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WO2024015281A1 - Polythérapie à base d'apilimod - Google Patents

Polythérapie à base d'apilimod Download PDF

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Publication number
WO2024015281A1
WO2024015281A1 PCT/US2023/027231 US2023027231W WO2024015281A1 WO 2024015281 A1 WO2024015281 A1 WO 2024015281A1 US 2023027231 W US2023027231 W US 2023027231W WO 2024015281 A1 WO2024015281 A1 WO 2024015281A1
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subject
acid
apilimod
pba
disorder
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Inventor
Peter Ronald Young
Carlo SPIRLI
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OrphAI Therapeutics Inc
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AI Therapeutics Inc
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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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
    • 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
    • A61K31/415—1,2-Diazoles
    • A61K31/4152—1,2-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. antipyrine, phenylbutazone, sulfinpyrazone
    • 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
    • A61K31/425—Thiazoles
    • A61K31/428—Thiazoles condensed with carbocyclic rings
    • 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
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca

Definitions

  • the invention relates to compositions and methods comprising apilimod for use in combination with other therapeutic agents in the treatment of neurological disease and disorders.
  • Neurodegenerative diseases and disorders cause progressive loss of neuronal function, and the societal burden of neurodegenerative diseases is increasing.
  • Neurodegenerative diseases may include amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Parkinson Disease (PD), Alzheimer’s Disease and Huntington disease (HD).
  • ALS amyotrophic lateral sclerosis
  • FDD frontotemporal dementia
  • PD Parkinson Disease
  • AD Alzheimer’s Disease
  • Huntington disease Huntington disease
  • ALS Amyotrophic lateral sclerosis
  • Apilimod also referred to as STA-5326, hereinafter “apilimod”
  • apilimod is recognized as a potent inhibitor of IL- 12 and IL-23.
  • IL- 12 and IL-23 are inflammatory cytokines normally produced by immune cells, such as B-cells and macrophages, in response to antigenic stimulation.
  • Autoimmune disorders and other disorders characterized by chronic inflammation are characterized in part by inappropriate production of these cytokines.
  • apilimod the selective inhibition of IL- 12/IL-23 transcription by apilimod was recently shown to be mediated by apilimod’s direct binding to phosphatidylinositol-3-phosphate 5-kinase (PIKfyve).
  • PIKfyve phosphatidylinositol-3-phosphate 5-kinase
  • PIKfyve plays a role in Toll-like receptor signaling, which is important in innate immunity.
  • the PIKfyve inhibitor APY0201 also selectively inhibits IL-12/IL-23 production in vitro and ex vivo in murine plasma.
  • the PIKfyve inhibitor YM201636 with a morpholino-pyrimidine (diazine) core was originally identified in a screen of PI3K class IA inhibitors and was reported to inhibit the proliferation of cancer cells in vitro as well as the growth of transplanted tumors in mice.
  • PIKfyve inhibitors including apilimod, have been shown to increase the survival of motor neurons.
  • compositions and methods relating to the use of a PIKfyve inhibitor for treating neurological diseases and disorders, particularly in combination with other therapeutic agents, e.g., AMX0035 (a fixed combination of sodium phenylbutyrate (PBA) and a bile acid (e.g., tauroursodeoxycholic acid (TUDCA)).
  • a PIKfyve inhibitor e.g., any PIKfyve inhibitors known or described herein, including but not limited to apilimod, APY0201, and YM201636
  • AMX0035 a fixed combination of sodium phenylbutyrate (PBA) and a bile acid (e.g., tauroursodeoxycholic acid (TUDCA)
  • PBA sodium phenylbutyrate
  • TUDCA tauroursodeoxycholic acid
  • a method described herein further comprises using additional therapeutic agents for treating neurological diseases (e.g., ALS), including glutamatergic agents (e.g., riluzole) and/or antioxidants (e.g., edaravone).
  • ALS neurological diseases
  • glutamatergic agents e.g., riluzole
  • antioxidants e.g., edaravone
  • some aspects of the present disclosure provide methods of treating a neurological disease or disorder in a subject in need thereof, the method comprising administering to the subject a PIKfyve inhibitor (e.g., any PIKfyve inhibitors known or described herein, including but not limited to apilimod, APY0201, and YM201636) or a pharmaceutically acceptable salt thereof and a composition comprising a bile acid (e.g., TUDCA) and 4- phenylbutyric acid (PBA).
  • a PIKfyve inhibitor e.g., apilimod, YM- 201636, APY0201
  • a PIKfyve inhibitor is in the composition comprising the bile acid and the PBA.
  • PIKfyve inhibitor e.g., any PIKfyve inhibitors known or described herein, including but not limited to apilimod, APY0201, and YM201636
  • a pharmaceutically acceptable salt thereof wherein the subject is receiving or has received treatment with a composition comprising a bile acid (e.g., TUDCA) and 4-phenylbutyric acid (PBA).
  • a bile acid e.g., TUDCA
  • PBA 4-phenylbutyric acid
  • compositions comprising a bile acid (e.g., TUDCA) and 4-phenylbutyric acid (PBA), wherein the subject is receiving or has received treatment with a PIKfyve inhibitor (e.g., any PIKfyve inhibitors known or described herein, including but not limited to apilimod, APY0201, and YM201636) or a pharmaceutically acceptable salt thereof.
  • a PIKfyve inhibitor e.g., any PIKfyve inhibitors known or described herein, including but not limited to apilimod, APY0201, and YM201636
  • the composition comprises 1 gram of TUDCA and 3 grams of PBA. In some embodiments, the composition is administered to the subject twice daily. In some embodiments, the composition is administered orally.
  • the apilimod is apilimod dimesylate.
  • a PIKfyve inhibitor e.g., any PIKfyve inhibitors known or described herein, including but not limited to apilimod, APY0201, and YM201636 is administered orally.
  • the methods further comprise administering to the subject a glutamatergic agent.
  • the glutamatergic agent is riluzole.
  • riluzole is administered to the subject twice daily and 50 mg of riluzole is administered in each administration.
  • the glutamatergic agent is administered orally.
  • the subject is not receiving or has not received treatment with a glutamatergic agent.
  • the glutamatergic agent that the subject is not receiving or has not received is riluzole.
  • the methods further comprise administering to the subject an antioxidant.
  • the antioxidant is edaravone.
  • edaravone is administered intravenously at a daily dose of 60 mg for 14 days, followed by 14 days of no administration, further followed by a daily dose of 60 mg for 10 days in a 14-day period, further followed by 14 days of no administration.
  • the antioxidant e.g., edaravone
  • the subject is not receiving or has not received treatment with an antioxidant.
  • the antioxidant the subject is not receiving or has not received treatment with is edaravone.
  • the methods further comprise administering to the subject a glutamatergic agent and an antioxidant.
  • the subject is not receiving or has not received treatment with a glutamatergic agent or an antioxidant.
  • the subject is not receiving or has not received treatment with riluzole or edaravone, respectively.
  • the neurological disease or disorder is selected from Alzheimer's disease, amyotrophic lateral sclerosis (ALS), attention deficit hyperactivity disorder, autism, cerebellar ataxia, Charcot-Marie-Tooth disease, Creutzfeldt-Jakob disease, dementia, epilepsy, Friedreich's ataxia, Huntington's disease, multiple sclerosis, obsessive compulsive disorder (OCD), Parkinson's disease, Rett syndrome, senile chorea, spinal ataxia, spinal cord injury, supranuclear palsy, or traumatic brain injury.
  • ALS amyotrophic lateral sclerosis
  • attention deficit hyperactivity disorder autism
  • cerebellar ataxia Charcot-Marie-Tooth disease
  • Creutzfeldt-Jakob disease dementia
  • epilepsy Friedreich's ataxia
  • Huntington's disease multiple sclerosis
  • obsessive compulsive disorder (OCD) Parkinson's disease
  • Rett syndrome senile chorea
  • spinal ataxia spinal
  • the neurological disease or disorder is dementia.
  • the dementia is selected from AIDS dementia complex (ADC), dementia associated with Alzheimer's disease (AD), dementia pugilistica, diffuse Lewy body disease, frontotemporal dementia, mixed dementia, senile dementia of Lewy body type, and vascular dementia.
  • ADC AIDS dementia complex
  • AD dementia associated with Alzheimer's disease
  • AD dementia pugilistica
  • diffuse Lewy body disease dementia pugilistica
  • frontotemporal dementia mixed dementia
  • senile dementia of Lewy body type vascular dementia.
  • the neurological disease or disorder is amyotrophic lateral sclerosis (ALS) or frontotemporal dementia (FTD).
  • the subject in need of treatment has repeat expansions in the C9ORF72 gene.
  • the subject in need of treatment has a mutation in the SOD1 gene.
  • the subject in need of treatment is one having a mutation in the TDP-43 gene.
  • the subject in need of treatment has accumulation of TDP-34 aggregates.
  • the subject is human.
  • PIKfyve inhibitor e.g., any PIKfyve inhibitors known or described herein, including but not limited to apilimod, APY0201, and YM201636
  • a pharmaceutically acceptable salt thereof e.g., a composition comprising a bile acid (e.g., TUDCA) and 4-phenylbutyric acid (PBA) in a method of treating a neurological disease or disorder in a subject in need thereof.
  • a PIKfyve inhibitor e.g., any PIKfyve inhibitors known or described herein, including but not limited to apilimod, APY0201, and YM201636
  • a composition comprising a bile acid (e.g., TUDCA) and 4-phenylbutyric acid (PBA) in a method of treating a neurological disease or disorder in a subject in need thereof.
  • TUDCA bile acid
  • PBA 4-phenylbutyric acid
  • PIKfyve inhibitor e.g., any PIKfyve inhibitors known or described herein, including but not limited to apilimod, APY0201, and YM201636
  • a pharmaceutically acceptable salt thereof in a method of treating a neurological disease or disorder in a subject in need thereof, wherein the subject is receiving or has received treatment with a composition comprising a bile acid (e.g., TUDCA) and 4- phenylbutyric acid (PBA).
  • a bile acid e.g., TUDCA
  • PBA 4- phenylbutyric acid
  • compositions comprising a bile acid (e.g., TUDCA) and 4-phenylbutyric acid (PBA) in a method of treating a neurological disease or disorder in a subject in need thereof, wherein the subject is receiving or has received treatment with a PIKfyve inhibitor (e.g., any PIKfyve inhibitors known or described herein, including but not limited to apilimod, APY0201, and YM201636) or a pharmaceutically acceptable salt thereof.
  • a PIKfyve inhibitor e.g., any PIKfyve inhibitors known or described herein, including but not limited to apilimod, APY0201, and YM201636
  • control bar indicates untreated cells while the DMSO bar indicates cells treated with 0.01% DMSO which is the buffer where all the compounds have been dissolved.
  • FIGURE 1 is a graph demonstrating the ability of AMX0035 (a fixed combination of TUDCA and PBA) and apilimod (6.25 nM) in combination to increase cell viability synergistically after glutamate exposure in iPSC-derived motoneurons from a C9orf72-ALS patient.
  • FIGURE 2 is a graph demonstrating the ability of AMX0035 (a fixed combination of TUDCA and PBA) and apilimod (6.25 nM) in combination to increase cell viability synergistically after glutamate exposure in iPSC-derived motoneurons from a SOD1-ALS patient. **** denotes significance ofp ⁇ 0.0001; *** denotes significance of p ⁇ 0.001; * denotes significance ofp ⁇ 0.05.
  • FIGURE 3 is a graph demonstrating the ability of AMX0035 (a fixed combination of TUDCA and PBA) and apilimod (6.25 nM) in combination to increase cell viability synergistically after growth factors deprivation (-GF) in iPSC-derived motoneurons from a TDP- 43-ALS patient. ** denotes significance ofp ⁇ 0.01 ; * denotes significance ofp ⁇ 0.05.
  • FIGURE 4 is a graph demonstrating the ability of AMX0035 (a fixed combination of TUDCA and PBA) and apilimod (6.25 nM) in combination to increase cell viability synergistically after glutamate exposure in iPSC-derived motoneurons from a Sporadic-ALS patient. **** denotes significance ofp ⁇ 0.0001; * denotes significance ofp ⁇ 0.05.
  • FIGURE 5 is a graph demonstrating the ability of AMX0035 (a fixed combination of TUDCA and PBA) and YM201636 (12.5 nM) in combination to increase cell viability synergistically after glutamate exposure in iPSC-derived motoneurons from a C9orf72-ALS patient. **** denotes significance ofp ⁇ 0.0001; *** denotes significance ofp ⁇ 0.001.
  • FIGURE 6 is a graph demonstrating the ability of AMX0035 (a fixed combination of TUDCA and PBA) and YM201636 (12.5 nM) in combination to increase cell viability synergistically after glutamate exposure in iPSC-derived motoneurons from a SOD1-ALS patient. **** denotes significance ofp ⁇ 0.0001; *** denotes significance ofp ⁇ 0.001.
  • FIGURE 7 is a graph demonstrating the ability of AMX0035 (a fixed combination of TUDCA and PBA) and YM201636 (12.5 nM) in combination to increase cell viability synergistically after growth factors deprivation (-GF) in iPSC-derived motoneurons from a TDP- 43-ALS patient.
  • -GF growth factors deprivation
  • FIGURE 8 is a graph demonstrating the ability of AMX0035 (a fixed combination of TUDCA and PBA) and YM201636 (12.5 nM) in combination to increase cell viability synergistically after glutamate exposure in iPSC-derived motoneurons from a Sporadic-ALS patient. **** denotes significance ofp ⁇ 0.0001; *** denotes significance ofp ⁇ 0.001.
  • FIGURE 9 is a graph demonstrating the ability of AMX0035 (a fixed combination of TUDCA and PBA) and APY0201 (6.25 nM) in combination to increase cell viability a synergistically fter glutamate exposure in iPSC-derived motoneurons from a C9orf72-ALS patient. **** denotes significance ofp ⁇ 0.0001; *** denotes significance of p ⁇ 0.001; * denotes significance ofp ⁇ 0.05.
  • FIGURE 10 is a graph demonstrating the ability of AMX0035 (a fixed combination of TUDCA and PBA) and APY0201 (6.25 nM) in combination to increase cell viability synergistically after glutamate exposure in iPSC-derived motoneurons from a SOD1-ALS patient. **** denotes significance ofp ⁇ 0.0001; *** denotes significance ofp ⁇ 0.001.
  • FIGURE 11 is a graph demonstrating the ability of AMX0035 (a fixed combination of TUDCA and PBA) and APY0201(6.25 nM) in combination to increase cell viability synergistically after growth factor deprivation in iPSC-derived motoneurons from a TDP-43- ALS patient. **** denotes significance ofp ⁇ 0.0001; *** denotes significance ofp ⁇ 0.001.
  • FIGURE 12 is a graph demonstrating the ability of AMX0035 (a fixed combination of TUDCA and PBA) and APY0201 (6.25 nM) in combination to increase cell viability synergistically after glutamate exposure in iPSC-derived motoneurons from a Sporadic-ALS patient. **** denotes significance ofp ⁇ 0.0001; *** denotes significance of p ⁇ 0.001; * denotes significance ofp ⁇ 0.05.
  • the term “pharmaceutically acceptable salt,” may be a salt formed from, for example, an acid and a basic group of a compound described herein (e.g., apilimod, , YM-201636, APY0201).
  • salts may be selected from, but are not limited to, sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, mesylate, dimesylate, lactate (e.g., D-lactate or L-lactate), salicylate, citrate, tartrate (e.g., L-tartrate), malonate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, besylate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, /?-tol ncn csnl fonate, pamoate (e.g.,
  • the salt of apilimod comprises methanesulfonate.
  • pharmaceutically acceptable salt may also refer to a salt prepared from a compound described herein (e.g., apilimod, YM-201636, APY0201), having an acidic functional group, such as a carboxylic acid functional group, and a pharmaceutically acceptable inorganic or organic base.
  • pharmaceutically acceptable salt may also refer to a bis-salt, e.g., an apilimod dimesylate salt.
  • Suitable bases include, but are not limited to, hydroxides of alkali metals such as sodium, potassium, and lithium; hydroxides of alkaline earth metal such as calcium and magnesium; hydroxides of other metals, such as aluminum and zinc; ammonia, and organic amines, such as unsubstituted or hydroxy-substituted mono-, di-, or trialkylamines; dicyclohexylamine; tributyl amine; pyridine; N-methyl, N-ethylamine; diethylamine; triethylamine; mono-, bis-, or tris-(2- hydroxy-lower alkyl amines), such as mono-, bis-, or tris-(2-hydroxyethyl)amine, 2-hydroxy- tert-butyl amine, or tris-(hydroxymethyl)methylamine, N, N,-di-lower alkyl-N-(hydroxy lower alkyl)-amines, such as N,N-dimethyl-
  • pharmaceutically acceptable salt may also refer to a salt prepared from apilimod (e.g., 2-[2- Pyridin-2-yl)-ethoxy]-4-N’-(3-methyl-benzilidene)-hydrazino]-6-(morpholin-4-yl)- pyrimidine), having a basic functional group, such as an amino functional group, and a pharmaceutically acceptable inorganic or organic acid.
  • apilimod e.g., 2-[2- Pyridin-2-yl)-ethoxy]-4-N’-(3-methyl-benzilidene)-hydrazino]-6-(morpholin-4-yl)- pyrimidine
  • Suitable acids include hydrogen sulfate, citric acid, acetic acid, oxalic acid, hydrochloric acid (HC1), hydrogen bromide (HBr), hydrogen iodide (HI), nitric acid, hydrogen bisulfide, phosphoric acid, lactic acid, salicylic acid, tartaric acid, bitartratic acid, ascorbic acid, succinic acid, maleic acid, besylic acid, fumaric acid, gluconic acid, glucuronic acid, formic acid, benzoic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, and /?-toliicncsiil Ionic acid.
  • the salts of a compound may be synthesized from the parent compound (e.g., 2-[2-Pyridin-2-yl)-ethoxy]-4-N’-(3-methyl-benzilidene)-hydrazino]-6-(morpholin-4-yl)- pyrimidine) by conventional chemical methods.
  • parent compound e.g., 2-[2-Pyridin-2-yl)-ethoxy]-4-N’-(3-methyl-benzilidene)-hydrazino]-6-(morpholin-4-yl)- pyrimidine
  • such salts can be prepared by reacting the parent compound (e.g., 2-[2-Pyridin-2-yl)-ethoxy]-4-N’-(3-methyl-benzilidene)- hydrazino]-6-(morpholin-4-yl)-pyrimidine) with the appropriate acid in water or in an organic solvent, or in a mixture of the two.
  • parent compound e.g., 2-[2-Pyridin-2-yl)-ethoxy]-4-N’-(3-methyl-benzilidene)- hydrazino]-6-(morpholin-4-yl)-pyrimidine
  • One salt form of a compound described herein may be converted to the free base and optionally to another salt form by methods well known to the skilled person.
  • the free base may be formed by passing the salt solution through a column containing an amine stationary phase e.g., a Strata-NI F column).
  • a solution of the salt in water may be treated with sodium bicarbonate and a base (e.g., hydroxide or carbonate bases) to decompose the salt.
  • the free base may then be combined with another acid using routine methods.
  • polymorph may refer to solid crystalline forms of a compound of the present disclosure (e.g., apilimod, YM-201636, APY0201) or complex thereof. Different polymorphs of the same compound may exhibit different physical, chemical and/or spectroscopic properties. Different physical properties include, but are not limited to, stability (e.g., to heat or light), compressibility and density (important in formulation and product manufacturing), and dissolution rates (which may affect bioavailability).
  • Differences in stability may result from changes in chemical reactivity (e.g., differential oxidation, such that a dosage form discolors more rapidly when comprised of one polymorph than when comprised of another polymorph) or mechanical characteristics (e.g., tablets crumble on storage as a kinetically favored polymorph converts to thermodynamically more stable polymorph) or both (e.g., tablets of one polymorph are more susceptible to breakdown at high humidity).
  • chemical reactivity e.g., differential oxidation, such that a dosage form discolors more rapidly when comprised of one polymorph than when comprised of another polymorph
  • mechanical characteristics e.g., tablets crumble on storage as a kinetically favored polymorph converts to thermodynamically more stable polymorph
  • both e.g., tablets of one polymorph are more susceptible to breakdown at high humidity.
  • Different physical properties of polymorphs may affect their processing. For example, one polymorph may be more likely to form solvates or may be more difficult to filter or wash free of impurities than another
  • hydrate may describe a compound of the present disclosure (e.g., apilimod, YM-201636, APY0201) or a salt thereof, which further includes a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces.
  • the term “clathrate” may refer to a compound of the present disclosure (e.g., apilimod, YM-201636, APY0201) or a salt thereof in the form of a crystal lattice that may contain spaces (e.g., channels) that may have a guest molecule (e.g., a solvent or water) trapped within.
  • a compound of the present disclosure e.g., apilimod, YM-201636, APY0201
  • a salt thereof in the form of a crystal lattice may contain spaces (e.g., channels) that may have a guest molecule (e.g., a solvent or water) trapped within.
  • prodrug may refer to a derivative of a compound described herein (e.g., apilimod, YM-201636, APY0201) that may hydrolyze, oxidize, or otherwise react under biological conditions (in vitro or in vivo) to provide a compound of the disclosure.
  • Prodrugs may only become active upon such reaction under biological conditions, or they may have activity in their unreacted forms.
  • prodrugs contemplated in this disclosure include, but are not limited to, analogs or derivatives that may comprise biohydrolyzable moieties such as biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzable ureides, and biohydrolyzable phosphate analogues.
  • Other examples of prodrugs may include, but are not limited to, derivatives of compounds of any one of the formulae disclosed herein that comprise -NO, -NO2, -ONO, or -ONO2 moieties.
  • Some of the compounds suitable for use in the methods described in this disclosure may have one or more double bonds, or one or more asymmetric centers. Such compounds may occur as racemates, racemic mixtures, single enantiomers, individual diastereomers, diastereomeric mixtures, and cis- or trans- or E- or Z- double isomeric forms. All such isomeric forms of these compounds are expressly included in the present disclosure.
  • the compounds of this disclosure may also be represented in multiple tautomeric forms, in such instances, the disclosure expressly includes all tautomeric forms of the compounds described herein (e.g., there may be a rapid equilibrium of multiple structural forms of a compound), the disclosure expressly includes all such reaction products). All such isomeric forms of such compounds are expressly included in the present disclosure. All crystal forms of compounds described herein (e.g., apilimod, YM-201636, APY0201) are expressly included in the present disclosure.
  • solvate or “pharmaceutically acceptable solvate,” may refer to a solvate formed from the association of one or more solvent molecules to one of the compounds disclosed herein (e.g., apilimod, YM-201636, APY0201).
  • solvate may include hydrates (e.g., hemi- hydrate, monohydrate, dihydrate, trihydrate, tetrahydrate, and the like).
  • analog may refer to a chemical compound that is structurally similar to another chemical compound but differs slightly in composition (e.g., as in the replacement of one atom by an atom of a different element or in the presence of a particular functional group, or the replacement of one functional group by another functional group).
  • an analog may be a compound that is similar or comparable in function and appearance, but not in structure or origin to the reference compound.
  • derivative may refer to compounds that have a common core structure and are substituted with various groups as described herein.
  • ND Neurodegenerative diseases
  • ALS amyotrophic lateral sclerosis
  • FDD frontotemporal dementia
  • PD Parkinson’s disease
  • AD Alzheimer’s disease
  • HD Huntington’s disease
  • AMX0035 (a fixed combination of sodium phenylbutyrate (PBA) and tauroursodeoxycholic acid (TUDCA)) is an approved medication for ALS marketed under the brand name Relyvrio.
  • Apilimod a PIKfyve inhibitor
  • AMX0035 in some aspects, demonstrates that administration of a PIKFyve inhibitor (e.g., any PIKfyve inhibitors known or described herein) and AMX0035 in induced pluripotent stem cell (iPSC)-derived motoneurons from an ALS patient has synergistic results in cell viability.
  • iPSC induced pluripotent stem cell
  • compositions and methods related to the use of a PIKfyve inhibitor e.g., any PIKfyve inhibitors known or described herein
  • a pharmaceutically acceptable salt thereof in combination with a bile acid (e.g., tauroursodeoxycholic acid (TUDCA)) and 4-phenylbutyric acid (PBA) for treating neurological diseases and disorders.
  • a bile acid e.g., tauroursodeoxycholic acid (TUDCA)
  • PBA 4-phenylbutyric acid
  • a method described herein comprises administering a PIKfyve inhibitor (e.g., any PIKfyve inhibitors known or described herein), or a pharmaceutically acceptable salt thereof, and a composition comprising a bile acid (e.g., TUDCA) and 4-phenylbutyric acid (PBA).
  • a PIKfyve inhibitor e.g., any PIKfyve inhibitors known or described herein
  • a composition comprising a bile acid (e.g., TUDCA) and 4-phenylbutyric acid (PBA).
  • a method described herein comprises administering to a subject a composition (e.g., in a solid oral dosage form such as a tablet) comprising a PIKfyve inhibitor (e.g., any PIKfyve inhibitors known or described herein), or a pharmaceutically acceptable salt thereof, a bile acid (e.g., TUDCA) and 4-phenylbutyric acid (PBA).
  • a composition e.g., in a solid oral dosage form such as a tablet
  • a PIKfyve inhibitor e.g., any PIKfyve inhibitors known or described herein
  • a pharmaceutically acceptable salt thereof e.g., a bile acid (e.g., TUDCA) and 4-phenylbutyric acid (PBA).
  • a method described herein comprises administering a PIKfyve inhibitor (e.g., any PIKfyve inhibitors known or described herein), or a pharmaceutically acceptable salt thereof, to a subject in need thereof, wherein the subject is receiving or has received treatment with a composition comprising a bile acid (e.g., TUDCA) and 4- phenylbutyric acid (PBA).
  • a PIKfyve inhibitor e.g., any PIKfyve inhibitors known or described herein
  • a pharmaceutically acceptable salt thereof e.g., TUDCA
  • PBA 4- phenylbutyric acid
  • a method described herein comprises administering a composition comprising a bile acid (e.g., TUDCA) and 4-phenylbutyric acid (PBA), to a subject in need thereof, wherein the subject is receiving or has received treatment with a PIKfyve inhibitor (e.g., any PIKfyve inhibitors known or described herein), or a pharmaceutically acceptable salt thereof.
  • a bile acid e.g., TUDCA
  • PBA 4-phenylbutyric acid
  • PIKfyve inhibitor may refer to a molecule that inhibits the expression and/or activity (e.g., kinase activity) of PIKfyve (phosphoinositide kinase, FYVE-type zinc finger containing).
  • PIKfyve phosphoinositide kinase is an enzyme that has evolutionarily conserved lipid and protein kinase that has pleiotropic cellular functions.
  • Phosphorylation of the phosphatidylinositol-3-phosphate (PI3P) by PIKfyve generates two phosphoinositide (PI) derivatives (1) phosphatidylinositol 3, 5 -bisphosphate [PtdIns(3,5)P2] or (2) phosphatidylinositol 5-phosphate (PtdIns5P).
  • PI phosphoinositide
  • the two phosphoinositide (PI) derivatives may govern various cellular processes, including, but not limited to, cytoskeleton rearrangements, remodeling the actin cytoskeleton, intracellular membrane trafficking pathways, endocytosis, epidermal growth factor receptor (EGFR) signaling, translocation of the glucose transporter GLUT4 after insulin stimulation, regulation of synapse strength and cell proliferation.
  • EGFR epidermal growth factor receptor
  • the FYVE finger domain of PIKfyve has been shown to play a vital role in localizing the protein to the cytosolic leaflet of endosomes through directly binding to membrane PtdIns3P and is thereby involved in multiple processes of endosome dynamics.
  • PIKfyve inhibition significantly increased the survival of ALS patient-derived motor neurons by converting PtdIns3P into PtdIns(3,5)P2, which enhanced the fusion of lysosomes with both endosomes and autophagosomes under cell stress.
  • PIKfyve inhibition can also lead to activation of transcription factor TFEB, which drives the clearance of toxic protein aggregates in ALS patients.
  • a PIKfyve inhibitor that may be used in accordance with the methods described herein is a small molecule.
  • Non-limiting examples of small molecule PIKfyve inhibitors include: apilimod and analogs or salts thereof, YM-201636 (CAS Number 371942-69-7), MOMIPP (CAS Number 1363421-46-8), MF4, APY0201 (CAS Number 1232221-74-7), AS2677131 (CAS Number 2171502-44-4), AS2795440, VRG101 (by Verge Genomics), Vacuolin-1 (CAS Number 351986-85-1), WX8 (MLS000543798; PubChem CID 135510930), NDF (MLS000699212; PubChem CID 9629709), WWL (MLS000703078), XB6 (MLS001167897), VRG50635 (by Verge Genomics; prodrug of VRG50648), VRG50648 (by Verge Genomics; active form of VRG50635) and XBA (MLS001167909).
  • PIKfyve inhibitors that may be used in any one of the methods described herein include, without limitation, small molecule PIKfyve inhibitors described in WO18175906, W0202009971, WO19046316, WO21163727, WO21113633, WO17218815, WO22169882, WO21247841, WO21247859, WO21247862, WO19113523, WO20243457, WO21146192, and WO21183439, WO18138106, WO22086993, US2021/0122752, US2020/0165246.
  • a PIKfyve inhibitor used in accordance with the present disclosure is a selective PIKfyve inhibitor (i.e., inhibitor that selectively inhibits PIKfyve versus other kinases).
  • the selective PIKfyve inhibitor is apilimod, or an analog or salt thereof.
  • a PIKfyve inhibitor used in accordance with the present disclosure is an RNAi agent or an antisense oligonucleotide (e.g., AS-201 or AS-202 by Acurastem) that targets an RNA (e.g., mRNA) encoded by the PIKfyve gene, e.g., as described in International Patent Application Publication No. WO2021155067, the entire contents of which and the sequences disclosed in the specification and the associated sequence listing are incorporated herein by reference.
  • an RNAi agent or an antisense oligonucleotide e.g., AS-201 or AS-202 by Acurastem
  • RNA e.g., mRNA encoded by the PIKfyve gene
  • apilimod refers to 2-[2-Pyridin-2-yl)-ethoxy]-4-N’-(3-methyl-benzilidene)- hydrazino]-6-(morpholin-4-yl)-pyrimidine (IUPAC name: (E)-4-(6-(2-(3- methylbenzylidene)hydrazinyl)-2-(2-(pyridin-2-yl)ethoxy)pyrimidin-4-yl)morpholine), represented by Formula I: or any pharmaceutically acceptable salt, solvate, clathrate, hydrate, polymorph, metabolite, prodrug, analog, or derivative thereof.
  • apilimod used in accordance with a method described herein is apilimod dimesylate.
  • Apilimod may be prepared, for example, according to the methods described in U.S. Pat. Nos. 7,923,557, and 7,863,270, and WO 2006/128129, the entire contents of each of which are incorporated herein by reference.
  • APY0201 refers to 2-[7-(4-morpholinyl)-2-(4-pyridinyl)pyrazolo[l,5- a]pyrimidin-5-yl] hydrazone, 3-methyl-benzaldehyde, represented by Formula II: or any pharmaceutically acceptable salt, solvate, clathrate, hydrate, polymorph, metabolite, prodrug, analog, or derivative thereof.
  • APY0201 is a selective PIKfyve inhibitor that inhibits IL- 12/23 production in vitro and ex vivo in murine plasma (e.g., as described in Hayakawa et al., Bioorg Med Chem. 2014 Jun 1;22(11):3021-9 and Drewry et al., J Med. Chem. 2022 Oct 13;65(19): 12860-12882, incorporated herein by reference).
  • YM201636 refers to a compound with CAS number of 371942-69-7 and a structure represented by Formula III: or any pharmaceutically acceptable salt, solvate, clathrate, hydrate, polymorph, metabolite, prodrug, analog, or derivative thereof.
  • YM201636 is a selective PIKfyve inhibitor with a morpholino-pyrimidine (diazine) core that was identified in a screen of PI3K class IA inhibitors.
  • MOMIPP refers to a compound with CAS number of 1363421-46-8 and a structure represented by Formula IV: or any pharmaceutically acceptable salt, solvate, clathrate, hydrate, polymorph, metabolite, prodrug, analog, or derivative thereof.
  • MF4 refers to a compound with a structure represented by Formula (V): wherein R is O, or any pharmaceutically acceptable salt, solvate, clathrate, hydrate, polymorph, metabolite, prodrug, analog, or derivative thereof.
  • R is O, or any pharmaceutically acceptable salt, solvate, clathrate, hydrate, polymorph, metabolite, prodrug, analog, or derivative thereof.
  • MF4 is described in, e.g., Lartigue et al., Traffic. 2009;10(7):883-893, incorporated herein by reference.
  • AS2677131 refers to a compound with CAS number of 2171502-44-4 and a structure represented by Formula (VI): or any pharmaceutically acceptable salt, solvate, clathrate, hydrate, polymorph, metabolite, prodrug, analog, or derivative thereof.
  • AS2677131 has been reported to inhibit the production of IL-12p40, IL-6, and IL-ip, potent pro-inflammatory cytokines in vitro, and block the development of arthritis in rats (Terajima M, et al. Eur J Pharmacol. 2016 Jun 5;780:93-105, incorporated herein by reference).
  • AS2795440 refers to 2, 3 -Dimethyl- IH-pyrrolo [3, 2-b]pyridine-5 -carboxy lie acid (l"-isopropyl-6-methyl-l",2",3",4",5",6"-hexahydro-[3,3';6',4"]terpyridin-5-yl)-amide, represented by Formula (VII): or any pharmaceutically acceptable salt, solvate, clathrate, hydrate, polymorph, metabolite, prodrug, analog, or derivative thereof.
  • AS2795440 has been reported to inhibit the production of IL-12p40, IL-6, and IL-ip, potent pro-inflammatory cytokines in vitro, and block the development of arthritis in rats (Terajima M, et al. Eur J Pharmacol. 2016 Jun 5;780:93-105, incorporated herein by reference).
  • Vacuolin-1 refers to a compound with CAS number of 351986-85-1 and a structure represented by Formula (VIII): or any pharmaceutically acceptable salt, solvate, clathrate, hydrate, polymorph, metabolite, prodrug, analog, or derivative thereof.
  • Vacuolin-1 has been reported to inhibit infection by chimeric vesicular stomatitis virus (VSV) that contains an envelope protein for either Zaire ebolavirus (VSV-ZEBOV) or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (VSVSARS-CoV-2) in vitro ( Kang Y, et al. PNAS. 2020 Aug 25;117(34):20803-20813, incorporated herein by reference).
  • VSV chimeric vesicular stomatitis virus
  • SARS-CoV-2 severe acute respiratory syndrome coronavirus 2
  • WX8 (MLS000543798; PubChem CID 135510930) refers to lH-indole-3- carbaldehyde [4-anilino-6-(4-morpholinyl)-l,3,5-triazin-2-yl]hydrazine, a compound represented by Formula (IX): or any pharmaceutically acceptable salt, solvate, clathrate, hydrate, polymorph, metabolite, prodrug, analog, or derivative thereof. WX8 has been reported to kill autophagy-dependent cancer cells with no effect on non-malignant human cells (Sharma G, et al. Autophagy. 2019; 15(10): 1694-1718, incorporated herein by reference).
  • NDF 3- methylbenzaldehyde (2,6-dimorpholin-4-ylpyrimidin-4-yl)hydrazine, represented by Formula (X): or any pharmaceutically acceptable salt, solvate, clathrate, hydrate, polymorph, metabolite, prodrug, analog, or derivative thereof.
  • Formula (X) any pharmaceutically acceptable salt, solvate, clathrate, hydrate, polymorph, metabolite, prodrug, analog, or derivative thereof.
  • NDF is described in Sharma G, et al. Autophagy. 2019; 15(10): 1694-1718, incorporated herein by reference.
  • WWL benzaldehyde [2,6-di(4-morpholinyl)-4- pyrimidinyl] hydrazone, represented by Formula (XI): or any pharmaceutically acceptable salt, solvate, clathrate, hydrate, polymorph, metabolite, prodrug, analog, or derivative thereof.
  • WWL is described in Sharma G, et al. Autophagy. 2019; 15(10): 1694-1718, incorporated herein by reference.
  • XBA N-(3-chloro-4-fhrorophenyl)-4,6- dimorpholino-l,3,5-triazin-2-amine hydrochloride, represented by Formula (XII): or any pharmaceutically acceptable salt, solvate, clathrate, hydrate, polymorph, metabolite, prodrug, analog, or derivative thereof.
  • Formula (XII) or any pharmaceutically acceptable salt, solvate, clathrate, hydrate, polymorph, metabolite, prodrug, analog, or derivative thereof.
  • XBA is described in Sharma G, et al. Autophagy. 2019; 15(10): 1694-1718., incorporated herein by reference .
  • XB6 (MLS001167897), refers to N-(4-ethylphenyl)- 4,6-dimorpholino- l,3,5-triazin-2-amine hydrochloride, represented by Formula (XIII):
  • XBA is described in Sharma G, et al. Autophagy. 2019; 15(10): 1694-1718., incorporated herein by reference .
  • the PIKfyve inhibitor is apilimod or a pharmaceutically acceptable salt thereof.
  • 30-300 e.g., 30-300, 30-200, 30-100, 30-80, 30-60, 30-50, 30- 40, 40-300, 40-200, 40-100, 40-80, 40-60, 40-50, 50-300, 50-200, 50-100, 50-80, 50-60, 60-300, 60-200, 60-100, 60-80, 80-300, 80-200, 80-100, 100-300, 1000-200, 200-300
  • milligrams per day of apilimod or a pharmaceutically acceptable salt thereof may be administered to a subject.
  • any one of the methods described herein in any one of the methods described herein, about 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 125, 150, 175, 200, 225, 250, 275, or 300 milligrams per day of apilimod or a pharmaceutically acceptable salt thereof, may be administered to a subject. In some embodiments, in any one of the methods described herein, about 100-300 milligrams/day of apilimod or a pharmaceutically acceptable salt thereof, is administered to the subject. In some embodiments, in any one of the methods described herein, about 200 or 250 milligrams/day of apilimod or a pharmaceutically acceptable salt thereof, is administered to the subject.
  • a subject in any one of the methods described herein, is administered apilimod twice a day, and each administration provides to the subject 75-150 (e.g., 75-150, 75-125, 75- 100, 100-150, 100-125, or 125-150 mg) milligrams of apilimod.
  • a subject in any one of the methods described herein, is administered apilimod twice a day, and each administration provides to the subject 75 milligrams, 100 milligrams, 125 milligrams, or 150 milligrams of apilimod.
  • apilimod or a pharmaceutically acceptable salt thereof is administered to the subject 1-3 (e.g., 1-3, 1-2, 2-3) times daily. In some embodiments, in any one of the methods described herein, apilimod or a pharmaceutically acceptable salt thereof, is administered to the subject 1, 2, 3 times daily. In some embodiments, in any one of the methods described herein, apilimod or a pharmaceutically acceptable salt thereof, is administered to the subject daily. In some embodiments, in any one of the methods described herein, apilimod or a pharmaceutically acceptable salt thereof, is administered to the subject twice daily.
  • apilimod or a pharmaceutically acceptable salt thereof is administered to the subject over a period of time.
  • the period of time may be 1 -60 (e.g, 1-60, 1-52, 1-50, 1-40, 1-30, 1-20, 1-16, 1-10, 1-8, 1-4, 4-60, 4-52, 4-50, 4-40, 4-30, 4-20, 4-16, 4-10, 4-8, 8-60, 8-52, 8-50, 8-40, 8-30, 8-20, 8-16, 8-10, 10-60, 10-52, 10-50, 10-40, 10- 30, 10-20, 10-16, 16-60, 16-52, 16-50, 16-40, 16-30, 16-20, 20-60, 20-52, 20-50, 20-40, 20-30, 30-60, 30-52, 30-50, 30-40, 40-60, 40-52, 40-50, 50-60, 50-52, 52-60) weeks.
  • the period of time is about 1, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 30, 40, 50, 52, 60 weeks. In some embodiments, in any one of the methods described herein, the period of time is about 4-16 weeks. In some embodiments, in any one of the methods described herein, the period of time is about 8 weeks. In some embodiments, in any one of the methods described herein, the period of time is about 52 weeks.
  • apilimod or a pharmaceutically acceptable salt thereof is administered to the subject according to a dosage regimen of about 30-300 mg per day for at least 1 week. In some embodiments, in any one of the methods described herein, apilimod or a pharmaceutically acceptable salt thereof, is administered to the subject according to a dosage regimen of about 100-300 mg per day for about 4 or 16 weeks. In some embodiments, in any one of the methods described herein, apilimod or a pharmaceutically acceptable salt thereof, is administered to the subject according to a dosage regimen of about 100 mg per day, twice a day for about 8 weeks, or optionally for about 52 weeks or longer.
  • apilimod or a pharmaceutically acceptable salt thereof is administered to the subject according to a dosage regimen of about 100-300 mg per day, twice a day for the remainder of the subject’s lifetime. In some embodiments, in any one of the methods described herein, apilimod or a pharmaceutically acceptable salt thereof, is administered to the subject according to a dosage regimen of about 100-300 mg per day, twice a day until the subject is no longer suitable for receiving treatment with apilimod.
  • a PIKfyve inhibitor e.g., apilimod, YM-201636, APY0201
  • a pharmaceutically acceptable salt thereof is used in combination with a composition comprising a bile acid (e.g., TUDCA) and 4-phenylbutyric acid (PBA) for treating neurological diseases and disorders.
  • a bile acid e.g., TUDCA
  • PBA 4-phenylbutyric acid
  • Bile acid may refer to naturally occurring surfactants having a nucleus derived from cholanic acid substituted with a 3a-hydroxyl group and optionally with other hydroxyl groups as well, typically at the C6, C7 or C12 position of the sterol nucleus.
  • Bile acid derivatives e.g., aqueous soluble bile acid derivatives
  • Bile acids conjugated with an amine are also encompassed by the term “bile acid”.
  • Bile acid derivatives may include, but are not limited to, derivatives formed at the hydroxyl and carboxylic acid groups of the bile acid with other functional groups, including but not limited to halogens and amino groups.
  • Soluble bile acids may include an aqueous preparation of a free acid form of bile acids combined with one of HC1, phosphoric acid, citric acid, acetic acid, ammonia, or arginine.
  • Suitable bile acids may include but are not limited to, taurursodiol (TURSO), ursodeoxycholic acid (UDCA), chenodeoxycholic acid (also referred to as “chenodiol” or “chenic acid”), cholic acid, hyodeoxy cholic acid, deoxy cholic acid, 7-oxolithocholic acid, lithocholic acid, iododeoxy cholic acid, iocholic acid, taurochenodeoxycholic acid, taurodeoxycholic acid, glycoursodeoxycholic acid, taurocholic acid, glycocholic acid, or an analog, derivative, or prodrug thereof.
  • tauroursodeoxycholic acid TUDCA
  • a phenylbutyrate compound may be an encompassing phenylbutyrate (a low molecular weight aromatic carboxylic acid) as a free acid (4- phenylbutyrate (4-PBA), 4-phenylbutyric acid, or phenylbutyric acid (PBA)), and pharmaceutically acceptable salts, co-crystals, polymorphs, hydrates, solvates, conjugates, derivatives, or pro-drugs thereof.
  • Phenylbutyrate compounds described herein may also encompass analogs of 4-PBA, including but not limited to Glyceryl Tri-(4-phenylbutyrate), phenylacetic acid (which is the active metabolite of PBA), 2-(4-Methoxyphenoxy) acetic acid (2-POAA-OMe), 2-(4-Nitrophenoxy) acetic acid (2-POAA-NO2), and 2-(2 -Naphthyloxy) acetic acid (2-NOAA), and their pharmaceutically acceptable salts.
  • Phenylbutyrate compounds may also encompass physiologically related 4-PBA species, such as but not limited to any substitutions for Hydrogens with Deuterium in the structure of 4-PBA.
  • Other HDAC2 inhibitors may be contemplated herein as substitutes for phenylbutyrate compounds.
  • the composition comprising bile acid (e.g., TUDCA) and PBA comprises 0.5-2 grams (e.g., 0.5-2, 0.5- 1.5, 0.5- 1, 1-2, 1-1.5, or 1.5-2 grams) of bile acid (e.g., TUDCA).
  • the composition comprising bile acid (e.g., TUDCA) and PBA comprises about 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0 grams or more of bile acid (e.g., TUDCA).
  • the composition comprising bile acid (e.g., TUDCA) and PBA comprises about 1 gram of bile acid (e.g., TUDCA). In some embodiments, in any one of the methods described herein, the composition comprising bile acid (e.g., TUDCA) and PBA comprises 1-5 grams (e.g., 1-5, 2-5, 3-5, 4-5, 1-4, 2-4, 3-4, 1-3, 2-3, or 1-2 grams) of PBA.
  • the composition comprising bile acid (e.g., TUDCA) and PBA comprises about 1, 1.5, 2, 2.5, 3, 3.5, 4 grams or more of PBA. In some embodiments, in any one of the methods described herein, the composition comprising bile acid (e.g., TUDCA) and PBA comprises about 3 grams of PBA.
  • the composition comprising bile acid (e.g., TUDCA) and PBA comprises 0.5- 2 grams (e.g., 0.5-2, 0.5-1.5, 0.5-1, 1-2, 1-1.5, or 1.5-2 grams) of bile acid (e.g., TUDCA) and 1-4 grams (e.g., 1-5, 2-5, 3-5, 4-5, 1-4, 2-4, 3-4, 1-3, 2-3, or 1-2 grams) of PBA.
  • the composition comprising bile acid (e.g., TUDCA) and PBA comprises a fixed combination of bile acid (e.g., TUDCA) and PBA.
  • the fixed combination of bile acid (e.g., TUDCA) and PBA comprises about 1 gram of bile acid (e.g., TUDCA) and about 3 grams of PBA.
  • the fixed combination comprising about 1 gram of TUDCA and about 3 grams of PBA may be referred to as “AMX0035.”
  • Compositions comprising a fixed combination of bile acid (e.g., TUDCA) and 4-phenylbutyric acid (PBA) are disclosed in U.S. Patent Application Publication No. US20220152054, the contents of which are incorporated herein.
  • the composition in any one of the methods described herein, is administered to the subject 1-6 (e.g., 1-6, 1-5, 1-4, 1-3, 1-2, 2-6, 2-5, 2-4, 2-3, 3-6, 3-5, 3-4, 4- 6, 4-5, 5-6) times daily. In some embodiments, in any one of the methods described herein, the composition is administered to the subject 1, 2, 3, 4, 5, 6 times daily. In some embodiments, in any one of the methods described herein, the composition is administered to the subject twice daily.
  • the subject 1-6 e.g., 1-6, 1-5, 1-4, 1-3, 1-2, 2-6, 2-5, 2-4, 2-3, 3-6, 3-5, 3-4, 4- 6, 4-5, 5-6 times daily.
  • the composition in any one of the methods described herein, is administered to the subject 1, 2, 3, 4, 5, 6 times daily. In some embodiments, in any one of the methods described herein, the composition is administered to the subject twice daily.
  • any one of the methods described herein may further comprise administering to the subject a glutamatergic agent.
  • a “glutamatergic agent” may be described as a composition, or a drug, or a chemical that directly modulates the excitatory amino acid (glutamate/aspartate) system in the body or brain.
  • the glutamatergic agent may be selected from, but is not limited to, a glutamate transporter modulating agent and a glutamate receptor antagonist.
  • the glutamate transporter modulating agent may be an excitatory amino acid reuptake inhibitor.
  • the glutamate receptor antagonist may be an N-methyl-D-aspartate (NMDA) receptor antagonist.
  • the glutamate receptor antagonist may be an antagonist of the a-amino-3 -hydroxy-5 -methyl-4-isoxazolepropionic acid receptor (AMPA) receptor, or the kainite receptor.
  • AMPA a-amino-3 -hydroxy-5 -methyl-4-isoxazolepropionic acid
  • the glutamatergic agent may be a glutamate receptor antagonist selected from, but not limited to, AP5 (R-2-amino-5-phosphonopentanoate), AP7 (2-amino-7- phosphonoheptanoic acid), CNQX (6-cyano-7-nitroquinoxaline-2, 3-dione), CPPene (3-[(R)-2- carboxypiperazin-4-yl]-prop-2-enyl-l-phosphonic acid), NBQX (2,3-dihydroxy-6-nitro-7- sulfamoyl-benzo[f]quinoxaline-2, 3-dione), and selfotel (CGS-19755).
  • AP5 R-2-amino-5-phosphonopentanoate
  • AP7 (2-amino-7- phosphonoheptanoic acid
  • CNQX (6-cyano-7-nitroquinoxaline-2, 3-dione)
  • CPPene (3-[(R)-2-
  • the glutamatergic agent may be a glutamate receptor antagonist selected from, but not limited to, amantadine, atomoxetine, AZD6765, agmatine, gacyclidine, ketamine, memantine, eliprodil, delucemin.
  • the glutamatergic agent may be selected from, but not limited to, BHV-5000, lamotrigine, lanicemine, riluzole, trigriluzole, and topiramate.
  • the glutamatergic agent is riluzole.
  • a method of treating a neurological disorder comprises administering a PIKfyve inhibitor (e.g., apilimod, YM-201636, APY0201), or a pharmaceutically acceptable salt thereof, and a composition comprising a bile acid (e.g., TUDCA) and PBA to a subject in need thereof, wherein the subject is receiving or has received treatment with a glutamatergic agent.
  • a PIKfyve inhibitor e.g., apilimod, YM-201636, APY0201
  • a composition comprising a bile acid (e.g., TUDCA) and PBA
  • a method of treating a neurological disorder comprises administering a PIKfyve inhibitor (e.g., apilimod, YM-201636, APY0201), or a pharmaceutically acceptable salt thereof, and a composition comprising a bile acid (e.g., TUDCA) and PBA to a subject in need thereof, wherein the subject is receiving or has received treatment with riluzole.
  • a PIKfyve inhibitor e.g., apilimod, YM-201636, APY0201
  • a composition comprising a bile acid (e.g., TUDCA) and PBA
  • a method of treating a neurological disorder comprises administering a PIKfyve inhibitor (e.g., apilimod, YM-201636, APY0201), or a pharmaceutically acceptable salt thereof, and a composition comprising a bile acid (e.g., TUDCA) and PBA to a subject in need thereof, wherein the subject is not receiving or has not received treatment with a glutamatergic agent (e.g., riluzole).
  • a PIKfyve inhibitor e.g., apilimod, YM-201636, APY0201
  • a composition comprising a bile acid (e.g., TUDCA) and PBA
  • any one of the methods described herein about 25-75 (e.g., 25- 75, 25-60, 25-50, 25-40, 25-30, 30-75, 30-60, 30-40, 30-50, 40-75, 40-60, 40-50, 50-75, 50-60, 60-75) milligrams of riluzole is administered to the subject. In some embodiments, in any one of the methods described herein, about 25, 30, 40, 50, 60, 75 milligrams of riluzole are administered to the subject. In some embodiments, in any one of the methods described herein, about 50 milligrams of riluzole is administered to the subject.
  • riluzole is administered to the subject 1-3 (e.g., 1-3, 1-2, 2-3) times daily. In some embodiments, in any one of the methods described herein, riluzole is administered to the subject 1, 2, 3 times daily. In some embodiments, in any one of the methods described herein, riluzole is administered to the subject twice daily. In some embodiments, in any one of the methods described herein, riluzole is administered to the subject twice daily and about 50 mg of riluzole is administered in each administration.
  • any one of the methods described herein further comprises administering to the subject an antioxidant.
  • an “antioxidant” may refer to substances that may prevent or slow damage to cells caused by free radicals, and unstable molecules that the body produces as a reaction to environmental and other pressures.
  • the terms “antioxidant” and “free-radical scavengers” may be used interchangeably.
  • the sources of antioxidants may be natural or artificial.
  • Antioxidants may include, but are not limited to, ascorbic acid, cysteine, cysteamine, edaravone, glutathione and bilirubin, amifostine (WR-2721), vitamin A, vitamin C, vitamin E, and flavonoids such as Indian holy basil (Ocimum sanctum), orientin and vicenin.
  • the antioxidant is edaravone.
  • a method of treating a neurological disorder comprises administering a PIKfyve inhibitor (e.g., apilimod, YM-201636, APY0201), or a pharmaceutically acceptable salt thereof, and a composition comprising a bile acid (e.g., TUDCA) and PBA to a subject in need thereof, wherein the subject is receiving or has received treatment with an antioxidant.
  • a PIKfyve inhibitor e.g., apilimod, YM-201636, APY0201
  • a composition comprising a bile acid (e.g., TUDCA) and PBA
  • a method of treating a neurological disorder comprises administering a PIKfyve inhibitor (e.g., apilimod, YM-201636, APY0201), or a pharmaceutically acceptable salt thereof, and a composition comprising a bile acid (e.g., TUDCA) and PBA to a subject in need thereof, wherein the subject is receiving or has received treatment with edaravone.
  • a PIKfyve inhibitor e.g., apilimod, YM-201636, APY0201
  • a composition comprising a bile acid (e.g., TUDCA) and PBA
  • a method of treating a neurological disorder comprises administering a PIKfyve inhibitor (e.g., apilimod, YM-201636, APY0201), or a pharmaceutically acceptable salt thereof, and a composition comprising a bile acid (e.g., TUDCA) and PBA to a subject in need thereof, wherein the subject is not receiving or has not received treatment with an antioxidant (e.g., edaravone).
  • a PIKfyve inhibitor e.g., apilimod, YM-201636, APY0201
  • a composition comprising a bile acid (e.g., TUDCA) and PBA
  • a method of treating a neurological disorder comprises administering a PIKfyve inhibitor (e.g., apilimod, YM-201636, APY0201), or a pharmaceutically acceptable salt thereof, and a composition comprising a bile acid (e.g., TUDCA) and PBA to a subject in need thereof, wherein the subject is receiving or has received treatment with an antioxidant and/or (e.g., and) a glutamatergic agent.
  • a PIKfyve inhibitor e.g., apilimod, YM-201636, APY0201
  • a composition comprising a bile acid (e.g., TUDCA) and PBA
  • a method of treating a neurological disorder comprises administering a PIKfyve inhibitor (e.g., apilimod, YM-201636, APY0201), or a pharmaceutically acceptable salt thereof, and a composition comprising a bile acid (e.g., TUDCA) and PBA to a subject in need thereof, wherein the subject is receiving or has received treatment with edaravone and/or (e.g., and) riluzole.
  • a PIKfyve inhibitor e.g., apilimod, YM-201636, APY0201
  • a composition comprising a bile acid (e.g., TUDCA) and PBA
  • a method of treating a neurological disorder comprises administering a PIKfyve inhibitor (e.g., apilimod, YM-201636, APY0201), or a pharmaceutically acceptable salt thereof, and a composition comprising a bile acid (e.g., TUDCA) and PBA to a subject in need thereof, wherein the subject is not receiving or has not received treatment with an antioxidant (e.g., edaravone) or a glutamatergic agent (e.g., riluzole).
  • a PIKfyve inhibitor e.g., apilimod, YM-201636, APY0201
  • a composition comprising a bile acid (e.g., TUDCA) and PBA
  • an antioxidant e.g., edaravone
  • a glutamatergic agent e.g., riluzole
  • about 25-80 e.g., 25- 80, 25-75, 25-60, 25-50, 25-40, 25-30, 30-80, 30-75, 30-60, 30-50, 30-40, 40-80, 40-75, 40-60, 40-50, 50-80, 50-75, 50-60, 60-80, 60-75, or 75-80
  • milligrams of edaravone is administered to the subject.
  • about 60 milligrams of edaravone is administered to the subject.
  • edaravone is administered intravenously to the subject.
  • about 75-125 e.g., 75-125, 75-115, 75-105, 75-95, 75-85, 85-125, 85-115, 85-105, 85-95, 95-125, 95-115, 95-105, 105-125, 105-115, 105-125, 105-115, or 115-125) milligrams of edaravone is administered to the subject.
  • about 75, 85, 95, 105, 115, or 125 milligrams of edaravone administered to the subject.
  • about 105 milligrams of edaravone is administered to the subject.
  • edaravone is administered orally to the subject.
  • edaravone is administered to the subject 1-3 (e.g., 1-3, 1-2, 2-3) times daily. In some embodiments, in any one of the methods described herein, edaravone is administered to the subject 1, 2, 3 times daily. In some embodiments, in any one of the methods described herein, wherein edaravone is administered to the subject daily.
  • edaravone is administered to the subject intermittently over a period of time.
  • the period of time may be about 1-12 (e.g., 1-12, 1-10, 1-8, 1-6, 1-4, 1-2, 2-12, 2-10, 2-8, 2-6, 2-4, 4-12, 4-10, 4-8, 4-6, 6-12, 6-10, 6-8, 8-12, 8-10, 10-12) weeks.
  • the period of time is about 1, 2, 4, 6, 8, 10, 12 weeks.
  • the period of time is about 8 weeks.
  • edaravone is administered to the subject for about 14 days, followed by about 14 days of no administration, further followed by administration for about 10 days in about a 14- day period, further followed by about 14 days of no administration.
  • edaravone is administered to the subject at a daily dose of about 60 mg for about 14 days, followed by about 14 days of no administration, further followed by administration of a daily dose of about 60 mg for about 10 days in about a 14-day period, further followed by about 14 days of no administration.
  • the different therapeutic agents may be formulated in compositions (e.g., different or same compositions) for administration to a subject.
  • the composition(s) may take any suitable form (e.g., liquids, aerosols, solutions, inhalants, mists, sprays; or solids, powders, ointments, pastes, creams, lotions, gels, patches and the like) for administration by any desired route (e.g., pulmonary, inhalation, intranasal, oral, buccal, sublingual, parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, intrapleural, intrathecal, transdermal, transmucosal, rectal, and the like).
  • a pharmaceutical composition of the disclosure may be in the form of an aqueous solution or powder for aerosol administration by inhalation or insufflation (either through the mouth or the nose), in the form of a tablet or capsule for oral administration; in the form of a sterile aqueous solution or dispersion suitable for administration by either direct injection or by addition to sterile infusion fluids for intravenous infusion; or in the form of a lotion, cream, foam, patch, suspension, solution, or suppository for transdermal or transmucosal administration.
  • the administration route of the composition comprising bile acid (e.g., TUDCA) and PBA, and/or a PIKfyve inhibitor (e.g., apilimod, YM-201636, APY0201), and/or the glutamatergic agent (e.g., riluzole) may be orally.
  • the administration route of the antioxidant e.g., edaravone
  • a “neurological disease or disorder,” as used herein, refers to a disease of the nervous system characterized by progressive loss of neuronal structure and function.
  • the neurological disease or disorder may be selected from a neurodegenerative disease or disorder, epilepsy, a neuromuscular disorder, or a neurodevelopmental disorder.
  • Neurodegenerative diseases and disorders that may be treated according to the methods described may be selected from, but are not limited to, Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS), diffuse Lewy body disease, motor neuron diseases, multiple sclerosis (MS), Parkinson’s disease (PD), Friedreich’s ataxia, prion disease, spinocerebellar ataxia (SCA), cerebellar ataxia, and spinal muscular atrophy (SMA).
  • AD Alzheimer’s disease
  • ALS amyotrophic lateral sclerosis
  • MS multiple sclerosis
  • PD Parkinson’s disease
  • Friedreich’s ataxia prion disease
  • SCA spinocerebellar ataxia
  • cerebellar ataxia cerebellar ataxia
  • SMA spinal muscular atrophy
  • neurodegenerative diseases and disorders that may be treated according to the methods described herein may be selected from, but are not limited to, Charcot-Marie-Tooth disease, Creutzfeldt- Jakob disease (CJD), progressive supranuclear palsy (PSP, Steele-Richardson-Olszewski syndrome), senile chorea, Huntington’s Chorea, spinal ataxia including spinocerebellar ataxia (SCA), Friedreich’s ataxia, Subacute sclerosing panencephalitis, frontotemporal lobar degeneration, and Hallerrorden-Spatz disease (Pantothenate kinase-associated neurodegeneration, PKAN).
  • CJD Creutzfeldt- Jakob disease
  • PSP Progressive supranuclear palsy
  • SEP Spinocerebellar ataxia
  • Friedreich s ataxia
  • Subacute sclerosing panencephalitis frontotemporal lobar degeneration
  • the methods described herein may be used for the treatment of ALS or frontotemporal dementia, where the patient in need of treatment may be a patient having repeat expansions in the C9ORF72 gene.
  • the GGGGCC repeat expansion in the C9ORF72 gene is the most common genetic cause of amyotrophic lateral sclerosis (ALS), accounting for about 10% of all ALS cases worldwide and 10% familial frontotemporal dementia (FTD).
  • the repeat expansion generates neurotoxic species including dipeptide repeat proteins (DPRs), nuclear RNA foci, and RNA/DNA G-quadruplexes.
  • DPRs dipeptide repeat proteins
  • nuclear RNA foci nuclear RNA foci
  • RNA/DNA G-quadruplexes RNA/DNA G-quadruplexes.
  • the repeat expansion also suppresses the production of C9ORF72 protein, a protein that normally regulates vesicle trafficking and lysosomal biogenesis.
  • C9ORF72 protein a protein that normally regulates vesicle trafficking and lysosomal biogenesis.
  • the repeat expansion in C9ORF72 triggered neurodegeneration through two mechanisms: accumulation of glutamate receptors and impaired clearance of neurotoxic dipeptide repeat proteins.
  • the methods described herein may be used for the treatment of ALS or frontotemporal dementia, where the patient in need of treatment may be a patient having repeat expansions in the C9ORF72 gene.
  • the methods described herein may be used for the treatment of ALS or frontotemporal dementia, where the patient in need of treatment may be a patient having mutations in the SOD1 gene.
  • the methods described herein may be used for the treatment of ALS or frontotemporal dementia, where the patient in need of treatment may be a patient having mutations in the TDP-43 gene.
  • the neurological disease or disorder may be dementia.
  • the patient in need of treatment of is one having an accumulation of TDP-43 aggregates, a product of the TARDBP gene, found in many sporadic and familial ALS.
  • Various forms of dementia may also be considered neurodegenerative diseases.
  • the term ‘dementia’ may describe a group of symptoms affecting memory, thinking and social abilities severely enough to interfere with daily functioning.
  • the present disclosure may provide methods of treating dementia, including AIDS dementia complex (ADC), dementia associated with Alzheimer’s disease (AD), dementia pugilistica, diffuse Lewy body disease, frontotemporal dementia, mixed dementia, senile dementia of Lewy body type, and vascular dementia.
  • ADC AIDS dementia complex
  • AD dementia associated with Alzheimer’s disease
  • AD dementia pugilistica
  • diffuse Lewy body disease dementia associated with Alzheimer’s disease
  • frontotemporal dementia dementia
  • mixed dementia senile dementia of Lewy body type
  • vascular dementia vascular dementia
  • the neurological disease or disorder may also be selected from, but not limited to, bipolar disorder, treatment resistant and major depression, general anxiety disorder, panic disorder, social anxiety, mood disorders, cognitive disorders, agitation, apathy, psychoses, post-traumatic stress disorders, irritability, disinhibition, learning disorders, memory loss, personality disorders, bipolar disorders, eating disorders, conduct disorder, pain disorders, delirium, drug addiction, tinnitus, mental retardation, cervical spondylotic myelopathy, spinal cord injury, hereditary cerebellar ataxia, Tourette syndrome, autism spectrum disorder, attention deficit hyperactivity disorder, obsessive compulsive disorder (OCD), traumatic brain injury, schizophrenia, fragile X syndrome, Parkinson’s Disease and Huntington’s disease.
  • bipolar disorder treatment resistant and major depression
  • general anxiety disorder panic disorder
  • social anxiety anxiety
  • mood disorders cognitive disorders
  • agitation apathy
  • psychoses post-traumatic stress disorders
  • irritability disinhibition
  • learning disorders memory loss
  • personality disorders bipolar disorders
  • neuromuscular disorders that may be treated according to the methods described herein may be selected from, but are not limited to, infantile spinal muscular atrophy (SMA1, Werdnig-Hoffmann disease), and juvenile spinal muscular atrophy (SMA3, Kugelberg- Welander disease).
  • SMA1 infantile spinal muscular atrophy
  • SMA3 juvenile spinal muscular atrophy
  • SMA3 Kugelberg- Welander disease
  • Neurodevelopmental disorders that may be treated according to the methods described herein may include but is not limit to Rett syndrome.
  • a “subject in need thereof’ refers to a subject in need of treatment for a neurological disease or disorder (e.g., a neurological disease or disorder as provided herein).
  • the subject in need may be one that is “non-responsive” or “refractory” to a standard therapy for the neurological disease or disorder.
  • the terms “non-responsive” and “refractory” may refer to the subject’s response to therapy as not clinically adequate to relieve one or more symptoms associated with the neurological disease” or disorder.
  • a “subject” may refer generally to a mammal.
  • the mammal may be e.g., a human, primate, mouse, rat, dog, cat, cow, horse, goat, camel, sheep, or a pig.
  • the subject may be a human.
  • the terms “subject” and “patient” may be used interchangeably herein.
  • treatment may describe the management and care of a subject having a neurological disease or disorder, and may include the administration of a therapeutic agent, or combination thereof, to slow the progression of the disease or disorder and/or to alleviate one or more symptoms of the neurological disease or disorder.
  • treating may include administering an amount of the therapeutic agent, or combination of agents, effective to alleviate one or more symptoms of the neurological disease or disorder.
  • adjuviate may refer to a process by which the severity of a symptom may be reduced or decreased, but it may not necessarily be eliminated, although it may be eliminated for a period of time, or temporarily. While elimination of the symptom may be preferred, it is not required.
  • prevention prevent or “prevent” refer to reducing or eliminating the onset of a symptom, especially in the context of preventing the progression of the disease or disorder, where progression may be defined by the onset one or more symptoms.
  • combination therapy or “co-therapy” may include the administration therapeutic agents as part of a specific treatment regimen intended to provide a beneficial effect from the co-action of these compounds.
  • the beneficial effect may result in the slowing of the progression of the neurological disease or disorder, and/or the alleviation of one or more symptoms of the neurological disease or disorder.
  • the beneficial effect of the combination may include, but is not limited to, pharmacokinetic or pharmacodynamic co-action resulting from the combination.
  • the beneficial effect of the combination may also relate to the mitigation of a toxicity, side effect, or adverse event associated with another agent in the combination.
  • “Combination therapy” may not be intended to encompass the administration of two or more of these therapeutic compounds as part of separate monotherapy regimens that incidentally and arbitrarily result in the combinations of the present disclosure.
  • a PIKfyve inhibitor e.g., apilimod, YM-201636, APY0201
  • a pharmaceutically acceptable salt thereof may be simultaneous with or sequential to the administration of one or more additional therapeutic agents e.g., a composition comprising a bile acid and 4-phenylbutyric acid (PBA), and/or the glutamatergic agent, and/or the antioxidant).
  • additional therapeutic agents e.g., a composition comprising a bile acid and 4-phenylbutyric acid (PBA), and/or the glutamatergic agent, and/or the antioxidant.
  • administration of the different components of a combination therapy may be at different frequencies.
  • the one or more additional therapeutic agents may be administered prior to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before), concomitantly with, or subsequent to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after) the administration of a PIKfyve inhibitor (e.g., apilimod, YM-201636, APY0201), or a pharmaceutically acceptable salt thereof.
  • a PIKfyve inhibitor e.g., apilimod, YM-201636, APY0201
  • the therapeutic agents may be administered in a composition.
  • the compositions may be a pharmaceutical composition.
  • a “pharmaceutical composition” is a formulation containing one or more therapeutic agents in a pharmaceutically acceptable form suitable for administration to a subject.
  • pharmaceutically acceptable may refer to those compounds, materials, compositions, carriers, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • a pharmaceutical composition may be prepared using a pharmaceutically acceptable excipient.
  • a “pharmaceutically acceptable excipient” may describe an excipient that may be useful in preparing a pharmaceutical composition that may be generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes excipient that may be acceptable for veterinary use as well as human pharmaceutical use.
  • Pharmaceutically acceptable excipients may be selected from, but are not limited to, sterile liquids, water, buffered saline, ethanol, polyol (for example, glycerol, propylene glycol, liquid polyethylene glycol and the like), oils, detergents, suspending agents, carbohydrates (e.g., glucose, lactose, sucrose or dextran), antioxidants (e.g., ascorbic acid or glutathione), chelating agents, low molecular weight proteins, or suitable mixtures thereof.
  • polyol for example, glycerol, propylene glycol, liquid polyethylene glycol and the like
  • oils for example, glycerol, propylene glycol, liquid polyethylene glycol and the like
  • detergents for example, glycerol, propylene glycol, liquid polyethylene glycol and the like
  • suspending agents e.g., carbohydrates (e.g., glucose, lactose, sucrose or dextran), antioxidants (e.g., ascor
  • a pharmaceutical composition may be provided in bulk or in dosage unit form. It may be advantageous to formulate pharmaceutical compositions in dosage unit form for ease of administration and uniformity of dosage.
  • dosage unit form as used herein may refer to physically discrete units suited as unitary dosages for the subject to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
  • the specification for the dosage unit forms of the disclosure may be dictated by and directly dependent on the unique characteristics of the active compound and the particular therapeutic effect to be achieved.
  • a dosage unit form may be an ampoule, a vial, a suppository, a dragee, a tablet, a capsule, an IV bag, or a single pump on an aerosol inhaler.
  • the dosages may vary depending on the agent, the age, weight, and clinical condition of the recipient patient, and the experience and judgment of the clinician or practitioner administering the therapy, among other factors affecting the selected dosage.
  • the dose may be a therapeutically effective amount.
  • Dosages may be provided in mg/kg/day units of measurement (which dose may be adjusted for the patient’s weight in kg, body surface area in m 2 , and age in years).
  • a “therapeutically effective amount” of a pharmaceutical composition may be that which provides an objectively identifiable improvement as noted by the clinician or other qualified observer.
  • alleviating a symptom of a disorder, disease, or condition may refer to an amount of a pharmaceutical composition to produce the desired biological effect in a subject or cell
  • a pharmaceutical composition may be in the form of an orally acceptable dosage form including, but not limited to, capsules, tablets, buccal forms, troches, lozenges, and oral liquids in the form of emulsions, aqueous suspensions, dispersions or solutions.
  • Capsules may contain mixtures of a compound of the present disclosure with inert fillers and/or diluents such as the pharmaceutically acceptable starches e.g., com, potato or tapioca starch), sugars, artificial sweetening agents, powdered celluloses, such as crystalline and microcrystalline celluloses, flours, gelatins, gums, etc.
  • carriers which are commonly used include lactose and com starch.
  • Lubricating agents such as magnesium stearate, can also be added.
  • oral administration in a capsule form useful diluents include lactose and dried com starch.
  • the compound of the present disclosure may be suspended or dissolved in an oily phase is combined with emulsifying and/or suspending agents.
  • certain sweetening and/or flavoring and/or coloring agents may be added.
  • a pharmaceutical composition may be in a solid oral dosage form.
  • a pharmaceutical composition may be in the form of a tablet.
  • the solid oral dosage form is an orally disintegrating tablet.
  • the tablet may comprise a unit dosage of a compound of the present disclosure together with an inert diluent or carrier such as a sugar or sugar alcohol, for example lactose, sucrose, sorbitol or mannitol.
  • the tablet may further comprise a non-sugar derived diluent such as sodium carbonate, calcium phosphate, calcium carbonate, or a cellulose or derivative thereof such as methyl cellulose, ethyl cellulose, hydroxypropyl methyl cellulose, and starches such as com starch.
  • the tablet may further comprise binding and granulating agents such as polyvinylpyrrolidone, disintegrants (e.g., swellable crosslinked polymers such as crosslinked carboxymethylcellulose), lubricating agents (e.g., stearates), preservatives (e.g., parabens), antioxidants (e.g., BHT), buffering agents (for example phosphate or citrate buffers), and effervescent agents such as citrate/bicarbonate mixtures.
  • binding and granulating agents such as polyvinylpyrrolidone, disintegrants (e.g., swellable crosslinked polymers such as crosslinked carboxymethylcellulose), lubricating agents (e.g., stearates), preservatives (e.g., parabens), antioxidants (e.g., BHT), buffering agents (for example phosphate or citrate buffers), and effervescent agents such as citrate/bicarbonate mixtures.
  • the tablet may be a coated tablet.
  • the coating may be a protective film coating (e.g., a wax or varnish) or a coating designed to control the release of the active agent, for example a delayed release (release of the active after a predetermined lag time following ingestion) or release at a particular location in the gastrointestinal tract.
  • a protective film coating e.g., a wax or varnish
  • a coating designed to control the release of the active agent for example a delayed release (release of the active after a predetermined lag time following ingestion) or release at a particular location in the gastrointestinal tract.
  • the latter may be achieved, for example, using enteric film coatings such as those sold under the brand name EudragitTM.
  • tablet formulations may be made by conventional compression, wet granulation or dry granulation methods and utilize pharmaceutically acceptable diluents, binding agents, lubricants, disintegrants, surface modifying agents (including surfactants), suspending or stabilizing agents, including, but not limited to, magnesium stearate, stearic acid, talc, sodium lauryl sulfate, microcrystalline cellulose, carboxymethylcellulose calcium, polyvinylpyrrolidone, gelatin, alginic acid, acacia gum, xanthan gum, sodium citrate, complex silicates, calcium carbonate, glycine, dextrin, sucrose, sorbitol, dicalcium phosphate, calcium sulfate, lactose, kaolin, mannitol, sodium chloride, talc, dry starches and powdered sugar.
  • pharmaceutically acceptable diluents including, but not limited to, magnesium stearate, stearic acid, talc, sodium lauryl
  • surface modifying agents include nonionic and anionic surface modifying agents.
  • Non-limiting examples of surface modifying agents may include, but are not limited to, poloxamer 188, benzalkonium chloride, calcium stearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters, colloidal silicon dioxide, phosphates, sodium dodecylsulfate, magnesium aluminum silicate, and triethanolamine.
  • a pharmaceutical composition may be in the form of a hard or soft gelatin capsule.
  • the compound of the present disclosure may be in a solid, semi-solid, or liquid form.
  • a pharmaceutical composition may be in the form of a sterile aqueous solution or dispersion suitable for parenteral administration.
  • parenteral includes, but is not limited to, subcutaneous, intracutaneous, intravenous, intramuscular, intra-articular, intraarterial, intrasynovial, intrastemal, intrathecal, intralesional and intracranial injection or infusion techniques.
  • a pharmaceutical composition may be in the form of a sterile aqueous solution or dispersion suitable for administration by either direct injection or by addition to sterile infusion fluids for intravenous infusion, and comprises a solvent or dispersion medium containing, water, ethanol, a polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, or one or more vegetable oils.
  • solutions or suspensions of the compound of the present disclosure as a free base or pharmacologically acceptable salt may be prepared in water suitably mixed with a surfactant.
  • suitable surfactants are given below.
  • Dispersions may also be prepared, non-limiting examples include, in glycerol, liquid polyethylene glycols and mixtures of the same in oils.
  • the pharmaceutical compositions for use in the methods of the present disclosure may further comprise one or more additives in addition to any carrier or diluent (such as lactose or mannitol) that may be present in the formulation.
  • the one or more additives may comprise or consist of one or more surfactants.
  • surfactants may have one or more long aliphatic chains such as fatty acids which enables them to insert directly into the lipid structures of cells to enhance drug penetration and absorption.
  • HLB hydrophilic-lipophilic balance
  • HLB values may be more hydrophobic, and may have greater solubility in oils, while surfactants with higher HLB values may be more hydrophilic and may have greater solubility in aqueous solutions.
  • hydrophilic surfactants may generally be considered to be those compounds having an HLB value greater than about 10
  • hydrophobic surfactants may be generally those having an HLB value less than about 10.
  • these HLB values are merely a guide since for many surfactants, the HLB values may differ by as much as about 8 HLB units, depending upon the empirical method chosen to determine the HLB value.
  • surfactants for use in the compositions of the disclosure are polyethylene glycol (PEG)-fatty acids and PEG-fatty acid mono and diesters, PEG glycerol esters, alcohol-oil transesterification products, polyglyceryl fatty acids, propylene glycol fatty acid esters, sterol and sterol derivatives, polyethylene glycol sorbitan fatty acid esters, polyethylene glycol alkyl ethers, sugar and its derivatives, polyethylene glycol alkyl phenols, polyoxyethylenepolyoxypropylene (POE-POP) block copolymers, sorbitan fatty acid esters, ionic surfactants, fat-soluble vitamins and their salts, water-soluble vitamins and their amphiphilic derivatives, amino acids and their salts, and organic acids and their esters and anhydrides.
  • PEG polyethylene glycol
  • PEG-fatty acid mono and diesters PEG glycerol esters
  • alcohol-oil transesterification products polyglyceryl
  • the therapeutic agents may be formulated for co-administration in a single dosage form, or they can be administered separately in different dosage forms. When administered separately, administration may be by the same or a different route of administration for each of the components of the combination therapy.
  • a PIKfyve inhibitor e.g., apilimod, YM-201636, APY0201
  • the PIKfyve inhibitor (e.g., apilimod), and/or AMX0035 and/or the glutamatergic agent and/or the antioxidant are administered in a single dosage form, or in separate dosage forms.
  • the term “therapeutically effective amount” refers to an amount sufficient to treat, ameliorate a symptom of, reduce the severity of, or reduce the duration of the neurological disease or disorder, or to enhance or improve the therapeutic effect of another therapy.
  • the precise effective amount for a subject may depend upon the subject’s body weight, size, and health; the nature and extent of the condition; and the therapeutic or combination of therapeutics selected for administration.
  • the combination therapy methods described herein provide a synergistic response.
  • the term “synergistic” refers to the efficacy of the combination being more than the additive effects of either single therapy alone.
  • the synergistic effect of combination therapy may permit the use of lower dosages and/or less frequent administration of at least one agent in the combination compared to its dose and/or frequency outside of the combination.
  • the synergistic effect may also be manifested in the avoidance or reduction of adverse or unwanted side effects associated with the use of either therapy in the combination alone.
  • All percentages and ratios used herein, unless otherwise indicated, are by weight. Other features and advantages of the present disclosure are apparent from the different examples.
  • the provided examples illustrate different components and methodology useful in practicing the present disclosure. The examples do not limit the claimed disclosure. Based on the present disclosure the skilled artisan can identify and employ other components and methodology useful for practicing the present disclosure.
  • Neurodegenerative diseases (ND) of the central nervous system (CNS) cause progressive loss of neuronal structure and function and their impact on society is increasing.
  • ALS amyotrophic lateral sclerosis
  • FDD frontotemporal dementia
  • PD Parkinson Disease
  • HD Huntington disease
  • ALS Amyotrophic lateral sclerosis
  • ALS often has a focal onset but subsequently spreads to different body regions, where failure of respiratory muscles typically limits survival to 2-5 years after disease onset (Goutman 2022).
  • ALS a progressive focal muscle weakness and wasting, which tends to spread with disease progression.
  • the weakness most commonly starts in the limb muscles, more often in distal muscles than in proximal muscles.
  • proximal muscles In about 25%- 30% of cases there is a bulbar onset of the disease, presenting with dysarthria, dysphagia, dysphonia, or more rarely with masseter weakness.
  • the disease is relentlessly progressive in most patients, with a median survival of about 3 years after symptom onset, where death is mostly attributed to respiratory failure. About 50% of patients will suffer from extramotor manifestations to some degree in addition to their motor problems.
  • FTD frontotemporal dementia
  • edaravone a free radical scavenger
  • riluzole a glutamate antagonist
  • NDA New Drug application
  • AMX0035 brand name Relyvrio
  • PBA sodium phenylbutyrate
  • TURSO taurursodiol
  • Apilimod dimesylate capsule is a first-in-class inhibitor of phosphatidy linositol-3- phosphate 5-kinase (PIKfyve) with an IC50 of 14nM and Kd of approximately 75 pM (range 69- 81 pM) (Gayle 2017; Cai 2013).
  • PIKfyve is a 240-kDa endosomal phosphatidylinositol (PI) 5 lipid kinase that catalyzes the phosphorylation of phosphatidylinositol 3-phosphate (PI(3)P) to phosphatidylinositol 3,5-bisphosphate (PI(3,5)P2).
  • PIKfyve normally synthesizes PI(3,5)P2 on endosomes and lysosomes, supporting lysosomal homeostasis (Rutherford 2006).
  • Pharmacological inhibition of PIKfyve with apilimod increases the activity of transcription factor EB (TFEB) (Gayle 2017), a master gene for lysosomal biogenesis that coordinates expression of lysosomal hydrolases, membrane proteins and genes involved in autophagy (Settieri 2011).
  • TFEB transcription factor EB
  • Active, nuclear TFEB levels have been found to be decreased in the brains of patients with ALS and AD (Wang 2016).
  • ALS amyotrophic lateral sclerosis
  • iMN patient-derived induced motor neurons
  • apilimod treatment ameliorated these deficits, improving neuron survival and reversing the accumulation of DPR aggregates (Shi 2018).
  • apilimod also potently inhibits the activation of microglial cells in vitro as demonstrated by the inhibition of the release of IL-12/IL-23 p40 production in response to tolllike receptor (TLR) activation. Coupled to its ability to inhibit inflammatory cytokine induction, apilimod therefore holds promise as a therapeutic for ALS.
  • Edaravone is a member of the substitute 2-pyrazolin-5-one class, has the chemical name 3-methyl-l-phenyl-2-pyrazolin-5-one.
  • Goutman 2022 the antioxidant properties
  • Edaravone protects neurons in the brain and spinal cord by eliminating the reactive oxygen species (ROS) such as hydroxyl radical, peroxyl radical, hydrogen peroxide, peroxynitrite, and many others that quicken and exacerbate the progression of neuronal degeneration, thus protecting from neurologic damage that leads to the death of motor neurons (Goutman 2022).
  • ROS reactive oxygen species
  • Edaravone also has anti-inflammatory properties against activated microglial cells which may contribute to its activity. Both oral and IV doses of Edaravone have been approved by the FDA.
  • AMX0035 is a fixed combination of the bile acid tauroursodeoxy cholic acid (TUDCA) and 4-phenylbutyric acid (PBA). AMX0035 is proposed to reduce neuronal death by simultaneously mitigating endoplasmic reticulum stress and mitochondrial dysfunction. Endoplasmic reticulum stress or dysfunction associated with protein misfolding, and aggregation has been implicated in the pathogenesis of ALS, as has disruption of mitochondrial function and structure.
  • Sodium phenylbutyrate is a histone deacetylase inhibitor that has been shown to upregulate heat shock proteins and act as a small molecular chaperone, thereby ameliorating toxicity from endoplasmic reticulum stress.
  • Taurursodiol recovers mitochondrial bioenergetic deficits through several mechanisms, including by preventing translocation of the Bax protein into the mitochondrial membrane, thus reducing mitochondrial permeability and increasing the apoptotic threshold of the cell (Paganoni 2020).
  • iPSC-derived motor neurons or growth factors-deprived iPSC-derived motor neurons (iMNs), in the case of iPSC derived from ALS patients with TDP-43 mutations.
  • iPSC derived motor neurons or growth factors-deprived iPSC-derived motor neurons (iMNs)
  • PBMC Peripheral blood mononuclear cell
  • iPSCs were generated using episomal plasmid-based reprogramming methods.
  • iPSCs were maintained in MTeSR medium according to standard Cedars Sinai protocols and differentiated into spinal neurons according to the direct induced motor neurons (diMNs) protocol, which generates a mixed population consisting of 20%-30% islet- Ipositive motor neurons (Coyne 2020). Briefly, iPSC colonies were maintained on Matrigel coated 10 cm dishes for three weeks before passaging for differentiation.
  • diMNs direct induced motor neurons
  • stage 1 media consisting of 47.5% IMDM (GIBCO), 47.5% F12 (GIBCO), 1% NEAA (GIBCO), 1% Pen/Strep (GIBCO), 2% B27 (GIBCO), 1% N2 (GIBCO), 0.2 mM LDN193189 (Stemgent), 10 mM SB431542 (StemCell Technologies), and 3 mM CHIR99021 (Sigma Aldrich) was added and exchanged daily until day 6. On day 6 of differentiation, cells were incubated in StemPro Accutase (GIBCO) for 5 minutes at 37°C.
  • Cells were collected from plates and centrifuged at 500 x g for 1.5 minutes. Cells were plated at 1 x 10 6 cells per well of a 6 well plate or 3 x 10 6 cells per T25 flask in stage 2 media consisting of 47.5% IMDM (GIBCO), 47.5% F12 (GIBCO), 1% NEAA (GIBCO), 1% Penicillin/Streptomycin (GIBCO), 2% B27 (GIBCO), 1% N2 (GIBCO), 0.2 mM LDN193189 (Stemgent), 10 mM SB431542 (StemCell Technologies), 3 mM CHIR99021 (Sigma Aldrich), 0.1 mM all-trans Retinoic Acid (RA) (Sigma Aldrich), and 1 mM Smoothened agonist (SAG) (Cayman Chemicals).
  • iMNs were plated in 24 well optical bottom plates (Cellvis) at a density of 250,000 neurons per well. Neurons were rinsed with IX PBS and fed with fresh stage 3 media daily to remove dead cells and debris. iMNs derived from TDP-43 mutated iPSC, were cultured in medium without growth factors (BDNF, GDNF and db-cAMP) for the last 48 hours.
  • BDNF growth factor
  • iMNs derived from c9orf72, SOD1 and sporadic iPSCs were then treated with glutamate by replacing media with artificial cerebrospinal fluid (ACSF) (Tocris) containing 0-, or 10-mM glutamate (Sigma Aldrich and incubated at 37°C with 5% CO2 for 4 hours. After 3.5 hours (or after the 48h growth factor depletion for the TDP-43 iMNs), one drop of NucBlueTM Live ReadyProbes (Thermo Fisher Scientific) and 1 mM propidium iodide (Thermo Fisher Scientific) and returned to the incubator for 30 minutes.
  • ACSF cerebrospinal fluid
  • iMNs were imaged with a Zeiss Axiovert microscope equipped with a Axiocam 503 videocamera, 2 images were taken (magnification 4x) and analyzed per well. PI and DAPIspots were counted using the FIJI software. Cell viability for each iMNs line and following each treatment is reported in Tables 1-3 (see also FIGURES 1- 12).
  • control bar indicates untreated cells while the DMSO bar indicates cells treated with 0.01% DMSO which is the buffer where all the compounds have been dissolved.
  • the combination of apilimod and AMX0035 provided an increase in viability of 51.62% with respect to untreated growth factor deprived cells while apilimod and AMX0035 alone provide an increase of 5.1% and 33.5%, respectively leading to a predicted additive response of 38.6% (Table 4).
  • the combination of apilimod with AMX0035 showed a synergistic effect (i.e. more than the sum of the improved viability with each compound alone) in any line tested.
  • the combination of YM201636 and AMX0035 provided an increase in viability of 46.31% with respect to glutamate while YM201636 and AMX0035 alone provide an increase of 4.15% and 30.91%, respectively leading to a predicted additive response of 35.1% (Table 5).
  • the combination provided an increase in viability of 38.7% with respect to glutamate only treated cells while YM201636 and AMX0035 alone provide an increase of 4.84% and 23.56%, respectively leading to a predicted additive response of 28.4% (Table 5).
  • the combination provided an increase in viability of 42.21% with respect untreated growth factor deprived cells while YM201636 and AMX0035 alone provide an increase of 4.03% and 27.65%, respectively leading to a predicted additive response of 32% (Table 5).
  • the combination provided an increase in viability of 40.04% with respect to glutamate only treated cells while YM201636 and AMX0035 alone provide an increase of 5.19% and 27.9%, respectively leading to a predicted additive response of 33.1% (Table 5).
  • the combination of YM201636 with AMX0035 showed a synergistic effect (i.e. more than the sum of the improved viability with each compound alone) in any line tested.
  • the combination of APY0201 and AMX0035 provided an increase in viability of 45.81% with respect to glutamate while APY0201 and AMX0035 alone provide an increase of 4.86% and 28.33%, respectively leading to a predicted additive response of 33.2% (Table 6).
  • the combination of APY0201 and AMX0035 provided an increase in viability of 45.72% with respect to glutamate while APY0201 and AMX0035 alone provide an increase of 4.02% and 30.08%, respectively leading to a predicted additive response of 34.1% (Table 6).
  • the combination of APY0201 and AMX0035 provided an increase in viability of 52.57% with respect to untreated growth factor deprived APY0201 and AMX0035 alone provide an increase of 8.34% and 32.68%, respectively leading to a predicted additive response of 41.02% (Table 6).
  • the combination of APY0201 and AMX0035 provided an increase in viability of 40.65% with respect to glutamate while APY0201 and AMX0035 alone provide an increase of 5.74% and 19.92%, respectively leading to a predicted additive response of 25.7% (Table 6).
  • the combination of APY0201 with AMX0035 showed a synergistic effect (i.e. more than the sum of the improved viability with each compound alone) in any line tested.
  • Table 1 Cell viability (Apilimod+AMX0035) with 10 pM Glutamate or growth factor depletion (TDP-43) treatment

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Abstract

L'invention concerne des méthodes de traitement d'une maladie ou d'un trouble neurologique (par exemple, la SLA) comprenant l'administration d'un inhibiteur de PIKFyve (par exemple, tout inhibiteur de PIKFyve connu ou décrit ici, comprenant, mais sans y être limité, apilimod, APY0201, et YM201636 ou un sel pharmaceutiquement acceptable de celui-ci), ou un sel pharmaceutiquement acceptable de celui-ci et une composition comprenant un acide biliaire (par exemple, TUDCA) et de l'acide 4-phénylbutyrique (PBA). Dans certains modes de réalisation, la composition comprend une combinaison fixe de TUDCA et de PBA. Dans certains modes de réalisation, d'autres agents thérapeutiques (par exemple, des agents glutamatergiques et/ou des antioxydants) sont administrés au sujet.
PCT/US2023/027231 2022-07-11 2023-07-10 Polythérapie à base d'apilimod Ceased WO2024015281A1 (fr)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2025024428A1 (fr) * 2023-07-25 2025-01-30 Amylyx Pharmaceuticals, Inc. Combinaison de taurursodiol (turso) et de phénylbutyrate de sodium pour le traitement de la paralysie supranucléaire progressive

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20210033597A1 (en) * 2018-12-31 2021-02-04 AcuraStem Incorporated Method for identifying effective treatments against neurodegenerative disorders
US20210077502A1 (en) * 2018-02-21 2021-03-18 Al Therapeutics, Inc. Combination therapy with apilimod and glutamatergic agents
US20220110948A1 (en) * 2013-03-24 2022-04-14 Amylyx Pharmaceuticals Inc. Compositions for improving cell viability and methods of use thereof

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Publication number Priority date Publication date Assignee Title
US20220110948A1 (en) * 2013-03-24 2022-04-14 Amylyx Pharmaceuticals Inc. Compositions for improving cell viability and methods of use thereof
US20210077502A1 (en) * 2018-02-21 2021-03-18 Al Therapeutics, Inc. Combination therapy with apilimod and glutamatergic agents
US20210033597A1 (en) * 2018-12-31 2021-02-04 AcuraStem Incorporated Method for identifying effective treatments against neurodegenerative disorders

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2025024428A1 (fr) * 2023-07-25 2025-01-30 Amylyx Pharmaceuticals, Inc. Combinaison de taurursodiol (turso) et de phénylbutyrate de sodium pour le traitement de la paralysie supranucléaire progressive

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