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WO2025019827A1 - Formulation, forme posologique solide et méthodes - Google Patents

Formulation, forme posologique solide et méthodes Download PDF

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Publication number
WO2025019827A1
WO2025019827A1 PCT/US2024/038866 US2024038866W WO2025019827A1 WO 2025019827 A1 WO2025019827 A1 WO 2025019827A1 US 2024038866 W US2024038866 W US 2024038866W WO 2025019827 A1 WO2025019827 A1 WO 2025019827A1
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WO
WIPO (PCT)
Prior art keywords
granule formulation
dosage form
disease
pharmaceutical composition
compound
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/US2024/038866
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English (en)
Inventor
Isaac V. COHEN
Shyeilla V. Dhuria
Melania H. FANOK
Christopher R. H. HALE
Abdul Khader MOHAMMAD
Yingqing RAN
Anantha Sudhakar
Harvey Wong
Ernie YULYANINGSIH
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Denali Therapeutics Inc
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Denali Therapeutics Inc
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Filing date
Publication date
Application filed by Denali Therapeutics Inc filed Critical Denali Therapeutics Inc
Publication of WO2025019827A1 publication Critical patent/WO2025019827A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4245—Oxadiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/10—1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles

Definitions

  • Neurodegenerative diseases such as Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), Alzheimer’s disease (AD), and Frontotemporal dementia (FTD) have a negative effect on the lives of millions of people.
  • Impairment of eukaryotic initiation factor 2B (eIF2B) activity is correlated to activation of the ISR pathway that is implicated in a variety neurodegenerative diseases including Parkinson’s disease, amyotrophic lateral sclerosis (ALS), Alzheimer’s disease, vanishing white matter (VWM) disease, and frontotemporal dementia.
  • ALS the most common form of motor neuron disease, is a progressive, ultimately fatal neurodegenerative disease, marked by a gradual degeneration of nerve cells of the central nervous system that control voluntary muscle movement.
  • Degeneration of motor neurons is characterized by muscle weakness, typically impacting arms and legs, speech, swallowing (dysphagia), and breathing.
  • dysphagia affects the lives of patients suffering from other diseases or conditions which may be treatable with a eIF2B modulator, such as cancer (e.g., cancer of the head and neck) or stroke.
  • a eIF2B modulator such as cancer (e.g., cancer of the head and neck) or stroke.
  • drug delivery to patients suffering from dysphagia can be problematic as oral delivery is often preferred for chronic treatment regimens.
  • the present disclosure provides a method for treating amyotrophic lateral sclerosis (ALS), comprising administering to a patient in need thereof, a pharmaceutical composition comprising Compound I: and pharmaceutically acceptable excipient, wherein the subject is administered a dose of about 100- 200 mg of the Compound I once per day.
  • ALS amyotrophic lateral sclerosis
  • the dose is about 200 mg. In some embodiments, the daily dose is 200 mg. [0006] In other embodiments, the dose is about 100 mg. In some embodiments, the daily dose is 100 mg.
  • the pharmaceutical composition comprises a granule formulation.
  • Compound I is a modulator of eukaryotic initiation factor 2B.
  • the synthesis and method of use thereof is described in PCT International Application Publication No. WO 2019/032743, which is herein incorporated by reference in its entirety.
  • reference to Compound I (CAS Registry number 2278265-85-1) is intended to encompass the compound per se, or a salt, such as a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, prodrug, solid form, cocrystal, solvate, and/or hydrate thereof.
  • a pharmaceutical composition or a unit dosage form comprising about 200 mg of Compound I and a pharmaceutically acceptable excipient.
  • the is provided a granule formulation comprising a eukaryotic initiation factor 2B (eIF2B) modulator, and its use as therapeutic agent, for example, in treating diseases mediated thereby such as Alzheimer's, Parkinson’s, amyotrophic lateral sclerosis (ALS), frontotemporal dementia, and cancer.
  • eIF2B eukaryotic initiation factor 2B
  • a granule formulation comprising a modulator of eukaryotic initiation factor 2B (Compound I, or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers, prodrug, or solid form thereof), that is useful in treating and/or preventing diseases mediated, at least in part, by eukaryotic initiation factor 2B, such as neurodegenerative diseases (e.g., neurodegeneration in prion disease) and cancer, as well as solid dosage forms and liquid suspensions comprising the same.
  • a solid dosage form comprising the granule formulation described herein.
  • a liquid suspension comprising the granule formulation.
  • the granule formulation, solid dosage forms, or liquid suspension as described herein is used for treating a patient suffering from dysphagia.
  • Dysphagia can occur due to many different disease processes or conditions that include, but are not limited to congenital disorders such as cleft lip and palate, cancer of the head, neck, certain esophageal structures, stroke, Parkinson’ s Disease (PD), Multiple Sclerosis (MS), amyotrophic lateral sclerosis (ALS).
  • PD congenital disorders
  • MS Multiple Sclerosis
  • ALS amyotrophic lateral sclerosis
  • the granule formulation, solid dosage forms, or liquid suspension as described herein is used for the treatment of amyotrophic lateral sclerosis (ALS).
  • ALS amyotrophic lateral sclerosis
  • a method for treating a disease or condition mediated, at least in part, by regulation of eukaryotic initiation factor 2B comprising administering an effective amount of the granule formulation, solid dosage forms, or liquid suspension as described herein, to a subject in need thereof.
  • the granular formulation is administered once per day during a treatment regimen of 14 to 28 days.
  • a diluent includes reference to one or more diluents, and equivalents thereof known to those skilled in the art.
  • Reference to “about” a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se.
  • the term “about” includes the indicated amount ⁇ 10%.
  • the term “about” includes the indicated amount ⁇ 5%.
  • the term “about” includes the indicated amount ⁇ 2.5%.
  • the term “about” includes the indicated amount + 1%, ⁇ 0.5%, or ⁇ 0.05%.
  • to the term “about X” includes description of “X”.
  • the phrase “one or more” refers to one to five, or one to three, or one or two.
  • the term “optional” or “optionally” means that the subsequently described event or circumstance may or may not occur, and thus the description includes instances where said event or circumstance occurs and instances where said event or circumstance does not.
  • Reference to Compound I is also intended to represent unlabeled forms as well as isotopically labeled forms of Compound I. It is understood that for any given atom, the isotopes may be present essentially in ratios according to their natural occurrence, or one or more particular atoms may be enhanced with respect to one or more isotopes using synthetic methods known to one skilled in the art.
  • hydrogen includes for example *H, 2 H, 3 H
  • carbon includes for example H C, 12 C, 13 C, 14 C
  • oxygen includes for example 16 O, 17 O, 18 O
  • nitrogen includes for example 13 N, 14 N, 15 N
  • sulfur includes for example 32 S, 33 S, 34 S, 33 S, 36 S, 37 S, 38 S
  • fluoro includes for example 17 F, 18 F, 19 F
  • chloro includes for example 3 ’C1, 36 C1, 37 C1, 38 C1, 39 C1; and the like.
  • granule refers to solid, dry aggregates of powder particles formed by a granulation process.
  • Granulation processes include wet granulation where liquids such as water, alcohols, or combinations thereof are mixed with the dry particles.
  • the terms “treat,” “treating,” “therapy,” “therapies,” and like terms refer to the administration of material, e.g., any one or more solid, crystalline or polymorphs of Compound I as described herein in an amount effective to prevent, alleviate, or ameliorate one or more symptoms of a disease or condition, i.e., indication, and/or to prolong the survival of the subject being treated.
  • the term “therapeutically effective” or “effective amount” indicates that the materials or amount of material is effective to prevent, alleviate, or ameliorate one or more symptoms of a disease or medical condition, and/or to prolong the survival of the subject being treated.
  • the therapeutically effective amount will vary depending on the compound, the disorder or condition and its severity and the age, weight, etc., of the mammal to be treated.
  • an effective amount is an amount sufficient to effectuate a beneficial or desired clinical result.
  • the effective amounts can be provided all at once in a single administration or in fractional amounts that provide the effective amount in several administrations.
  • prevention or “preventing” means any treatment of a disease or condition that causes the clinical symptoms of the disease or condition not to develop.
  • Compounds may, in some embodiments, be administered to a subject (including a human) who is at risk or has a family history of the disease or condition.
  • Subject refers to an animal, such as a mammal (including a human), that has been or will be the object of treatment, observation or experiment. The methods described herein may be useful in human therapy, and/or veterinary applications. In some embodiments, the subject is a mammal. In certain embodiments, the subject is a human.
  • composition refers to a pharmaceutical preparation suitable for administration to an intended subject for therapeutic purposes that contains at least one pharmaceutically active compound, including any solid form thereof.
  • the composition may include at least one pharmaceutically acceptable component (e.g., Compound I) to provide an improved formulation of the compound, such as a suitable diluent.
  • diluent refers to a chemical compound that is used to dilute the compound of interest prior to delivery. Diluents can also serve to stabilize compounds. Non-limiting examples of diluents include starch, saccharides, disaccharides, sucrose, lactose, polysaccharides, cellulose, cellulose ethers, hydroxypropyl cellulose, sugar alcohols, xylitol, sorbitol, maltitol, microcrystalline cellulose, calcium or sodium carbonate, lactose, lactose monohydrate, dicalcium phosphate, cellulose, compressible sugars, dibasic calcium phosphate dehydrate, mannitol, microcrystalline cellulose, and tribasic calcium phosphate.
  • Suitable diluents to include in the formulation of the disclosure are cellulose and its derivatives, lactose and other suitable sugar derivatives, such as mannitol, sorbitol or calcium phosphates.
  • thickening agent refers to an agent used to increase the viscosity or thicken liquid formulations.
  • a thickening agent can be utilized to improve product properties, including drug delivery, stabilization, demulcent effects, and texturizing, and also can often can make swallowing slightly easier for patients suffering from dysphagia.
  • the range of materials that serve this function is very broad, but typically includes hydrocolloid gums, synthetic polymers, sugars, polyol syrups, and many other miscellaneous materials.
  • Non-limiting examples of thickening agents include polyols, sugars or oligosaccharides (e.g., liquid sorbitol, liquid maltitol, sucrose, fructose, dextrose, maltodextrin, polydextrose), carbomers, silicones, clays (aluminum silicates), glycerine, fatty acids, hard fats, vinyl polymers (e.g., water soluble polyvinylpyrrolidones, ethylene-vinyl acetates, polyvinyl alcohol, etc.), and hydrocolloid gums (e.g., plant-derived hydrocolloids, such as pectin, agar, alginates, acacia, tragacanth, Karaya gum, guar gum, starches, cellulose, locust bean, etc., products of fermentation, such as xanthan gum, dextran, gellan gum, pullulan, etc., semi-synthetic hydrocolloids, such
  • suspending agent also known as hydrophilic colloids, refers to an agent which forms a colloidal dispersion with water and increases the viscosity of the continuous phase. Suspending agents typically form a film around a particle and decrease interparticle attraction. Most suspending agents perform two functions (i.e. besides acting as a suspending agent, they may also impart viscosity to the solution).
  • Non-limiting examples of suspending agents include natural (e.g., gelatin, starch, tragacanth, kaolin, acacia, bantonite, etc.), semi-synthetic (e.g., HEC, sodium carboxymethylcellulose (Na-CMC), microcrystalline cellulose (MC), composites of sodium carboxymethylcellulose (Na-CMC) and microcrystalline cellulose (MC), etc.), and synthetic agents (PVP, polyvinyl alcohol, carbopol, etc.).
  • natural e.g., gelatin, starch, tragacanth, kaolin, acacia, bantonite, etc.
  • semi-synthetic e.g., HEC, sodium carboxymethylcellulose (Na-CMC), microcrystalline cellulose (MC), composites of sodium carboxymethylcellulose (Na-CMC) and microcrystalline cellulose (MC), etc.
  • synthetic agents e.g., polyvinyl alcohol, carbopol, etc.
  • surfactant refers to a substance which per se can lower the surface tension (or interfacial tension) between two liquids or between a liquid and a solid.
  • surfactant used herein refers to a substance capable of acting as a wetting agent, an emulsifier, a detergent, or a dispersant, or a substance capable of acting as wetting agent.
  • Suitable surfactants include, e.g., sodium lauryl sulfate, a poloxamer, and the like.
  • anti-foaming agent refers to a chemical additive that reduces or hinders the formation of foam upon aeration as a result of agitation in a pharmaceutical process or upon shaking or mixing with a liquid (e.g., water or other beverage).
  • a liquid e.g., water or other beverage.
  • anti-foaming agents include insoluble oils, polydimethylsiloxanes and other silicones, certain alcohols, stearates, glycols, or a pharmaceutical agent which prevents bubble formation and gas retention to alleviate bloating (e.g., simethicone).
  • sweetener refers to a chemical additive that is added to either mask an unpleasant taste or enhance the perception of sweet taste in some oral pharmaceutical preparations.
  • Suitable sweeteners are known in the art and include aspartame, acesulfame potassium, alitame, sucralose, sucrose, saccharose, erythritol, mannitol, fructose, sorbitol, xylitol, maltitol, saccharin, and the like.
  • the term sweetener may also include a flavoring agent, such as citric acid, orange flavor, lemon flavor, vanilla flavor, and the like.
  • pharmaceutically acceptable indicates that the indicated material docs not have properties that would cause a reasonably prudent medical practitioner to avoid administration of the material to a patient, taking into consideration the disease or conditions to be treated and the respective route of administration. For example, it is commonly required that such a material be essentially sterile, e.g., for injectables.
  • % w/w refers to the weight of a component based on the total weight of a composition comprising the component. For example, if component A is present in an amount of 50% w/w in a 100 mg composition, component A is present in an amount of 50 mg.
  • compositions, or unit dosage form, or granule formulation comprising 2-(4-chlorophenoxy)-A-[3-[5-[cA-3-(trilluoromethoxy)cyclobutylJ-l,3,4-oxadiazol-2-ylJ- l-bicyclo[l.l.l]pentanyl] acetamide, designated herein as Compound I, having the following formula:
  • Compound I and a surfactant, and a diluent.
  • composition, unit dosage form, or granule formulation further comprises one or more additives, such as a thickening agent, a suspending agent, an anti-foaming agent, and/or a sweetener.
  • additives such as a thickening agent, a suspending agent, an anti-foaming agent, and/or a sweetener.
  • Compound I is present in an amount from about 10 %w/w to about 50 %w/w, from about 10 %w/w to about 40 from about 40 %w/w to about 50 %w/w, or from about 10 %w/w to about 20 %w/w.
  • Compound I is present in an amount from about 10 %w/w to about 20 %w/w, or about 10 ⁇ cvil-w, or about 13 %w/w to about 17 %w/w, or about 14 %w/w to about 15 %w/w, about 11 %w/w, about 12 %w/w, about 13 %w/w, about 14 %w/w, about 15 %w/w, about 16 %w/w, about 17 %w/w, about 18 %w/w, about 19 %w/w, or about 20 %w/w. In certain embodiments, Compound I is present at an amount of about 14.14 %w/w.
  • the diluent is present in an amount from about 50 %w/w to about 60 %w/w, or about 53 %w/w to about 57 %w/w, or about 54 %w/w to about 56 %w/w, or about 50 %w/w, about 51 %w/w, about 52 %w/w, about 53 %w/w, about 54 %w/w, about 55 %w/w, about 56 %w/w, about 57 %w/w, about 58 %w/w, about 59 %w/w, or about 60 %w/w. In certain embodiments, the diluent is present at an amount of about 55.0 %w/w.
  • the diluent comprises starch, a saccharide, disaccharide, sucrose, lactose, polysaccharide, cellulose, cellulose ether, hydroxypropyl cellulose, sugar alcohol, xylitol, sorbitol, maltitol, microcrystalline cellulose, calcium carbonate, sodium carbonate, lactose, lactose monohydrate, dicalcium phosphate, cellulose, compressible sugars, dibasic calcium phosphate dehydrate, mannitol, microcrystalline cellulose, or tribasic calcium phosphate.
  • the diluent comprises mannitol.
  • the surfactant present in an amount from about 0.1 %w/w to about 0.5 or about 0.25 %w/w to about 0.45 % w/w, or about 0.1 %w/w, about 0.2 %w/w, about 0.3 %w/w, about 0.4 %w/w, about 0.5 %w/w. In certain embodiments, the surfactant is present at an amount of about 0.35 %w/w.
  • the surfactant is sodium lauryl sulfate, a poloxamer, or the like. In certain embodiments, the surfactant is sodium lauryl sulfate.
  • the granule formulation comprises a thickening agent.
  • the granule formulation comprises a thickening agent present in an amount from about 10 %w/w to about 20 %w/w, or about 13 %w/w to about 17 or about 14 %w/w to about 15 %w/w, or about 10 %w/w, about 11 %w/w, about 12 %w/w, about 13 %w/w, about 14 %w/w, about 15 %w/w, about 16 %w/w, about 17 %w/w, about 18 %w/w, about 19 %'NIVI, or about 20 %w/w.
  • the thickening agent is present at an amount of about 15.2 %w/w.
  • the thickening agent comprises a polyol, sugar, or oligosaccharide (e.g., liquid sorbitol, liquid maltitol, sucrose, fructose, dextrose, maltodextrin, poly dextrose), carbomer, silicone, clay (aluminum silicates), glycerine, fatty acid, hard fat, vinyl polymer (e.g., water soluble polyvinylpyrrolidone, ethylene-vinyl acetate, polyvinyl alcohol, etc.), or a hydrocolloid gums (e.g., plant-derived hydrocolloids, such as pectin, agar, Alginates, acacia, tragacanth, Karaya gum, guar gum, starches, cellulose, locust bean, etc., products of fermentation, such as xanthan gum, dextran, gellan gum, pullulan, etc., semi-synthetic hydrocolloid
  • the pharmaceutical composition, unit dosage form, or granule formulation comprises a suspending agent.
  • the pharmaceutical composition, unit dosage form, or granule formulation comprises a suspending agent present in an amount from about 10 %w/w to about 20 %w/w, or about 13 %w/w to about 17 %w/w, or about 14 % il i to about 15 ⁇ cvil-w, or about 10 %w/w, about 11 %w/w, about 12 %w/w, about 13 %w/w, about 14 %w/w, about 15 %w/w, about 16 %w/w, about 17 %w/w, about 18 %w/w, about 19 %w/w, or about 20 %w/w.
  • the suspending agent is present at an amount of about 14.14 %w/w.
  • the suspending agent is natural (e.g., gelatin, starch, tragacanth, kaolin, acacia, bantonite, etc.), semi-synthetic (e.g., HEC, sodium carboxymethylcellulose (Na-CMC), microcrystalline cellulose (MC), composites of sodium carboxymethylcellulose (Na-CMC) and microcrystalline cellulose (MC), etc.), or synthetic (PVP, polyvinyl alcohol, carbopol, etc.).
  • natural e.g., gelatin, starch, tragacanth, kaolin, acacia, bantonite, etc.
  • semi-synthetic e.g., HEC, sodium carboxymethylcellulose (Na-CMC), microcrystalline cellulose (MC), composites of sodium carboxymethylcellulose (Na-CMC) and microcrystalline cellulose (MC), etc.
  • PVP polyvinyl alcohol, carbopol, etc.
  • the suspending agent is microcrystalline cellulose (MCC), sodium carboxymethylcellulose (Na-CMC), or a microcrystalline cellulose (MCC) and sodium carboxymethylcellulose (Na-CMC) composite.
  • the suspending agent is a microcrystalline cellulose (MCC) and sodium carboxymethylcellulose (Na-CMC) composite.
  • the pharmaceutical composition, unit dosage form, or granule formulation comprises an anti-foaming agent.
  • the pharmaceutical composition, unit dosage form, or granule formulation comprises an anti-foaming agent present in an amount from about 0.5 %w/w to about 1.5 %w/w, or about 0.8 %w/w to about 1.2 %w/w, or about 0.5 %w/w, about 0.6 %w/w, about 0.7 %w/w, about 0.8 %w/w, about 0.9 %w/w, about 1 %w/w, about 1.1 %w/w, about 1.2 %w/w, about 1.3 %w/w, about 1.4 %w/w, or about 1.5 %w/w.
  • the anti-foaming agent is present at an amount of about 1.06 %w/w.
  • the anti-foaming agent comprises an insoluble oil, polydimethylsiloxane or other silicone, certain alcohols, stearate, glycol, or a pharmaceutical agent which prevents bubble formation and gas retention to alleviate bloating (e.g., simethicone).
  • the anti-foaming agent comprises simethicone.
  • the antifoaming agent comprises simethicone as an emulsion.
  • the anti-foaming agent comprises simethicone as an emulsion which contains about 30% simethicone.
  • the pharmaceutical composition, unit dosage form, or granule formulation comprises a sweetener.
  • the pharmaceutical composition, unit dosage form, or granule formulation comprises a sweetener present in an amount from about 0.05 %w/w to about 0.1 %w/w, or about 0.05 %w/w, about 0.06 %w/w, about 0.07 %w/w, about 0.08 %w/w, about 0.09 %w/w, about 0.1 %w/w.
  • the sweetener comprises aspartame, acesulfame potassium, alitamc, sucralose, sucrose, saccharose, erythritol, mannitol, fructose, sorbitol, xylitol, maltitol, saccharin, or the like. In certain embodiments, the sweetener is sucralose.
  • the pharmaceutical composition, unit dosage form, or granule formulation comprises a coloring agent or dye.
  • compositions, unit dosage form, or granule formulation comprising:
  • Compound I in an amount from about 10 to about 20 %w/w; a diluent in an amount from about 50 %w/w to about 60 %w/w; a thickening agent in an amount from about 10 %w/w to about 20 %w/w; a suspending agent in an amount from about 10 %w/w to about 20 %w/w; a surfactant in an amount from about 0.1 %w/w to about 0.5 %w/w; an anti-foaming agent in an amount from about 0.5 %w/w to about 1.5 %w/w; and a sweetener in an amount from about 0.05 %w/w to about 0.1 %w/w.
  • Compound I in an amount from about 13 to about 17 %w/w; a diluent in an amount from about 53 %w/w to about 57 %w/w; a thickening agent in an amount from about 13 %w/w to about 17 %w/w; a suspending agent in an amount from about 13 %'NIVI to about 17 %w/w; a surfactant in an amount from about 0.25 %w/w to about 0.45 %w/w; an anti-foaming agent in an amount from about 0.8 %w/w to about 1.2 %w/w; and a sweetener in an amount from about 0.05 %w/w to about 0.1 %w/w.
  • compositions, unit dosage form, or granule formulation comprising:
  • compositions, unit dosage form, or granule formulation consisting essentially of:
  • Compound I in an amount from about 10 %w/w to about 20 %w/w; mannitol in an amount from about 50 %w/w to about 60 %w/w; glycerin in an amount from about 10 %w/w to about 20 %w/w; xanthan gum in an amount from about 0.5 %w/w to about 1.5 %w/w; a microcrystalline cellulose (MCC) and sodium carboxymethylcellulose (Na-CMC) composite in an amount from about 10 % /lvi to about 20 %w/w; sodium lauryl sulfate in an amount from about 0.1 %w/w to about 0.5 %w/w; simethicone in an amount from about 0.5 %w/w to about 1.5 %w/w; and sucralose in an amount from about 0.05 %w/w to about 0.1 %w/w.
  • compositions, unit dosage form, or granule formulation consisting essentially of:
  • Compound I in an amount from about 13 %w/w to about 17 %w/w; mannitol in an amount from about 53 %w/w to about 57 %w/w; glycerin in an amount from about 13 %w/w to about 17 %w/w; xanthan gum in an amount from about 0.5 %w/w to about 1.5 %w/w; a microcrystalline cellulose (MCC) and sodium carboxymethylcellulose (Na-CMC) composite in an amount from about 13 % ilvi to about 17 %w/w; sodium lauryl sulfate in an amount from about 0.25 %wlvi to about 0.45 %w/w; simethicone in an amount from about 0.8 %vil'N to about 1.2 %w/w; and sucralose in an amount from about 0.05 %w/w to about 0.1 %w/w.
  • MMC microcrystalline cellulose
  • Na-CMC sodium carboxymethylcellulose
  • compositions, unit dosage form, or granule formulation consisting essentially of:
  • MCC microcrystalline cellulose
  • Na-CMC sodium carboxymethylcellulose
  • the granule formulation described herein may be prepared by a process of wet or dry granulation.
  • the pharmaceutical composition, unit dosage form, or granule formulation described herein is prepared by a process of wet granulation.
  • Compound I may be mixed with a suitable diluent, and a surfactant, and wet granulated. The granules are then dried and milled to the desired size.
  • Compound I may be mixed with a diluent, and a surfactant, and alternatively with a dry binder, and compacted. The compactatc may then be milled to the desired particle size.
  • the granules can be prepared the method of extrusion - spheronization.
  • a process for preparing a pharmaceutical composition, unit dosage form, or granule formulation comprising Compound I comprising: mixing a diluent and a suspending agent to provide a pre-granule formulation; sizing the pre-granule formulation; adding Compound I to the pre-granule formulation; spraying the pre-granule formulation with a granulation suspension comprising a thickening agent and a granulation solvent to provide a wet mass; drying the wet mass to provide dry granules; and milling the dry granules.
  • the granulation solvent is water.
  • the granulation suspension further comprises an anti-foaming agent.
  • the pre-granule formulation further comprises a surfactant.
  • the pre-granule formulation further comprises a thickening agent.
  • the pre-granule formulation further comprises a sweetener.
  • the milling step comprises a 18 mesh screen, or a 20 mesh screen, or a 22 mesh screen, or a 24 mesh screen.
  • the pre-granule formulation is sized prior to spraying the pre-granule formulation with a granulation suspension. In certain embodiments, the pre-granule formulation is sized using a mesh screen prior to spraying the pre-granule formulation with a granulation suspension. In certain embodiments, the mesh screen is a 18 mesh screen, or a 20 mesh screen, or a 22 mesh screen, or a 24 mesh screen.
  • a pharmaceutical composition, unit dosage form, or granule formulation prepared by a process as described herein.
  • the granule formulation is comprised of dry granules having a particle size of less than about 1,250 micron, or less than about 1,000 micron, or less than about 850 micron, or less than about 841 micron. In certain embodiments, granule formulation is comprised of particles with a size of between about 1 micron to about 1250 micron, or about 1 micron to about 1,000 micron,, or about 1 micron to about 850 micron, or about 1 micron to about 841 micron, as determined by sieve classification.
  • a solid dosage form comprising the granule formulation as described herein.
  • the solid dosage form is packaged in a tablet, a capsule, a stickpack, a sachet, a bottle, or a cachet, or other packaging material known to people skilled in the art.
  • the solid dosage form is a capsule, a stick pack, a sachet, a bottle, or a cachet.
  • the solid dosage form is packaged in a capsule.
  • the solid dosage form is packaged in a stickpack.
  • the solid dosage form is packaged in a sachet.
  • the solid dosage form is packaged in a cachet.
  • the granule formulation or solid dosage form can be administered orally (e.g., via a capsule) or, or for those who are unable to swallow capsules, a subject may ingest the granule formulation or solid dosage form either reconstituted in water for oral administration or feeding tube administration, or with a soft food vehicle.
  • a method for treating amyotrophic lateral sclerosis in a patient suffering therefrom comprising administering to Compound I the patient orally once daily.
  • a method for treating amyotrophic lateral sclerosis comprising administering Compound I orally once daily to a patient suffering from amyotrophic lateral sclerosis, and monitoring the patient.
  • the monitoring comprises assessing the change in disease severity over time as measured by the amyotrophic lateral sclerosis Functional Rating Scale-Revised (ALSFRS-R) total score and survival.
  • ALSFRS-R Functional Rating Scale-Revised
  • the patient has a score that increases by 5% or more, or 10% or more, or 15% or more, or 20% or more, or the patient has a score that increases by at least 5, or at least 6, or at least 7, or at least 8, or at least 9, or at least 10, or at least 11, or at least 12, or at least 13, or at least 14, or at least 15, or at least 16, or at least 17, or at least 18, or at least 19, or at least 20, or at least 21, or at least 22, or at least 23, or at least 24, or at least 25, or at least 26, or at least 27, or at least 28, or at least 29, or at least 30, or at least 31, or at least 32, or at least 33, or at least 34, or at least 35, after 24 weeks.
  • the monitoring comprises assessing one or more secondary endpoint.
  • exemplary secondary endpoints include: i) monitoring function, such as the change in ALSFRS-R total score over time, where each type of function is scored from 4 (normal) to 0 (no ability), with a maximum total score of 48 and a minimum total score of 0 (patients with higher scores have more physical function); ii) monitoring Combined Assessment of Function and Survival (CAFS), namely a combined assessment of function and survival uses ALSFRS-R total score as the function measure and death or permanent assisted ventilation as the survival component; iii) monitoring a change in respiratory function over time as assessed by slow vital capacity (SVC); iv) monitoring a change in muscle strength over time as measured isometrically using hand-held dynamometry and grip strength; and/or v) monitoring survival evaluated as time to death or permanent assisted ventilation (PAV).
  • 200 mg of Compound I is administered orally once daily.
  • liquid suspension comprising the granule formulation as described herein.
  • a method for preparing a mixture or liquid suspension of Compound I comprising adding the granule formulation or the solid dosage form described herein, to a soft food or liquid, and optionally mixing or shaking the soft food or liquid.
  • a method for preparing a mixture of Compound I with a soft food comprising adding the granule formulation or the solid dosage form described herein, to a soft food, and optionally mixing or shaking the soft food.
  • the soft food is yogurt, jelly, cottage cheese, a blended drink, such as a smoothie or shake, or a fruit puree, such as apple sauce.
  • a method for preparing a liquid suspension of Compound 1, comprising adding the granule formulation or the solid dosage form described herein, to a liquid, and optionally mixing or shaking the liquid.
  • the granule formulation or solid dosage form may be administered to the patient without the need for co-administering water or another fluid.
  • the granule formulation, solid dosage forms, or liquid suspension as described herein, may be administered in either single or multiple doses.
  • the amounts of compound to be administered can be determined by standard procedures taking into account factors such as the compound activity (in vitro, e.g. the compound IC50 vs. target, or in vivo activity in animal efficacy models), pharmacokinetic results in animal models (e.g. biological half-life or bioavailability), the age, size, and weight of the subject, and the disorder associated with the subject. The importance of these and other factors are well known to those of ordinary skill in the art. Generally, a dose will be in the range of about 0.01 to 50 mg/kg, also about 0.1 to 20 mg/kg of the subject being treated. Multiple doses may be used.
  • the specific dose level of Compound I for any particular subject will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination and the severity of the particular disease in the subject undergoing therapy.
  • a dosage may be expressed as a number of milligrams of a compound described herein per kilogram of the subject’s body weight (mg/kg). Dosages of between about 0.1 and 150 mg/kg may be appropriate. In some embodiments, about 0.1 and 100 mg/kg may be appropriate. In other embodiments a dosage of between 0.5 and 60 mg/kg may be appropriate.
  • a dosage of from about 0.0001 to about 100 mg per kg of body weight per day, from about 0.001 to about 50 mg of compound per kg of body weight, or from about 0.01 to about 10 mg of compound per kg of body weight may be appropriate.
  • body weight Normalizing according to the subject’s body weight is particularly useful when adjusting dosages between subjects of widely disparate size, such as occurs when using the drug in both children and adult humans or when converting an effective dosage in a non-human subject such as dog to a dosage suitable for a human subject.
  • the granule formulation, solid dosage form, or liquid suspension as described herein comprises one or more solid forms of 2-(4-chlorophenoxy)-N-[3-[5-[cis-3- (trifluoromethoxy)cyclobutyl]-l,3,4-oxadiazol-2-yl]-l-bicyclo[l.l.l]pent-l-yl]acetamide (“Compound I”).
  • Solid forms of Compound I are collectively referred to herein as “solid forms of Compound I.”
  • solid form refers to a type of solid-state material that includes amorphous as well as crystalline forms.
  • crystalline form refers to polymorphs as well as solvates, hydrates, etc.
  • polymorph refers to a particular crystal structure having particular physical properties such as X-ray diffraction, melting point, and the like.
  • references to a form of Compound I or a salt, co-crystal, solvate, or hydrate thereof means that at least 50% to 99% (e.g., at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99%) of Compound I or a salt, co-crystal, solvate, or hydrate thereof present in a composition is in the designated form.
  • reference to Compound I Form A means that at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% of Compound I present in a composition is Form A
  • reference to Compound I Form B means that at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% of Compound I present in a composition is Form B
  • reference to Compound I Form C means that at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% of Compound I present in a composition is Form C
  • reference to Compound I Form D means that at least 50%, at least 55%, at least 60%, at least 65%, at least
  • amorphous refers to a state in which the material lacks long range order at the molecular level and, depending upon temperature, may exhibit the physical properties of a solid or a liquid. Typically such materials do not give distinctive X-ray diffraction patterns and, while exhibiting the properties of a solid, are more formally described as a liquid. Upon heating, a change from solid to liquid properties occurs which is characterized by a change of state, typically second order (glass transition).
  • co-crystal refers to a molecular complex of a compound disclosed herein and one or more non-ionized co-crystal formers connected via non-covalent interactions.
  • the co-crystals disclosed herein may include a non-ionized form of Compound I (e.g., Compound I free form) and one or more non-ionized co-crystal formers, where non-ionized Compound I and the co-crystal former(s) are connected through non-covalent interactions.
  • co-crystals disclosed herein may include an ionized form of Compound I (e.g., a salt of Compound I) and one or more non-ionized co-crystals formers, where ionized Compound I and the co-crystal former(s) are connected through non-covalent interactions.
  • Co-crystals may additionally be present in anhydrous, solvated or hydrated forms.
  • co-crystals may have improved properties as compared to the parent form (i.e., the free molecule, zwitterion, etc.) or a salt of the parent compound.
  • Improved properties can be increased solubility, increased dissolution, increased bioavailability, increased dose response, decreased hygroscopicity, increased stability, a crystalline form of a normally amorphous compound, a crystalline form of a difficult to salt or unsalable compound, decreased form diversity, more desired morphology, and the like.
  • Methods for making and characterizing co-crystals are known to those of skill in the art.
  • the term “co-crystal former” or “co-former” refers to one or more pharmaceutically acceptable bases or pharmaceutically acceptable acids disclosed herein in association with Compound I, or any other compound disclosed herein.
  • solvate refers to a complex formed by combination of solvent molecules with molecules or ions of the solute.
  • the solvent can be an organic compound, an inorganic compound, or a mixture of both.
  • solvate includes a “hydrate” (i.e., a complex formed by combination of water molecules with molecules or ions of the solute), hemi-hydrate, channel hydrate, etc.
  • solvents include, but are not limited to, methanol, N,N-dimethylformamide, tetrahydrofuran, dimethylsulfoxide, and water.
  • the solvated forms are equivalent to unsolvated forms and are encompassed within the scope of the present disclosure.
  • Compound I is a free base. In some embodiments, Compound I is a salt or a co-crystal. In some embodiments, Compound I is a pharmaceutically acceptable salt or cocrystal. In some embodiments, Compound I is a solvate. In some embodiments, Compound I is a hydrate. In some embodiments, Compound I is an anhydrate. In some embodiments, Compound I is an amorphous form.
  • “Substantially pure form of a polymorph,” in some embodiments, means that in the referenced material, at least 99.9% of the material is the referenced polymorph. “Substantially pure form (of a polymorph),” in some embodiments, means that in the referenced material, at least 99.5% of the material is the referenced polymorph. “Substantially pure form (of a polymorph),” in some embodiments, means that in the referenced material, at least 99% of the material is the referenced polymorph. “Substantially pure form (of a polymorph),” in some embodiments, means that in the referenced material, at least 98% of the material is the referenced polymorph.
  • “Substantially pure form (of a polymorph),” in some embodiments, means that in the referenced material, at least 97% of the material is the referenced polymorph. “Substantially pure form (of a polymorph),” in some embodiments, means that in the referenced material, at least 96% of the material is the referenced polymorph. “Substantially pure form (of a polymorph),” in some embodiments, means that in the referenced material, at least 95% of the material is the referenced polymorph.
  • the term “contacting” means that the compound! s) arc caused to be in sufficient proximity to a particular molecule, complex, cell, tissue, organism, or other specified material that potential binding interactions and/or chemical reaction between the compound and other specified material can occur.
  • High energy milling refers to the mechanical reduction, in a mill, of a solid to smaller nanoparticles.
  • Examples of high energy milling or nano-milling include wet grinding, jet milling, fluidized bed jet milling, agitated bead milling, and ball milling.
  • high energy milling or nano-milling reduces the particle size to less than about 1 micron.
  • the d90 for nano-milled material is less than about 900 nm, less than about 800 nm, less than about 700 nm, less than about 600 nm, less than about 500 nm, less than about 400 nm, less than about 300 nm, less than about 200 nm, or less than about 100 nm.
  • the d90 for nanomilled material is less than about 100 nm. In some embodiments the d90 for nano-mill ed material is between 100 and 1 nm. “D90” (or d90) means that 90% of the sample is smaller than the referenced size.
  • the peaks listed for a X-ray powder diffractogram is meant to include a variation of ⁇ 0.2 “20 or ⁇ 0.1 “20.
  • the temperature recited for a DSC thermogram is meant to include a variation of ⁇ 3 “Celsius.
  • the value recited for a thermogravimetric analysis (TGA) is meant to include a variation of ⁇ 2% in weight loss.
  • Compound I may be present in a crystalline or amorphous form, including those described below (Form A, Form B, Form C, or Form D).
  • Compound I is crystalline and a Form A polymorph (hereinafter “Compound I Form A” or “Form A”) that exhibits an X-ray powder diffraction pattern (hereinafter XRPD or diffractogram) having characteristic peaks expressed in + 0.2 degrees 2-theta at 22.2, 22.6, and 22.9.
  • XRPD X-ray powder diffraction pattern
  • the X-ray powder diffraction pattern is made using CuKa radiation.
  • the XRPD is obtained on a diffractometer using CuKcc radiation at a wavelength of about 1.54 A.
  • micronized Form A polymorph is provided herein.
  • the Form A polymorph diffractogram further comprises one or more peaks expressed in + 0.2 degrees 2-theta selected from 17.8, 20.0, 20.8, and 21.0. In one embodiment, the Form A polymorph diffractogram further comprises two or more peaks expressed in ⁇ 0.2 degrees 2-theta selected from 17.8, 20.0, 20.8, 21.0 and 26.7. In one embodiment, the Form A polymorph diffractogram further comprises three or more peaks expressed in + 0.2 degrees 2-theta selected from: 15.9, 17.8, 19.5, 20.0, 20.8, 21.0, and 26.7. In one embodiment, the Form A polymorph diffractogram further comprises one or more peaks expressed in ⁇ 0.2 degrees 2-theta selected from 15.9, 17.8, 19.5, 20.0, 20.8, 21.0, 22.2, 22.6, 22.9, and 26.7.
  • the compound is the Form A polymorph having an X-ray powder diffraction pattern substantially free of peaks at 16.4, 16.9, 18.5, 23.3, 25.1, and 25.8 ⁇ 0.05 degrees 2-theta.
  • Compound I Form A is characterized by a differential scanning calorimetry (DSC) curve that comprises an endotherm at about 126.5 °C (onset temperature).
  • DSC differential scanning calorimetry
  • Compound I Form A is characterized by a thermogravimetric analysis (TGA) thermogram showing a weight loss of about 0.08% up to about 150 °C.
  • Compound I Form A is an anhydrate. In one embodiment, Compound I Form A has an aqueous solubility of about 9.7 microgram/mL.
  • a single crystal of Compound I Form A is in a monoclinic crystal system and P2i/c space group.
  • the Form A polymorph is a polymorph obtained by vacuum drying of a Form B polymorph described below.
  • the Form A polymorph is produced by subjecting a solution of Compound I to diffusion of the vapor of a counter solvent at room temperature.
  • Amorphous compound I may be dissolved, for instance in a solvent such as dimethylacetamide, and subjected to vapor diffusion of a counter solvent, e.g., vapor of a counter solvent such as water.
  • a counter solvent e.g., vapor of a counter solvent such as water.
  • Other solvent counter solvent pairs include and are not limited to heptane vapor diffused into a solution of Compound I in dichloromethane, or cyclohexane vapor diffusion into a solution of Compound I in 1,4-dioxane.
  • Compound I is crystalline and a Form B polymorph (hereinafter “Compound I Form B”) that exhibits an X-ray powder diffraction pattern having characteristic peaks expressed in + 0.2 degrees 2-theta at 16.4 and 16.9.
  • the X-ray powder diffraction pattern is made using CuKal radiation.
  • the XRPD is obtained on a diffractometer using CuKal radiation at a wavelength of about 1.54 A.
  • the Form B diffractogram further comprises one or more peaks expressed in ⁇ 0.2 degrees 2-theta selected from at 19.2, and 22.6. In one embodiment, the Form B diffractogram further comprises two or more peaks expressed in ⁇ 0.2 degrees 2-theta selected from at 10.2, 13.6, 19.2, and 22.6. In one embodiment, the Form B diffractogram further comprises three or more peaks expressed in ⁇ 0.2 degrees 2-theta selected from 10.2, 13.6, 19.2, 22.2, 22.6, and 27.9. In one embodiment the Form B diffractogram further comprises one or more peaks expressed in ⁇ 0.2 degrees 2-theta selected from 10.2, 13.6, 16.4, 16.9, 19.2, 22.2, 22.6, and 27.9.
  • the compound is the Form B polymorph having an X-ray powder diffraction pattern substantially free of peaks at 18.5, 22.9, 23.3, 25.1, and 25.8, ⁇ 0.05 degrees 2- theta.
  • the Form B polymorph is a 1,4-dioxane solvate.
  • the Form B polymorph upon vacuum drying, converts to Form A characterized by an X-ray powder diffractogram comprising peaks expressed in ⁇ 0.2 degrees 2-theta at: 22.2, 22.6, and 22.9.
  • crystalline Compound I is a Form C polymorph (herein after “Compound I Form C”) that exhibits an X-ray powder diffraction pattern having characteristic peaks expressed in ⁇ 0.2 degrees 2-theta at 18.5, 23.3, 25.1, and 25.8.
  • the X-ray powder diffraction pattern is made using CuKa radiation.
  • the XRPD is obtained on a diffractometer using CuKcc radiation at a wavelength of about 1.54 A.
  • micronized Form C polymorph is provided herein.
  • the Form C polymorph diffractogram further comprises one or more peaks expressed in + 0.2 degrees 2-theta selected from 17.3, 17.9, and 20.2. In one embodiment, the Form C polymorph diffractogram further comprises two or more peaks expressed in ⁇ 0.2 degrees 2- theta selected from 14.4, 17.3, 17.9, 20.2, and 20.6. In one embodiment, the Form C polymorph diffractogram further comprises three or more peaks expressed in + 0.2 degrees 2-theta selected from
  • the Form C polymorph diffractogram further comprises one or more peaks expressed in ⁇ 0.2 degrees 2-theta selected from 14.4, 17.3, 17.9,
  • the compound is the Form C polymorph having an X-ray powder diffraction pattern substantially free of peaks at 16.4, 16.9, 22.2, 22.6, and 22.9, + 0.05 degrees 2- theta.
  • Compound I Form C is characterized by a differential scanning calorimetry (DSC) curve that comprises an endotherm onset at about 132.3 °C.
  • DSC differential scanning calorimetry
  • the Compound I Form C is an anhydrate. In one embodiment, the Compound I Form C has an aqueous solubility of about 1.02 micrograms/mL.
  • a single crystal of Compound I Form C is in a monoclinic crystal system and P1 /c space group.
  • Form C polymorph is produced by subjecting a Form A polymorph of 2-(4-chlorophenoxy)-N-[3-[5-[cis-3-(trifluoromethoxy)cyclobutyl]-l,3,4-oxadiazol-2-yl]-l- bicyclo[l.l.l]pent-l-yl]acetamide that exhibits an X-ray powder diffraction pattern having peaks expressed in + 0.2 degrees 2-theta at 22.2, 22.6, and 22.9, wherein the X-ray powder diffraction pattern is made using CuKa radiation, to high energy milling.
  • Form A was subjected to 100 polymorph screening experiments including anti-solvent addition, solid vapor diffusion, liquid vapor diffusion, slurry, evaporation, slow cooling, polymer induced crystallization, grinding, and humidity induced phase transition; none of these experiments resulted in any other stable crystals including Form C.
  • Form C was not obtained until Form A was subjected to nano-milling, a form of high energy milling, which is not a routine method for identifying polymorphic forms.
  • Nano-milling requires specialized equipment including a milling chamber and specialized beads (e.g., beads of suitable hardness and size for nano-milling).
  • the beads are less than or equal to 0.8 mm in diameter.
  • the beads are zirconia beads or yttria-stabilized zirconia beads.
  • any crystalline compound described herein is in a substantially pure form.
  • Form C polymorph is substantially pure.
  • Micronization of any form of Compound I is achieved using standard micronizing procedures, for instance, a jet mill. Particle size obtained after micronization depends on many factors such as the initial particle size, the number of passes through the micronizer, the feeder rate, the feed pressure, the mill pressure, and the like,
  • micronized Compound I e.g., micronized Form A, micronized Form C
  • micronized Compound I e.g., micronized Form A, micronized Form C
  • Compound I (e.g., Form A, Form C), is nano-milled and has a d90 ⁇ 1 pm. In some embodiments, Compound I (e.g., Form A, Form C), is nano-milled and has a particle size distribution d90 ranging from about 1 pm to about 1 nm. In some embodiments, Compound I (e.g., Form A, Form C), is nano-milled and has a d90 ⁇ 0.5 pm (500 nm). In some embodiments, Compound I (e.g., Form A, Form C), is nano-milled and has a d90 ⁇ 0.1 pm (100 nm). In some embodiments, Compound I (e.g., Form A, Form C), is nano-milled and has a d90 ⁇ 0.01 pm (10 nm).
  • Compound I, Form D an amorphous form of 2-(4- chlorophenoxy)-A-[3-[5-[c»-3-(trifluoromethoxy)cyclobutyl]-l,3,4-oxadiazol-2-yl]-l- bicyclo[l.l.l]pentanyl] acetamide
  • Compound I, Form D is characterized by a glass transition temperature of about 27 °C (Compound I Form D) from a heat-cool-heat differential scanning calorimetry (DSC) cycle.
  • DSC differential scanning calorimetry
  • Compound I Form D is characterized by a differential scanning calorimetry (DSC) curve that comprises an endotherm (glass transition) at about 26.8 °C (onset temperature).
  • Eukaryotic initiation factor 2B functions as a guanine nucleotide exchange factor (GEF) that catalyzes the exchange of guanosine-5’ -diphosphate (GDP) with guanosine-5’ -triphosphate (GTP) on eukaryotic initiation factor 2, thereby allowing the GTP bound eukaryotic initiation factor 2 to bind to the initiating methionine transfer RNA and initiate protein synthesis.
  • GEF guanine nucleotide exchange factor
  • ISR integrated stress response pathway
  • ATF4 Activating Transcription Factor 4
  • TARDBP RNA-binding/stress-granule protein TAR DNA binding protein
  • eIF2B inhibits the ISR and ISR dependent stress granule formation and is found to be neuroprotective in multiple disease models.
  • Impairment of eukaryotic initiation factor 2B activity is correlated to activation of the ISR pathway that is implicated in a variety of neurodegenerative diseases including Parkinson’s disease, amyotrophic lateral sclerosis (ALS), Alzheimer’s disease, vanishing white matter disease (VWMD), and frontotemporal dementia.
  • Parkinson’s disease amyotrophic lateral sclerosis (ALS), Alzheimer’s disease, vanishing white matter disease (VWMD), and frontotemporal dementia.
  • Loss-of-function mutations in eIF2B that impair protein translation can cause progressive neurodegenerative syndromes.
  • maladaptive PERK activation and eIF2B inhibition occur as part of the cellular response to an accumulation of misfolded proteins in the endoplasmic reticulum (Stutzbach L. D. et aL, 2013, Acta Neuropathol Commun. Jul 6; 1( 1) :31).
  • the resulting deficit in protein synthesis contributes to synaptic dysfunction and memory impairment.
  • eIF2B inhibition is also linked to stress granule formation and pathogenic protein aggregation.
  • the granule formulation, solid dosage forms, or liquid suspension disclosed herein can be used to modulate a eIF2B mediated disease or condition.
  • a method for treating a disease or condition mediated, at least in part, by eukaryotic initiation factor 2B the method comprising administering an effective amount of the granule formulation, the solid dosage form, or the liquid suspension as described herein, to a subject in need thereof.
  • the term “modulating” or “modulate” refers to an effect of altering a biological activity, especially a biological activity associated with a particular biomolecule such as eIF2B.
  • an agonist or antagonist of a particular biomolecule modulates the activity of that biomolecule, e.g., eIF2B, by either increasing (e.g. agonist, activator), or decreasing (e.g. antagonist, inhibitor) the activity of the biomolecule.
  • activity is typically indicated in terms of an inhibitory concentration (IC50) or excitation concentration (EC50) of the compound for an inhibitor or activator, respectively, with respect to, for example, eIF2B.
  • the term “eIF2B mediated disease or condition,” refers to a disease or condition in which the biological function of eIF2B, including any mutations thereof, affects the development, course, and/or symptoms of the disease or condition, and/or in which modulation of eIF2B alters the development, course, and/or symptoms of the disease or condition.
  • the eIF2B mediated disease or condition includes a disease or condition for which eIF2B modulation provides a therapeutic benefit, e.g. wherein treatment with the granule formulation, solid dosage forms, or liquid suspension disclosed herein, provides a therapeutic benefit to the subject suffering from or at risk of the disease or condition.
  • the granule formulation, solid dosage forms, or liquid suspension disclosed herein can be used to treat a neurodegenerative disease or disorder.
  • the pharmaceutical composition, unit dosage form, granule formulation, solid dosage forms, or liquid suspension disclosed herein can be used to treat cellular proliferative disorders, including both cancerous and non-cancerous cellular proliferative disorders.
  • Treatment of cellular proliferative disorders may comprise, but is not limited to, inhibiting cellular proliferation, including rapid proliferation. It is contemplated that Compound I, and any of its forms as described herein can be used to treat any type of cancer, including, but not limited to, carcinomas, sarcomas, lymphomas, leukemias and germ cell tumors.
  • Exemplary cancers include, but arc not limited to, adrenocortical carcinoma, anal cancer, appendix cancer, basal cell carcinoma, cholangiocarcinoma, bladder cancer, bone cancer, osteosarcoma or malignant fibrous histiocytoma, brain cancer (e.g., brain stem glioma, astrocytoma (e.g., cerebellar, cerebral, etc.), atypical teratoid/rhabdoid tumor, central nervous system embryonal tumors, malignant glioma, craniopharyngioma, ependymoblastoma, ependymoma, medulloblastoma, medulloepithelioma, pineal parenchymal tumors of intermediate differentiation, supratentorial primitive neuroectodermal tumors and/or pineoblastoma, visual pathway and/or hypothalamic glioma, brain and spinal cord tumors, etc.), breast cancer,
  • noncancerous cellular proliferative disorders include, but are not limited to, fibroadenoma, adenoma, intraductal papilloma, nipple adenoma, adenosis, fibrocystic disease or changes of breast, plasma cell proliferative disorder (PCPD), restenosis, atherosclerosis, rheumatoid arthritis, myofibromatosis, fibrous hamartoma, granular lymphocyte proliferative disorders, benign hyperplasia of prostate, heavy chain diseases (HCDs), lymphoproliferative disorders, psoriasis, idiopathic pulmonary fibrosis, scleroderma, cirrhosis of the liver, IgA nephropathy, mesangial proliferative glomerulonephritis, membranoproliferative glomerulonephritis, hemangiomas, vascular and non-vascular intraocular proliferative
  • the granule formulation, solid dosage forms, or liquid suspension disclosed herein can be used to treat cancer, pre-cancerous syndromes and diseases/inj uries associated with activated unfolded protein response pathways, such as Alzheimer’s disease, neuropathic pain, spinal cord injury, traumatic brain injury, ischemic stroke, stroke, Parkinson’s disease, diabetes, metabolic syndrome, metabolic disorders, Huntington’s disease, Creutzfeldt- Jakob Disease, fatal familial insomnia, Gerstmann-Straussler-Scheinker syndrome, and related prion diseases, amyotrophic lateral sclerosis, progressive supranuclear palsy, myocardial infarction, cardiovascular disease, inflammation, organ fibrosis, chronic and acute diseases of the liver, fatty liver disease, liver steatosis, liver fibrosis, chronic and acute diseases of the lung, lung fibrosis, chronic and acute diseases of the kidney, kidney fibrosis, chronic traumatic encephalopathy (CTE), neurodegeneration,
  • CTE chronic traumatic
  • the pharmaceutical composition, unit dosage form, granule formulation, solid dosage forms, or liquid suspension disclosed herein can be used to treat or lessen the severity of cancer, Alzheimer’s disease, stroke, Type 1 diabetes, Parkinson disease, Huntington’s disease, amyotrophic lateral sclerosis, myocardial infarction, cardiovascular disease, atherosclerosis, arrhythmias, or age-related macular degeneration.
  • the pharmaceutical composition, unit dosage form, granule formulation, solid dosage forms, or liquid suspension disclosed herein can be used to treat neuropathic pain.
  • the ocular disease includes vascular leakage (e.g., edema or neovascularization for any occlusive or inflammatory retinal vascular disease, such as rubeosis irides, neovascular glaucoma, pterygium, vascularized glaucoma filtering blebs, conjunctival papilloma), choroidal neovascularization (e.g., neovascular age-related macular degeneration (AMD), myopia, prior uveitis, trauma, or idiopathic), macular edema (e.g., post-surgical macular edema, macular edema secondary to uveitis including retinal and/or choroidal inflammation, macular vascular leakage (e.g., edema or neovascularization for any occlusive or inflammatory retinal vascular disease, such as rubeosis irides, neovascular glaucom
  • the neovascular age-related macular degeneration is wet age- related macular degeneration.
  • the neovascular age-related macular degeneration is dry age-related macular degeneration and the patient is characterized as being at increased risk of developing wet age-related macular degeneration.
  • Compound I and any of its forms as described herein can be used to treat viral infections (e.g., to prevent the initiation of viral protein synthesis).
  • viruses which can be treated using the compounds disclosed herein include, but are not limited to, picornaviridae (e.g., polioviruses), reoviridae (e.g., rotaviruses), togaviridae (e.g., encephalitis viruses, yellow fever virus, rubella virus, etc.), orthomyxoviridae (e.g., influenza viruses), paramyxoviridae (e.g., respiratory syncytial virus, measles virus, mumps virus, parainfluenza virus, etc.), rhabdoviridae (e.g., rabies virus), coronaviridae, bunyaviridae, flaviviridae, filoviridae, arenaviridae, bunyaviridae and retrovirid
  • the pharmaceutical composition, unit dosage form, granule formulation, solid dosage forms, or liquid suspension disclosed herein can be used to treat disorders associated with dysphagia.
  • Impairment of swallowing is a feature of ALS resulting from weakness or spasticity of muscles affecting the tongue, lips, palate, jaw, pharynx, larynx and upper trunk, causing difficulties for patients in the oral consumption of dry, tough-textured or crumbly food, and thin liquids.
  • Dysphagia is characterized in terms of the type and severity of difficulty during any of the four “stages” of swallowing.
  • One important aspect of swallowing is protecting the windpipe or airway during swallowing. When airway protection does not occur, material enters the trachea and aspiration can occur. Aspiration is a serious health concern because ingested material that made it into the airway collects bacteria and can often lead to lung infection and so-called aspiration pneumonia.
  • pharmaceutical composition, unit dosage form, the granule formulation, solid dosage forms, or liquid suspension disclosed herein can be used to treat disorders associated with viral infections.
  • disorders include, but are not limited to neurological symptoms (e.g., encephalitis, meningoencephalitis, paralysis, myelopathy, neuropathy, aseptic meningitis, hemiparesis, dementia, dysphagia, lack of muscular coordination, impaired vision, coma, etc.), wasting symptoms (e.g., inflammatory cell infiltration, perivascular cuffing of blood vessels, demyelination, necrosis, reactive gliosis, etc.), gastroenteritis symptoms (e.g., diarrhea, vomiting, cramps, etc.), hepatitis symptoms (nausea, vomiting, right upper quadrant pain, raised liver enzyme levels (e.g., AST, ALT, etc.), jaundice, etc.), hemorrhagic fever symptoms (e.g., headache, fever, chills
  • neurological symptoms e.
  • the pharmaceutical composition, unit dosage form, granule formulation, solid dosage forms, or liquid suspension disclosed herein can be used to treat disorders characterized by unwanted synthesis and/or abnormal accumulation of one or more mutant and/or wild-type proteins. It is contemplated that the compounds disclosed herein that can inhibit translation initiation and thus can reduce the load on the protein-folding machinery and, accordingly, may reduce the severity of the disorder.
  • disorders associated with unwanted synthesis and/or abnormal accumulation of one or more mutant and/or wild-type proteins include, but are not limited to, Tay- Sachs disease, cystic fibrosis, phenylketonuria, Fabry disease, Alzheimer’s disease, Huntington’s disease, Parkinson’s disease, frontotemporal dementia, congophilic angiopathy, prion related disorders (i.e., transmissible spongiform encephalopathies such as Creutzfeldt-Jacob disease, kuru, fatal familial insomnia, scrapie, bovine spongiform encephalopathy, etc.), and the like.
  • the pharmaceutical composition, unit dosage form, granule formulation, solid dosage forms, or liquid suspension disclosed herein are capable of inhibiting neuronal cell death, such as in prion disease.
  • the method includes administering a therapeutically effective amount of the granule formulation, solid dosage forms, or liquid suspension disclosed herein, to a patient in need of.
  • the disorder is a neurodegenerative disease.
  • neurodegenerative disease refers to a disease or condition in which the function of a subject’s nervous system becomes impaired.
  • Examples of neurodegenerative diseases include, e.g., Alexander’s disease, Alper’s disease, Alzheimer’s disease, Amyotrophic lateral sclerosis, Ataxia telangiectasia, Batten disease (also known as Spielmeyer-Vogt-Sjogren-Batten disease), Bovine spongiform encephalopathy (BSE), Canavan disease, Cockayne syndrome, Corticobasal degeneration, Creutzfeldt- Jakob disease, frontotemporal dementia, vanishing white matter disease, Gerstmann- Straussler-Scheinker syndrome, Huntington’ s disease, HIV-associated dementia, Kennedy’s disease, Krabbe’s disease, kuru, Lewy body dementia, Machado-Joseph disease (Spinocerebellar ataxi
  • Other embodiments include use of the presently disclosed granule formulation, solid dosage forms, or liquid suspension in therapy. Some embodiments include their use in the treatment of a neurodegenerative disease.
  • the presently disclosed granule formulation, solid dosage forms, or liquid suspension for use in the treatment of Alzheimer’ s disease, Parkinson’ s disease, vanishing white matter disease, dementia, or ALS.
  • the dementia is frontotemporal dementia.
  • granule formulation for treating Alzheimer’s disease, Parkinson’s disease, vanishing white matter disease, dementia, or ALS.
  • kits that include the granule formulation, solid dosage forms, or liquid suspension as described herein, and suitable packaging.
  • a kit further includes instructions for use.
  • a kit includes the granule formulation, solid dosage forms, or liquid suspension as described herein, and a label and/or instructions for use in the treatment of the indications, including the diseases or conditions, described herein.
  • articles of manufacture that include the granule formulation, solid dosage forms, or liquid suspension as described herein, in a suitable package (e.g., a capsule, sachet, cachet, or stickpack.
  • a suitable package e.g., a capsule, sachet, cachet, or stickpack.
  • Granulation Suspension Simethicone emulsion is added to purified water and mixed, followed by the addition of glycerin. Sufficient time is allowed for a homogenous suspension to form. This constitutes the granulation suspension to be sprayed on the dry powder mix.
  • Excipients In a granulator bowl, the following ingredients are added and mixed: mannitol, Vivapur, sodium lauryl sulfate, sucralose, and xanthan gum. The mixture is removed from the bowl and screened on a 20 mesh screen for de-lumping.
  • Granulation Half of the screened mixture is added back into the granulator followed by Compound I and the remaining half of the mixture. This blend is mixed for about 5 minutes, followed by spraying of the granulation suspension. Additional water is added to the granulation as needed.
  • Drying, milling, final blend The wet mass thus obtained is dried to a pre-determined target LOD.
  • the dry granules are milled using a comil with 20 mesh screen.
  • the milled granules are mixed for about 3 minutes in a tumble blender.
  • the final blend is discharged and stored in double PE bags until further use.
  • Co-processed composite consisting of microcrystalline cellulose (MCC) and sodium carboxymethylcellulose (Na-CMC).
  • simethicone emulsion contains 149 g of simethicone.
  • Stick pack The final blend obtained above is filled into stick packs of pre-determined strengths by filling the granules into stick packs to a target weight.
  • Capsule The granules were mechanically filled into size 0 white opaque/white opaque hard gelatin capsules.
  • a multi-center clinical trial evaluating the safety and efficacy of Compound I for the treatment of ALS is conducted as follows. Participants complete a screening visit to assess eligibility criteria. Once Compound I eligibility criteria are confirmed, participants complete a baseline assessment and are randomized in a 3:1 ratio to either active Compound I or matching placebo. Compound I or placebo is administered orally once daily for 24 weeks.
  • the primary endpoint for the clinical trial is the change in disease severity over time as measured by the Amyotrophic Lateral Sclerosis Functional Rating Scalc-Rcviscd (ALSFRS-R) total score and survival. Each type of function is scored from 4 (normal) to 0 (no ability), with a maximum total score of 48 and a minimum total score of 0. Patients with higher scores have more physical function. Secondary endpoints for the clinical trial include:
  • Function Change in ALSFRS-R total score over time. Each type of function is scored from 4 (normal) to 0 (no ability), with a maximum total score of 48 and a minimum total score of 0. Patients with higher scores have more physical function.
  • CAFS Combined Assessment of Function and Survival

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Abstract

La présente divulgation concerne d'une manière générale une formulation de granulés comprenant un modulateur du facteur d'initiation eucaryote 2B (eIF2B), et son utilisation en tant qu'agent thérapeutique, par exemple, dans le traitement de maladies médiées par celui-ci telles que la maladie d'Alzheimer, la maladie de Parkinson, la SLA, la démence frontotemporale et le cancer.
PCT/US2024/038866 2023-07-20 2024-07-19 Formulation, forme posologique solide et méthodes Pending WO2025019827A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20210147435A1 (en) * 2017-08-09 2021-05-20 Denali Therapeutics Inc. Compounds, compositions and methods
US20210292311A1 (en) * 2019-02-13 2021-09-23 Denali Therapeutics Inc. Compounds, compositions and methods

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20210147435A1 (en) * 2017-08-09 2021-05-20 Denali Therapeutics Inc. Compounds, compositions and methods
US20210292311A1 (en) * 2019-02-13 2021-09-23 Denali Therapeutics Inc. Compounds, compositions and methods

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