any one of Claims 73-75, wherein a mobile phase of step (c) is comprised of a gradient that starts at about 95% of 0.5% (v/v) aqueous phosphoric acid and about 5% of acetonitrile and over the course of 2-30 minutes changes to about 5% of 0.5% (v/v) aqueous phosphoric acid and about 95% of acetonitrile. 78. The method of any one of Claims 73-76, wherein the mobile phase is comprised of a gradient that starts at about 95% of 0.5% (v/v) aqueous phosphoric acid and about 5% of acetonitrile and over the course of 15-25 minutes changes to about 5% of 0.5% (v/v) aqueous phosphoric acid and about 95% of acetonitrile. 79. The method of any one of Claims 73-77, wherein the flow rate of a mobile phase of step (c) is about 50 µL/minute to about 2 mL/minute. 80. The method of any one of Claims 73-78, further comprising keeping the temperature of a reverse phase chromatography column of step (b) to about 25 °C to about 80 °C. Attorney Docket No.38709-0035WO1 81. The method of any one of Claims 73-79, further comprising detecting one or more impurities by collecting UV spectral data from about 200 nM to about 400 nM. 82. The method of any one of Claims 73-80, further comprising detecting TURSO by monitoring ultraviolet absorbance at 203 nm (± 1 nM). 83. The method of any one of Claims 73-81, further comprising detecting sodium phenylbutyrate by monitoring ultraviolet absorbance at 260 nm (± 1 nM). 84. The method of any one of Claims 73-82, wherein detecting one or more impurities by collecting UV spectral data, wherein the UV spectral data is collected at 203 nM (± 1 nM) or 260 nM (± 1 nM).
PCT/US2024/045366 2023-09-08 2024-09-05 Formulation containing taurursodiol and sodium phenylbutyrate Pending WO2025054311A1 (en)

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Citations (4)

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WO2023133463A1 (en) * 2022-01-06 2023-07-13 Cyrano Therapeutics, Inc. Improved nasal administration of parkinson's therapeutics
WO2023168280A1 (en) * 2022-03-02 2023-09-07 Amylyx Pharmaceuticals, Inc. A bile acid and a phenylbutyrate with cyp p450 or transporter substrates for treating amyotrophic lateral sclerosis
WO2023224995A1 (en) * 2022-05-17 2023-11-23 Amylyx Pharmaceuticals, Inc. Combination of taurursodiol and sodium phenylbutyrate for treating amyotrophic lateral sclerosis

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US20230210869A1 (en) * 2019-12-16 2023-07-06 Amylyx Pharmaceuticals, Inc. Compositions of bile acids and phenylbutyrate compounds
WO2023133463A1 (en) * 2022-01-06 2023-07-13 Cyrano Therapeutics, Inc. Improved nasal administration of parkinson's therapeutics
WO2023168280A1 (en) * 2022-03-02 2023-09-07 Amylyx Pharmaceuticals, Inc. A bile acid and a phenylbutyrate with cyp p450 or transporter substrates for treating amyotrophic lateral sclerosis
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