Compositions and methods for treating subjects with hepatic impairment

Abstract

Provided herein are methods of administering a combination of TURSO or a pharmaceutically acceptable salt thereof and 4-phenylbutyric acid (4-PBA) or a pharmaceutically acceptable salt thereof to a subject with hepatic impairment. Also provided are methods of treating a neurodegenerative diseases in a subject with hepatic impairment, comprising administering a combination of TURSO or a pharmaceutically acceptable salt thereof and 4-PBA or a pharmaceutically acceptable salt thereof to the subject.

Description

[0001] COMPOSITIONS AND METHODS FOR TREATING SUBJECTS WITH HEPATIC IMPAIRMENT

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims priority to U.S. Application No. 63 / 536,535, filed on September 5, 2023, the contents of which are hereby incorporated by reference in its entirety.

[0004] BACKGROUND

[0005] Hepatic impairment has the potential to alter drug pharmacokinetics and / or drug pharmacodynamics. Accordingly, there is a need for improved treatment of diseases or disorders (e.g. neurodegenerative diseases) of patients with hepatic impairment.

[0006] SUMMARY

[0007] Hepatic metabolism and excretion accounts for substantial portion of the elimination of certain compounds, including, for example bile acids such as taurursodiol or salts thereof, and 4-phenylbutyric acid (4-PBA) or salts thereof. Hepatic impairment therefore has the potential to alter the pharmacokinetics of these compounds. Applicant has found that administration of similar dosages of TURSO and sodium phenylbutyrate to subjects with hepatic impairment and subjects with normal hepatic function provide similar safety and tolerability profiles. The pharmacokinetic profiles in subjects with hepatic impairment suggest that dosing regimens used for subjects with normal hepatic function can be useful for subjects with hepatic impairment. In some cases, a reduced dosing (e.g., a 20% to 80% reduction) can be considered for subjects with more severe hepatic impairment.

[0008] In some aspects, provided herein are methods comprising administering a combination of TURSO or a pharmaceutically acceptable salt thereof and 4- phenylbutyric acid (4-PBA) or a pharmaceutically acceptable salt thereof to a subject with hepatic impairment.

[0009] In some embodiments, the subject has a Child-Pugh score of about 5-6 points. In some embodiments, the subject has a Child-Pugh score of about 7-9 points.

[0010] In some embodiments of any of the above embodiments, the methods disclosed herein include administering about 1 gram of TURSO and about 3 grams of sodium phenylbutyrate once a day. In some embodiments, the methods include administering about 1 gram of TURSO and about 3 grams of sodium phenylbutyrate twice a day. In some embodiments, the methods include administering about 1 gram of TURSO and about 3 grams of sodium phenylbutyrate once a day for about 14 days or more, followed by administering about 1 gram of TURSO and about 3 grams of sodium phenylbutyrate twice a day.

[0011] In some embodiments, the subject has a Child-Pugh score of about 10-15 points.

[0012] In some embodiments, the methods include administering a combination of TURSO and sodium phenylbutyrate to the subject, wherein TURSO is administered at an amount of less than 1 gram and sodium phenylbutyrate is administered at an amount of less than 3 grams per administration. In some embodiments, TURSO is administered at an amount of about 0.5 gram and sodium phenylbutyrate is administered at an amount of about 1.5 gram per administration. In some embodiments, TURSO is administered at an amount of about 0.5 gram and sodium phenylbutyrate is administered at an amount of about 1.5 gram twice a day.

[0013] In some embodiments of any of the above embodiments, the subject has or is suspected as having a neurodegenerative disease. In some embodiments, the neurodegenerative disease is selected from the group consisting of Amyotrophic Lateral Sclerosis (ALS), Wolfram Syndrome, and Progressive Supranuclear Palsy (PSP).

[0014] In some aspects, provided herein are methods of treating a neurodegenerative disease in a subject with hepatic impairment, comprising administering a combination of TURSO or a pharmaceutically acceptable salt thereof and 4-PB A or a pharmaceutically acceptable salt thereof to the subject. In some embodiments, the subject has a Child-Pugh score of about 5-6 points. In some embodiments, the subject has a Child-Pugh score of about 7-9 points. In some embodiments, the methods include administering about 1 gram of TURSO and about 3 grams of sodium phenylbutyrate once a day. In some embodiments, the methods include administering about 1 gram of TURSO and about 3 grams of sodium phenylbutyrate twice a day. In some embodiments, the methods include administering about 1 gram of TURSO and about 3 grams of sodium phenylbutyrate once a day for about 14 days or more, followed by administering about 1 gram of TURSO and about 3 grams of sodium phenylbutyrate twice a day.

[0015] In some embodiments, the subject has a Child-Pugh score of about 10-15 points. In some embodiments, the methods include administering a combination of TURSO and sodium phenylbutyrate to the subject, wherein TURSO is administered at an amount of less than 1 gram and sodium phenylbutyrate is administered at an amount of less than 3 grams per administration. In some embodiments, TURSO is administered at an amount of about 0.5 gram and sodium phenylbutyrate is administered at an amount of about 1.5 gram per administration. In some embodiments, TURSO is administered at an amount of about 0.5 gram and sodium phenylbutyrate is administered at an amount of about 1.5 gram twice a day. In some embodiments, the neurodegenerative disease is ALS, Wolfram Syndrome, or PSP.

[0016] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Methods and materials are described herein for use in the present invention; other, suitable methods and materials known in the art can also be used. The materials, methods, and examples are illustrative only and not intended to be limiting. All publications, patent applications, patents, sequences, database entries, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control.

[0017] Other features and advantages of the invention will be apparent from the following detailed description and figures, and from the claims.

[0018] DETAILED DESCRIPTION

[0019] Provided herein are methods of administering a combination of (1) taurursodiol (TURSO), ursodeoxycholic acid (UDCA), or pharmaceutically acceptable salts thereof and (2) 4-phenylbutyric acid (4-PB A) or pharmaceutically acceptable salts thereof to a subject with hepatic impairment. In some embodiments, the methods comprising administering a combination of TURSO or a pharmaceutically acceptable salt thereof (e.g., TURSO) and 4-PB A or a pharmaceutically acceptable salt thereof (e.g., sodium phenylbutyrate).

[0020] Hepatic metabolism and excretion accounts for substantial portion of the elimination of TURSO or a pharmaceutically acceptable salt thereof and 4-PB A or a pharmaceutically acceptable salt thereof. Hepatic impairment therefore has the potential to alter the pharmacokinetics of these compounds. Accordingly, the present disclosure provides pharmacokinetic characteristics of TURSO or a pharmaceutically acceptable salt thereof and its metabolites, including UDCA and glycoursodeoxycholic acid (GUDCA), and 4-PBA or a pharmaceutically acceptable salt thereof and its metabolites, including phenylacetic acid (PAA) and phenylacetylglutamine (PAGN), following the administration of a combination of TURSO or a pharmaceutically acceptable salt thereof and 4-PBA or a pharmaceutically acceptable salt thereof to a subject with hepatic impairment.

[0021] Some embodiments provide a method of administering a combination of TURSO and sodium phenylbutyrate to a subject in need thereof, comprising administering about 1 gram of TURSO and about 3 grams of sodium phenylbutyrate once a day for 14 days or more (e.g., about 3 weeks), followed by administering about 1 gram of TURSO and about 3 grams of sodium phenylbutyrate twice a day, wherein the subject has mild hepatic impairment. In some embodiments, the subject has a Child-Pugh score of about 5-6 points.

[0022] Some embodiments provide a method of administering a combination of TURSO and sodium phenylbutyrate to a subject in need thereof, comprising administering about 1 gram of TURSO and about 3 grams of sodium phenylbutyrate once a day for 14 days or more (e.g., about 3 weeks), followed by administering about 1 gram of TURSO and about 3 grams of sodium phenylbutyrate twice a day, wherein the subject has moderate or severe hepatic impairment. In some embodiments, the subject has a Child-Pugh score of about 7-15 points. In some embodiments, the subject has a Child-Pugh score of about 10-15 points.

[0023] Some embodiments provide a method of administering a combination of TURSO and sodium phenylbutyrate to a subject in need thereof, comprising administering TURSO at an amount of about 1 gram or less per administration and sodium phenylbutyrate at an amount of about 3 grams or less per administration, wherein the subject has moderate or severe hepatic impairment. In some embodiments, the subject has a Child-Pugh score of about 7-15 points. In some embodiments, the subject has a Child-Pugh score of about 10-15 points. In some embodiments, the dose administered to a subject with severe hepatic impairment or with a Child-Pugh score of about 10-15 points is reduced compared to a dose used for subjects with normal hepatic functions. For example, the reduction can be about 5% to about 90% (e.g., about 10%, 20%, 30%, 40%, 50%, 60% or more).

[0024] Also provided is a method of administering a combination of TURSO and sodium phenylbutyrate to a subject in need thereof, comprising administering TURSO and sodium phenylbutyrate at a frequency of twice a day or less (e.g, once a day, once every two days, or once every three days), wherein the subject has moderate or severe hepatic impairment. In some embodiments, the subject has a Child-Pugh score of about 7-15 points. In some embodiments, the subject has a Child-Pugh score of about 10-15 points.

[0025] In some aspects, provided herein are methods of treating a neurodegenerative diseases in a subject with hepatic impairment, comprising administering a combination of TURSO or a pharmaceutically acceptable salt thereof and 4-PBA or a pharmaceutically acceptable salt thereof to the subject.

[0026] Compounds

[0027] Taurursodiol

[0028] Taurursodiol (TURSO) or pharmaceutically acceptable salts thereof can be utilized in the methods disclosed herein. Taurursodiol (also called ursodoxi col taurine or tauroursodeoxy cholic acid) is a naturally occurring hydrophilic bile acid which is the taurine conjugated form of ursodeoxycholic acid (UDCA). TURSO has the following structure:

[0029] TURSO is transformed in the liver into UDCA, and glycoursodeoxycholic acid (GUDCA), and is excreted in majority in feces. UDCA and GUDCA have the following structures:

[0030] In some embodiments, a pharmaceutically acceptable salt of TURSO is utilized in the methods disclosed herein. Exemplary bases that can be used to form pharmaceutically acceptable salts of TURSO include hydroxides of alkali metals, including sodium, potassium, and lithium; hydroxides of alkaline earth metals such as calcium and magnesium; hydroxides of other metals, such as aluminum and zinc; ammonia, organic amines such as unsubstituted or hydroxyl -substituted mono-, di-, or tri-alkylamines, dicyclohexylamine; tributyl amine; pyridine; N-methyl, N- ethylamine; diethylamine; triethylamine; mono-, bis-, or tris-(2-OH-(Cl-C6)- alkylamine), such as N,N-dimethyl-N-(2 -hydroxy ethyl)amine or tri -(2- hydroxyethyl)amine; N-methyl-D-glucamine; morpholine; thiomorpholine; piperidine; pyrrolidine; and amino acids such as arginine, lysine, and the like.

[0031] In some embodiments, UDCA or a pharmaceutically acceptable salt thereof is utilized in the methods disclosed herein in place of TURSO. Exemplary bases that can be used to form pharmaceutically acceptable salts of UDCA include hydroxides of alkali metals, including sodium, potassium, and lithium; hydroxides of alkaline earth metals such as calcium and magnesium; hydroxides of other metals, such as aluminum and zinc; ammonia, organic amines such as unsubstituted or hydroxylsubstituted mono-, di-, or tri-alkylamines, dicyclohexylamine; tributyl amine; pyridine; N-methyl, N-ethylamine; diethylamine; triethylamine; mono-, bis-, or tris- (2-OH-(Cl-C6)-alkylamine), such as N,N-dimethyl-N-(2-hydroxyethyl)amine or tri - (2-hydroxyethyl)amine; N-methyl-D-glucamine; morpholine; thiomorpholine; piperidine; pyrrolidine; and amino acids such as arginine, lysine, and the like. 4-phenylbutyric acid

[0032] 4-phenylbutyric acid (4-PBA) or pharmaceutically acceptable salts thereof can be utilized in the methods disclosed herein.

[0033] 4-phenylbutyric acid is a monocarboxylic acid the structure of which is that of butyric acid substituted with a phenyl group at C-4 and has the following structure:

[0034] In some embodiments, a pharmaceutically acceptable salt of 4-PBA is utilized in the methods disclosed herein. Pharmaceutically acceptable salts of 4-PBA include, for example, sodium, potassium, magnesium, calcium, ammonium, zinc, or lithium salts. Salts of phenylbutyrate with an organic amine, such as lysine or arginine, are also contemplated herein.

[0035] In some embodiments, the pharmaceutically acceptable salt of 4-PBA is sodium phenylbutyrate with the following structure:

[0036] 4-PBA is metabolized to phenyl acetate, an active metabolite, that conjugates with glutamine via acetylation to form phenylacetylglutamine (PAGN), which is finally excreted by kidneys. PAGN has the following structure:

[0037] Methods of Treatment

[0038] Provided herein are methods for administering a combination of TURSO or a pharmaceutically acceptable salt thereof and 4-PBA or a pharmaceutically acceptable salt thereof to a subject with hepatic impairment. In some embodiments, the subject has mild hepatic impairment. In some embodiments, the subject has moderate hepatic impairment. In some embodiments, the subject has severe hepatic impairment. The severity of hepatic impairment can be determined using methods known in the art. For example, the Child-Pugh criteria can be used to determine whether a subject has mild, moderate, or severe hepatic impairment. See, e.g., Christensen, J Hepatol 41(2):344- 50 (2004).

[0039] In some embodiments, mild hepatic impairment corresponds with Child-Pugh Group A with a Child-Pugh score of 5-6 points, moderate hepatic impairment corresponds with Child-Pugh Group B with a Child-Pugh score of 7-9 points, and severe hepatic impairment corresponds with Child-Pugh Group C with a Child-Pugh score of 10-15 points, where the Child-Pugh scores are determined based on the following characteristics:

[0040] In some embodiments, ascites is assessed (e.g. by a physician by physical examination and / or ultrasound) based on the following criteria - absent: no ascites is detectable by manual and also not by ultrasound investigation; slight: ascites palpitation doubtful, but ascites measurable by ultrasound investigation; moderate: ascites detectable by palpitation and by ultrasound investigation.

[0041] In some embodiments, encephalopathy is assessed (e.g., by a physician) based on the following criteria - grade 0: normal consciousness, personality, neurological examination, electroencephalogram; grade 1 : restless, sleep-disturbed, irritable / agitated, tremor, impaired handwriting, 5 cycles per second waves; grade 2: lethargic, time-disoriented, inappropriate, asterixis, ataxia, slow triphasic waves; grade 3 : somnolent, stuporous, place-disoriented, hyper-active reflexes, rigidity, slower waves; grade 4: unrousable coma, no personality / behavior, decerebrate, slow 2 to 3 cycles per second delta activity.

[0042] In some embodiments, the subject has chronic liver disease and / or cirrhosis. In some embodiments, the subject has one of more of: liver biopsy results with histological findings consistent with cirrhosis; computerized tomographic or ultrasonographic evidence of hepatic fibrosis, with or without portal hypertension; physical examination evidence of chronic liver disease; or colloid shift on a liverspleen scan.

[0043] In some embodiments, the subject has a history of stable cirrhosis. The subject may show clinical and / or laboratory evidence of cirrhosis selected from one or more of: hepatosplenomegaly, mild to moderate ascites (e.g., a score of 2 or 3 on the Child- Pugh criteria), jaundice, mild pedal edema, spider angiomata, testicular atrophy, palmar erythema, diminished axillary and / or pubic hair, parotid gland enlargement, clubbing of the fingers, or diffuse hyperpigmentation of the skin. The subject may have one or more abnormal laboratory tests selected from alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and total bilirubin (all above the upper limit of normal), albumin and platelet count (both below the lower limit of normal), and prolonged prothrombin time.

[0044] The methods described herein can include selecting a subject with mild, moderate, or severe hepatic impairment, prior to administration of a combination of TURSO or a pharmaceutically acceptable salt thereof and 4-PB A or a pharmaceutically acceptable salt thereof. In some embodiments, the methods include selecting a subject that is Child-Pugh Group A or has a Child-Pugh score of about 5-6 points. In some embodiments, the methods include selecting a subject that is Child- Pugh Group B or has a Child-Pugh score of about 7-9 points. In some embodiments, the methods include selecting a subject that is Child-Pugh Group C or has a Child- Pugh score of about 10-15 points.

[0045] In some embodiments, the methods include administering a combination of TURSO and sodium phenylbutyrate to the subject.

[0046] In some embodiments, the subject has or is suspected as having one or more neurodegenerative diseases. In some embodiments, the subject has or is suspected as having Amyotrophic Lateral Sclerosis (ALS), Wolfram Syndrome, a tauopathy selected from the group consisting of progressive supranuclear palsy (PSP), Alzheimer’s disease (AD), cerebral amyloid angiopathy, corticobasal degeneration, Creutzfeldt- Jakob disease, dementia pugilistica, diffuse neurofibrillary tangles with calcification, Down's syndrome, frontotemporal dementia (FTD), frontotemporal dementia with parkinsonism linked to chromosome 17, frontotemporal lobar degeneration (FTLD-TAU), corticobasal degeneration, Pick’s disease, argyrophilic grain disease, post-encephalitic parkinsonism, chronic traumatic encephalopathy, primary age-related tauopathy, stroke, traumatic brain injury, Gerstmann-Straussler- Scheinker disease, Hallervorden-Spatz disease, inclusion body myositis, multiple system atrophy, myotonic dystrophy, Niemann-Pick disease type C, non-Guamanian motor neuron disease with neurofibrillary tangles, postencephalitic parkinsonism, prion protein cerebral amyloid angiopathy, progressive subcortical gliosis, subacute sclerosing panencephalitis, tangle only dementia, multi-infarct dementia, and ischemic stroke.

[0047] Some embodiments provide methods of treating one or more neurodegenerative diseases in a subject with hepatic impairment, comprising administering TURSO or a pharmaceutically acceptable salt thereof and phenylbutyric acid or a pharmaceutically acceptable salt thereof to the subject.

[0048] Non-limiting examples of neurodegenerative diseases that can be treated using the methods disclosed herein include Amyotrophic Lateral Sclerosis (ALS), Wolfram Syndrome, a tauopathy selected from the group consisting of progressive supranuclear palsy (PSP), Alzheimer’s disease (AD), cerebral amyloid angiopathy, corticobasal degeneration, Creutzfeldt- Jakob disease, dementia pugilistica, diffuse neurofibrillary tangles with calcification, Down's syndrome, frontotemporal dementia (FTD), frontotemporal dementia with parkinsonism linked to chromosome 17, frontotemporal lobar degeneration (FTLD-TAU), corticobasal degeneration, Pick’s disease, argyrophilic grain disease, post-encephalitic parkinsonism, chronic traumatic encephalopathy, primary age-related tauopathy, stroke, traumatic brain injury, Gerstmann-Straussler-Scheinker disease, Hallervorden-Spatz disease, inclusion body myositis, multiple system atrophy, myotonic dystrophy, Niemann-Pick disease type C, non-Guamanian motor neuron disease with neurofibrillary tangles, postencephalitic parkinsonism, prion protein cerebral amyloid angiopathy, progressive subcortical gliosis, subacute sclerosing panencephalitis, tangle only dementia, multi-infarct dementia, and ischemic stroke.

[0049] Treatment of neurodegenerative diseases using the compounds disclosed herein (e.g., TURSO or a pharmaceutically acceptable salt thereof and 4-PBA or a pharmaceutically acceptable salt thereof) are described in U.S. Pat No. 9,872,865, U.S. Patent Publication No. 20210186990, and PCT publication No. WO 2023081482, the contents of which are incorporated herein in their entirety. Methods described in the present disclosure can include treatment of a disease or disorder per se, as well as treatment for one or more symptoms of the disease or disorder. “Treating” a disease does not require 100% abolition of the disease or disease symptoms in the subject. Any relief or reduction in the severity of symptoms or features of the disease is contemplated. In some embodiments, “treating” may be or comprise a delay in onset of symptoms or delay in progression of symptoms or the loss of function associated with the disease; alternatively or additionally, in some embodiments, “treating” may be or comprise a reduction in the frequency or severity of symptoms or features of the disease; alternatively or additionally, “treating” may be or comprise eliminating or reducing one or more side effects of a treatment or eliminating or reducing one or more direct or indirect effects of disease progression. The subject may not exhibit signs of the disease but may be at risk for the disease. The disclosure contemplates any degree of delay in the onset of symptoms, alleviation of one or more symptoms of the disease, or delay in the progression of any one or more disease symptoms.

[0050] In some embodiments, the methods include selection of a subject, for example, by obtaining a sample from a candidate subject and testing the sample for an indication that the subject is suitable for selection. The subject can be confirmed or identified, e.g. by a health care professional, as having a condition or disease or at risk for developing the condition or disease. Multiple parties can be included in subject selection. For example, a first party can obtain a sample from a candidate subject and a second party can test the sample. In some instances, subjects are selected and / or referred by a medical practitioner (e.g., a general practitioner). Samples can include, for example, cells or populations of cells.

[0051] The terms “administer”, “administering”, or “administration” as used herein refers to administering the compounds described herein to a subject using any art- known method, e.g., ingesting, injecting, implanting, absorbing, or inhaling, the drug, regardless of form. In some embodiments, one or more of the compounds disclosed herein can be administered to a subject by ingestion orally. For example, the methods include administration of an effective amount of compound or compound composition to achieve the desired or stated effect. Specific dosage and treatment regimens for any particular subject will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health status, sex, diet, time of administration, rate of excretion, drug combination, the severity and course of the disease, condition or symptoms, the subject’s disposition to the disease, condition or symptoms, and the judgment of the treating physician.

[0052] Following administration, the subject can be evaluated to detect, assess, or determine their level of disease. In some embodiments, treatment can continue until a change (e.g., reduction) in the level of disease in the subject is detected. In some embodiments, treatment methods can include assessing a level of disease in the subject prior to treatment, during treatment, and / or after treatment.

[0053] Upon improvement of a patient's condition (e.g., a change (e.g., decrease) in the level of disease in the subject), a maintenance dose of a compound, composition or combination of this disclosure may be administered, if necessary. Subsequently, the dosage or frequency of administration, or both, may be reduced, as a function of the symptoms, to a level at which the improved condition is retained. Patients may, however, require intermittent treatment on a long-term basis upon any recurrence of disease symptoms.

[0054] The term “subject” as used herein, refers to any animal. In some instances, the subject is a mammal. In some instances, the term “subject”, as used herein, refers to a human (e.g., a man, a woman, or a child).

[0055] Some embodiments further include determining or having determined one or more pharmacokinetic parameters of one or more agents in the subject, wherein the one or more agents are selected from the group consisting of 4-PBA or pharmaceutically acceptable salts thereof, phenylacetic acid (PAA), phenylacetylglutamine (PAGN), TURSO or pharmaceutically acceptable salts thereof, ursodeoxycholic acid (UDCA), and (glycoursodeoxycholic acid) GUDCA.

[0056] The pharmacokinetic parameters can include one or more of the following:

[0057]

[0058] The pharmacokinetic parameters can be determined using techniques known in the art using a biological sample (e.g., a blood or urine sample) of the subject. Dosing

[0059] The compounds of the present disclosure can generally be administered in a therapeutically effective amount. An “effective amount” is an amount sufficient to effect beneficial or desired results. For example, a therapeutically effective amount can be one that achieves the desired therapeutic effect. This amount can be the same or different from a prophylactically effective amount, which is an amount necessary to prevent onset of disease or disease symptoms. An effective amount can be administered in one or more administrations, applications or dosages. A therapeutically effective amount of a therapeutic compound (i.e., an effective dosage) depends on the therapeutic compounds selected. The skilled artisan will appreciate that certain factors may influence the dosage and timing required to effectively treat a subject, including but not limited to the severity of the disease or disorder, previous treatments, the general health and / or age of the subject, and other diseases present. Moreover, treatment of a subject with a therapeutically effective amount of the therapeutic compounds described herein can include a single treatment or a series of treatments.

[0060] TURSO or a pharmaceutically acceptable salt thereof (e.g., TURSO) and 4- PBA or a pharmaceutically acceptable salt thereof (e.g., sodium phenylbutyrate) can be administered separately or concurrently, including as a part of a regimen of treatment. The compounds can be administered daily (e.g. once a day, twice a day, or three times a day or more), weekly, monthly, or quarterly. The compounds can be administered over a period of weeks, months, or years. For example, the compounds can be administered over a period of at least or about 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 1 year, 2 years, 3 years, 4 years, or at least or about 5 years, or more.

[0061] TURSO or a pharmaceutically acceptable salt thereof (e.g., TURSO) can be administered at an amount of about 0.5 to about 5 grams per day (e.g., about 0.5 to about 4.5, about 0.5 to about 4, about 0.5 to about 3.5, about 0.5 to about 3, about 0.5 to about 2.5, about 0.5 to about 2, about 0.5 to about 1.5, about 0.5 to about 1, about 1 to about 5, about 1 to about 4.5, about 1 to about 4, about 1 to about 3.5, about 1 to about 3, about 1 to about 2.5, about 1 to about 2, about 1 to about 1.5, about 1.5 to about 5, about 1.5 to about 4.5, about 1.5 to about 4, about 1.5 to about 3.5, about 1.5 to about 3, about 1.5 to about 2.5, about 1.5 to about 2, about 2 to about 5, about 2 to about 4.5, about 2 to about 4, about 2 to about 3.5, about 2 to about 3, about 2 to about 2.5, about 2.5 to about 5, about 2.5 to about 4.5, about 2.5 to about 4, about 2.5 to about 3.5, about 2.5 to about 3, about 3 to about 5, about 3 to about 4.5, about 3 to about 4, about 3 to about 3.5, about 3.5 to about 5 about 3.5 to about 4.5, about 3.5 to about 4, about 4 to about 5, about 4 to about 4.5, or about 4.5 to about 5 grams per day). In some embodiments, TURSO or a pharmaceutically acceptable salt thereof (e.g., TURSO) is administered at an amount of about 1 to about 2 grams per day (e.g., about 1 to about 1.8 grams, about 1 to about 1.6 grams, about 1 to about 1.4 grams, about 1 to about 1.2 grams, about 1.2 to about 2.0 grams, about 1.2 to about 1.8 grams, about 1.2 to about 1.6 grams, about 1.2 to about 1.4 grams, about 1.4 to about 2.0 grams, about 1.4 to about 1.8 grams, about 1.4 to about 1.6 grams, about 1.6 to about 2.0 grams, about 1.6 to about 1.8 grams, about 1.8 to about 2.0 grams). In some embodiments, TURSO is administered at an amount of about 1 gram per day. For example, TURSO can be administered at an amount of about 1 gram once a day. In some embodiments, TURSO is administered at an amount of about 2 grams per day. For example, TURSO can be administered at an amount of about 1 gram twice a day.

[0062] 4-PBA or a pharmaceutically acceptable salt thereof (e.g., sodium phenylbutyrate) can be administered at an amount of about 0.5 to about 10 grams per day (e.g., about 1 to about 10, about 1 to about 9, about 1 to about 8, about 1 to about 7, about 1 to about 6, about 1 to about 5, about 1 to about 4, about 1 to about 3, about 1 to about 2, about 2 to about 10, about 2 to about 9, about 2 to about 8, about 2 to about 7, about 2 to about 6, about 2 to about 5, about 2 to about 4, about 2.5 to about 9.5, about 2.5 to about 8.5, about 2.5 to about 7.5, about 2.5 to about 6.5, about 2.5 to about 5.5, about 2.5 to about 4.5, about 3 to about 10, about 3 to about 9, about 3 to about 8, about 3 to about 7, about 3 to about 6.5, about 3 to about 6, about 3 to about 5, about 4 to about 10, about 4 to about 9, about 4 to about 8, about 4 to about 7, about 4 to about 6, about 5 to about 10, about 5 to about 9, about 5 to about 8, about 5 to about 7, about 6 to about 10, about 6 to about 9, about 6 to about 8, about 7 to about 10, about 7 to about 9, about 8 to about 10 grams per day). In some embodiments, 4- PBA or a pharmaceutically acceptable salt thereof (e.g., sodium phenylbutyrate) is administered at an amount of about 3 to about 6 grams per day (e.g., about 3 to about 5.5 grams, about 3 to about 5.0 grams, about 3 to about 4.5 grams, about 3 to about 4.0 grams, about 3 to about 3.5 grams, about 3.5 to about 6 grams, about 3.5 to about 5.5 grams, about 3.5 to about 5.0 grams, about 3.5 to about 4.5 grams, about 3.5 to about 4.0 grams, about 4.0 to about 6 grams, about 4.0 to about 5.5 grams, about 4.0 to about 5.0 grams, about 4.0 to about 4.5 grams, about 4.5 to about 6 grams, about 4.5 to about 5.5 grams, about 4.5 to about 5.0 grams, about 5.0 to about 6 grams, about 5.0 to about 5.5 grams, or about 5.5 to about 6.0 grams). In some embodiments, sodium phenylbutyrate is administered at an amount of about 3 grams per day. For example, sodium phenylbutyrate can be administered at an amount of about 3 grams once a day. In some embodiments, sodium phenylbutyrate is administered at an amount of about 6 grams per day. For example, sodium phenylbutyrate can be administered at an amount of about 3 grams twice a day.

[0063] In some embodiments, the TURSO or a pharmaceutically acceptable salt thereof (e.g., TURSO) and 4-PBA or a pharmaceutically acceptable salt thereof (e.g., sodium phenylbutyrate) are administered at a ratio by weight of about 2.5: 1 to about 3.5: 1 (e.g., about 3: 1).

[0064] The methods described herein can include administering about 1 gram of TURSO once a day and about 3 grams of sodium phenylbutyrate once a day, or about 1 gram of TURSO twice a day and about 3 grams of sodium phenylbutyrate twice a day. In some embodiments, the methods include administering about 1 gram of TURSO once a day and about 3 grams of sodium phenylbutyrate once a day for at least about 14 days (e.g., at least about 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 27, 30, 35, or 40 days), followed by administering about 1 gram of TURSO twice a day and about 3 grams of sodium phenylbutyrate twice a day (e.g. for about 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 1 year, 2 years, 3 years, 4 years, or at least or about 5 years, or more).

[0065] In some embodiments, the methods described herein include administering to a subject about 5 mg / kg to about 100 mg / kg of body weight (e.g. about 10 to about 50, about 5 to about 10, about 10 to about 15, about 15 to about 20, about 20 to about 25, about 25 to about 30, about 30 to about 35, about 35 to about 40, about 40 to about 45, about 45 to about 50, about 50 to about 55, about 55 to about 60, about 60 to about 65, about 65 to about 70, about 70 to about 75, about 75 to about 80, about 80 to about 85, about 85 to about 90, about 90 to about 95, or about 95 to about 100 mg / kg of body weight) of TURSO or a pharmaceutically acceptable salt thereof (e.g., TURSO).

[0066] In some embodiments, the methods described herein include administering to a subject about 10 mg / kg to about 400 mg / kg of body weight (e.g., about 10 to about 15, about 15 to about 20, about 20 to about 25, about 25 to about 30, about 30 to about 35, about 35 to about 40, about 40 to about 45, about 45 to about 50, about 50 to about 55, about 55 to about 60, about 60 to about 65, about 65 to about 70, about 70 to about 100, about 100 to about 150, about 150 to about 200, about 200 to about 300, or about 300 to about 400 mg / kg of body weight) of 4-PBA or a pharmaceutically acceptable salt thereof (e.g., sodium phenylbutyrate).

[0067] In some embodiments, TURSO or a pharmaceutically acceptable salt thereof (e.g., TURSO) is administered in an amount of about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 mg / kg of the subject’s body weight. In some embodiments, 4-PBA or a pharmaceutically acceptable salt thereof (e.g., sodium phenylbutyrate) is administered in an amount of about 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 100, or 150 mg / kg of body weight.

[0068] In some embodiments, the dosage and frequency of administration for a subject with mild hepatic impairment or a subject having a Child-Pugh score of about 5-6 points is substantially the same as those for a subject without hepatic impairment. In some embodiments, the dosage and frequency of administration for a subject with moderate or severe hepatic impairment or a subject having a Child-Pugh score of about 7-15 points is substantially the same as those for a subject without hepatic impairment. In some embodiments, the amount of the compounds administered to a subject with moderate or severe hepatic impairment or a subject having a Child-Pugh score of about 7-15 points per administration is less than that administered to a subject without hepatic impairment. In some embodiments, the frequency of administration for a subject with moderate or severe hepatic impairment or a subject having a Child- Pugh score of about 7-15 points is less frequent as compared to a subject without hepatic impairment.

[0069] Some embodiments provide a method of administering TURSO and sodium phenylbutyrate to a subject in need thereof, comprising administering about 1 gram of TURSO and about 3 grams of sodium phenylbutyrate once a day for about 3 weeks, followed by administering about 1 gram of TURSO and about 3 grams of sodium phenylbutyrate twice a day (e.g., for about weeks, months, or years), wherein the subject has mild hepatic impairment. In some embodiments, the subject has a Child- Pugh score of about 5-6 points. Some embodiments provide a method of administering TURSO and sodium phenylbutyrate to a subject in need thereof, comprising administering about 1 gram of TURSO and about 3 grams of sodium phenylbutyrate once a day for about 3 weeks, followed by administering about 1 gram of TURSO and about 3 grams of sodium phenylbutyrate twice a day (e.g., for about weeks, months, or years), wherein the subject has moderate or severe hepatic impairment. In some embodiments, the subject has a Child-Pugh score of about 7-15 points. In some embodiments, the subject has a Child-Pugh score of about 7-9 points. In some embodiments, the subject has a Child- Pugh score of about 10-15 points.

[0070] Some embodiments provide a method of administering a combination of TURSO and sodium phenylbutyrate to a subject in need thereof, comprising administering at an amount of about 1 gram or less per administration (e.g., about 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2 or 0.1 grams per administration), and sodium phenylbutyrate at an amount of about 3 grams or less per administration (e.g., about 2.8, 2.7, 2.6, 2.5, 2.4, 2.3, 2.2, 2.1, 2, 1.9, 1.8, 1.7, 1.6, 1.5, 1.4, 1.3, 1.2, 1.1, 1, 0.9, 0.8, 0.7, or 0.6 grams per administration), wherein the subject has moderate or severe hepatic impairment. In some embodiments, the subject has a Child-Pugh score of about 7-15 points. In some embodiments, the subject has a Child-Pugh score of about 7-9 points. In some embodiments, the subject has a Child-Pugh score of about 10-15 points. For example, provided here are methods of administering a combination of TURSO and sodium phenylbutyrate to a subject with severe hepatic impairment or a Child-Pugh score of about 10-15 points, comprising administering about 0.5 gram of TURSO and about 1.5 gram of sodium phenylbutyrate twice daily.

[0071] In some embodiments, the dose administered to a subject with severe hepatic impairment or with a Child-Pugh score of about 10-15 points is reduced compared to a dose used for subjects with normal hepatic functions. For example, the reduction can be about 5% to about 90% (e.g., about 10%, 20%, 30%, 40%, 50%, 60% or more) per administration. In some embodiments, the dose reduction is about 50% per administration.

[0072] Some embodiments provide a method of administering a combination of TURSO and sodium phenylbutyrate to a subject in need thereof, comprising administering TURSO and sodium phenylbutyrate at a frequency of twice a day or less, wherein the subject has moderate or severe hepatic impairment. In some embodiments, the subject has a Child-Pugh score of about 7-15 points. In some embodiments, the TURSO and sodium phenylbutyrate are administered at a frequency of once a day. In some embodiments, the TURSO and sodium phenylbutyrate are administered at a frequency of less than once a day (e.g., once every two days, once every three days, once every four days, once every five days, once every six days, or once every seven days). In some embodiments, the subject has a Child-Pugh score of about 7-9 points. In some embodiments, the subject has a Child-Pugh score of about 10-15 points.

[0073] Pharmaceutical Composition

[0074] When employed as pharmaceuticals, the compounds of the disclosure can be administered in the form of pharmaceutical compositions. A pharmaceutical composition refers to a combination of one or more compounds of the present disclosure, and at least one pharmaceutically acceptable carrier. For example, the present disclosure provides pharmaceutical compositions comprising TURSO or a pharmaceutically acceptable salt thereof separately or in combination with 4-PBA or a pharmaceutically acceptable salt thereof. The TURSO or a pharmaceutically acceptable salt thereof and the 4-PBA or a pharmaceutically acceptable salt thereof can be in separate dosage forms or in the same dosage form.

[0075] These compositions can be prepared in a manner well known in the pharmaceutical art, and can be administered by a variety of routes, depending upon whether local or systemic treatment is desired and upon the area to be treated.

[0076] Pharmaceutical compositions are typically formulated to be compatible with its intended route of administration. Examples of routes of administration include parenteral (subcutaneous, intracutaneous, intravenous, intradermal, intramuscular, intra-articular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques), oral (e.g., inhalation), transdermal (topical), transmucosal, and rectal administration.

[0077] Pharmaceutical compositions can be in the form of a solution or powder. Suitable powders may include those that are substantially soluble in water. Pharmaceutical compositions may be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as, for example, Tween 80) and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3 -butanediol. Among the acceptable vehicles and solvents that may be employed are mannitol, water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, or carboxymethyl cellulose or similar dispersing agents which are commonly used in the formulation of pharmaceutically acceptable dosage forms such as emulsions and or suspensions. Other commonly used surfactants such as Tweens or Spans and / or other similar emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.

[0078] Pharmaceutical compositions can be orally administered in any orally acceptable dosage form including, but not limited to, powders, capsules, tablets, emulsions and aqueous suspensions, dispersions and solutions, or hydrogel formulations. In the case of powders for oral administration, the powders can be substantially dissolved in water prior to administration. In the case of tablets for oral use, carriers which are commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, may be added. For oral administration in a capsule form, useful diluents include lactose and dried com starch. When aqueous suspensions and / or emulsions are administered orally, the active ingredient may be suspended or dissolved in an oily phase is combined with emulsifying and / or suspending agents. If desired, certain sweetening, flavoring, or coloring agents may be added.

[0079] Pharmaceutical compositions can also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and / or other solubilizing or dispersing agents known in the art. The pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration. In some embodiments, the invention provides kits that include the bile acid and phenylbutyrate compounds. The kit may also include instructions for the physician and / or patient, syringes, needles, box, bottles, vials, etc.

[0080] In some embodiments, TURSO or a pharmaceutically acceptable salt thereof and 4-PBA or a pharmaceutically acceptable salt thereof are formulated as a single dosage form. In some embodiments, the pharmaceutical composition utilized for the methods disclosed herein include TURSO and sodium phenylbutyrate and one or more excipients. The pharmaceutical composition can include about 5% to about 15% w / w (e.g., about 6% to about 14%, about 7% to about 13 %, about 8% to about 12%, about 8% to about 11%, about 9% to about 10 %, or about 9.7% w / w) of TURSO and about 15% to about 45% w / w (e.g., about 20% to about 40%, about 25% to about 35%, about 28% to about 32%, or about 29% to about 30%, e.g., about 29.2% w / w) of sodium phenylbutyrate. In some embodiments, the composition includes about 9.7% w / w of TURSO and 29.2% w / w of sodium phenylbutyrate. The sodium phenylbutyrate and TURSO can be present in the composition at a ratio by weight of between about 1 : 1 to about 4: 1 (e.g., about 2: 1 or about 3: 1). In some embodiments, the ratio between sodium phenylbutyrate and TURSO is about 3: 1.

[0081] Compositions of the present disclosure can include about 8% to about 24% w / w of dextrates (e.g., about 9% to about 23%, about 10% to about 22%, about 10% to about 20%, about 11% to about 21%, about 12% to about 20%, about 13% to about 19%, about 14% to about 18%, about 14% to about 17%, about 15% to about 16%, or about 15.6% w / w of dextrates). Both anhydrous and hydrated dextrates are contemplated herein. The dextrates of the present disclosure can include a mixture of saccharides developed from controlled enzymatic hydrolysis of starch. Some embodiments of any of the compositions described herein include hydrated dextrates (e.g., NF grade, obtained from JRS Pharma, Colonial Scientific, or Quadra).

[0082] In some embodiments, the pharmaceutical composition includes about 1% to about 6% w / w of sugar alcohol (e.g., about 2% to about 5%, about 3% to about 4%, or about 3.9% w / w of sugar alcohol). Sugar alcohols can be derived from sugars and contain one hydroxyl group (-OH) attached to each carbon atom. Both disaccharides and monosaccharides can form sugar alcohols. Sugar alcohols can be natural or produced by hydrogenation of sugars. Exemplary sugar alcohols include but are not limited to, sorbitol, xylitol, and mannitol. In some embodiments, the pharmaceutical composition comprises about 1% to about 6% w / w (e.g., about 2% to about 5%, about 3% to about 4%, or about 3.9% w / w) of sorbitol.

[0083] In some embodiments, the pharmaceutical composition includes about 22% to about 35% w / w of maltodextrin (e.g., about 22% to about 33%, about 24% to about 31%, about 25% to about 32%, about 26% to about 30%, or about 28% to about 29% w / w, e.g., about 28.3% w / w of maltodextrin). Maltodextrin can form a flexible helix enabling the entrapment of the active ingredients (e.g., any of the phenylbutyrate compounds and bile acids described herein) when solubilized into solution, thereby masking the taste of the active ingredients. Maltodextrin produced from any suitable sources are contemplated herein, including but not limited to, pea, rice, tapioca, com, and potato. In some embodiments, the maltodextrin is pea maltodextrin. In some embodiments, the composition includes about 28.3% w / w of pea maltodextrin. For example, pea maltodextrin obtained from Roquette (KLEPTOSE® LINECAPS) can be used.

[0084] In some embodiments, the pharmaceutical composition includes sugar substitutes (e.g. sucralose). For example, the compositions can include about 0.5% to about 5% w / w of sucralose (e.g., about 1% to about 4%, about 1% to about 3%, or about 1% to about 2%, e.g., about 1.9% w / w of sucralose). Other sugar substitutes contemplated herein include but are not limited to aspartame, neotame, acesulfame potassium, saccharin, and advantame.

[0085] In some embodiments, the pharmaceutical composition includes one or more flavorants. In some embodiments, the pharmaceutical composition includes about 2% to about 15% w / w of flavorants (e.g., about 3% to about 13%, about 3% to about 12%, about 4% to about 9%, about 5% to about 10%, or about 5% to about 8%, e.g., about 7.3% w / w). Flavorants can include substances that give another substance flavor, or alter the characteristics of a composition by affecting its taste. Flavorants can be used to mask unpleasant tastes without affecting physical and chemical stability, and can be selected based on the taste of the drug to be incorporated. Suitable flavorants include but are not limited to natural flavoring substances, artificial flavoring substances, and imitation flavors. Blends of flavorants can also be used. For example, the compositions described herein can include two or more (e.g., two, three, four, five or more) flavorants. Flavorants can be soluble and stable in water. Selection of suitable flavorants can be based on taste testing. For example, multiple different flavorants can be added to a composition separately, which are subjected to taste testing. Exemplary flavorants include any fruit flavor powder (e.g., peach, strawberry, mango, orange, apple, grape, raspberry, cherry or mixed berry flavor powder). In some embodiments, the pharmaceutical composition includes about 0.5% to about 1.5% w / w (e.g., about 1% w / w) of a mixed berry flavor powder and / or about 5% to about 7% w / w (e.g., about 6.3% w / w) of a masking flavor.

[0086] In some embodiments, the pharmaceutical composition further includes silicon dioxide or silica. Addition of silica to the composition can prevent or reduce agglomeration of the components of the composition. Silica can serve as an anticaking agent, adsorbent, disintegrant, or glidant. In some embodiments, the pharmaceutical composition includes about 0.1% to about 2% w / w (e.g., about 0.3% to about 1.5%, about 0.5% to about 1.2%, or about 0.8% to about 1%, e.g., 0.9% w / w) of silica. In soe embodiments, the silica is porous silica. Porous silica may have a higher H2O absorption capacity and / or a higher porosity as compared to fumed silica, at a relative humidity of about 20% or higher (e.g., about 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% or higher). The porous silica can have an H2O absorption capacity of about 5% to about 40% (e.g. about 20% to about 40%, or about 30% to about 40%) by weight at a relative humidity of about 50%. The porous silica can have a higher porosity at a relative humidity of about 20% or higher (e.g., about 30%, 40%, 50%, 60%, 70%, 80%, 90% or higher) as compared to that of fumed silica. In some embodiments, the porous silica have an average particle size of about 2 pm to about 10 pm (e.g. about 3 pm to about 9 pm, about 4 pm to about 8 pm, about 5 pm to about 8 pm, or about 7.5 pm). In some embodiments, the porous silica have an average pore volume of about 0.1 cc / gm to about 2.0 cc / gm (e.g., about 0.1 cc / gm to about 1.5 cc / gm, about 0.1 cc / gm to about 1 cc / gm, about 0.2 cc / gm to about 0.8 cc / gm, about 0.3 cc / gm to about 0.6 cc / gm, or about 0.4 cc / gm). In some embodiments, the porous silica have a bulk density of about 50 g / L to about 700 g / L (e.g. about 100 g / L to about 600 g / L, about 200 g / L to about 600 g / L, about 400 g / L to about 600 g / L, about 500 g / L to about 600 g / L, about 540 g / L to about 580 g / L, or about 560 g / L). In some embodiments, the compositions described herein include about 0.05% to about 2% w / w (e.g., any subranges of this range described herein) of Syloid® 63FP (WR Grace).

[0087] In some embodiments, the pharmaceutical composition includes one or more buffering agents. For example, the compositions can include about 0.5% to about 5% w / w (e.g., about 1% to about 4% w / w, about 1.5% to about 3.5% w / w, or about 2% to about 3% w / w, e.g. about 2.7% w / w) of buffering agents. Buffering agents can include weak acid or base that maintain the acidity or pH of a composition near a chosen value after addition of another acid or base. Suitable buffering agents are known in the art. In some embodiments, the buffering agent is a phosphate, such as a sodium phosphate (e.g., sodium phosphate dibasic anhydrous). For example, the pharmaceutical composition can include about 2.7% w / w of sodium phosphate dibasic.

[0088] The pharmaceutical composition can also include one or more lubricants. For example, the compositions can include about 0.05% to about 1% w / w (e.g., about 0.1% to about 0.9%, about 0.2% to about 0.8 %, about 0.3% to about 0.7%, or about 0.4% to about 0.6%, e.g. about 0.5% w / w) of lubricants. Exemplary lubricants include, but are not limited to sodium stearyl fumarate, magnesium stearate, stearic acid, metallic stearates, talc, waxes and glycerides with high melting temperatures, colloidal silica, polyethylene glycols, alkyl sulphates, glyceryl behenate, and hydrogenated oil. Additional lubricants are known in the art. In some embodiments, the pharmaceutical composition includes about 0.05% to about 1% w / w (e.g., any of the subranges of this range described herein) of sodium stearyl fumarate. For example, the pharmaceutical composition can include about 0.5% w / w of sodium stearyl fumarate.

[0089] In some embodiments, the pharmaceutical composition includes about 29.2% w / w of sodium phenylbutyrate, about 9.7% w / w of TURSO, about 15.6% w / w of dextrates, about 3.9% w / w of sorbitol, about 1.9% w / w of sucralose, about 28.3% w / w of maltodextrin, about 7.3% w / w of flavorants, about 0.9% w / w of silicon dioxide, about 2.7% w / w of sodium phosphate (e.g. sodium phosphate dibasic), and about 0.5% w / w of sodium stearyl fumerate.

[0090] In some embodiments, the pharmaceutical composition further includes one or both of acacia and medium-chain triglycerides. EXAMPLES

[0091] The invention is further described in the following examples, which do not limit the scope of the invention described in the claims.

[0092] Example 1: Clinical study

[0093] A clinical study is conducted to evaluate the pharmacokinetic characteristics of sodium phenylbutyrate and its major metabolites and ursodeoxicoltaurine (TURSO) and its major metabolites, as well as the safety and tolerability of AMX0035 (sodium phenylbutyrate and TURSO), in participants with hepatic function impairment and in healthy participants.

[0094] Study Objectives

[0095] The primary objective of the study is to evaluate the PK characteristics of sodium phenylbutyrate (PB) and its major metabolites, phenylacetic acid (PAA) and phenylacetylglutamine (PAGN), and ursodoxicol taurine (TURSO) and its major metabolites, ursodeoxycholic acid (UDCA) and glycoursodeoxycholic acid (GUDCA), after a single dose and following multiple doses of AMX0035 in participants with hepatic function impairment and in healthy participants.

[0096] The secondary objective of the study is to evaluate the safety and tolerability of AMX0035 in participants with impaired hepatic function and in healthy participants.

[0097] Endpoints

[0098] A primary endpoint is a comparison of blood PK parameters for PB, PAA, PAGN, TURSO, UDCA, and GUDCA between healthy participants and participants with disease severities (mild, moderate, and severe). A further primary endpoint is a comparison of urine PK parameters for PB, PAA, and PAGN between healthy participants and participants with disease severities (mild, moderate, and severe).

[0099] Secondary endpoints include:

[0100] • Frequency of TEAEs in healthy participants and participants with disease severities (mild, moderate, and severe)

[0101] • Change from baseline for clinical safety labs, ECG, and vital signs for healthy participants and participants with disease severities (mild, moderate, and severe)

[0102] Study Design

[0103] A Phase I, open label, parallel, multiple dose study of AMX0035 in participants with impaired hepatic function and in healthy participants is conducted since hepatic metabolism and excretion accounts for substantial portion of the elimination of AMX0035, and hepatic impairment has the potential to alter the pharmacokinetics (PK) of the drug. The study consists of a Screening Period of up to 21 days, an in-clinic 9-day Treatment Period, and a Follow-up Phone Call 30 days after discharge. An End of Study Visit will occur within 7 days of the last blood draw or early termination for participants who do not complete all assessments through Day 9.

[0104] Participants who meet all inclusion and exclusion criteria will be admitted to the clinical trial unit (CTU) on Day -1. Day -1 assessments will include a urine pregnancy test (females of childbearing potential only) and an assessment of prior and concomitant medication. On Day 1, participants will receive a single dose of AMX0035 in the morning following by an ECG and blood and urine PK sampling. On Days 2 to 6, participants will receive AMX0035 BID (one sachet in the morning and one sachet in the evening). On Day 7, participants will receive a single dose in the morning. Blood and urine samples will be collected to assess the PK of the drug. All participants will remain in the CTU until the Day 7 48-hour post-dose PK blood sample is collected and exit procedures are performed on Day 9.

[0105] No water or food is allowed (except for administration of study drug as instructed) between 1 hour prior and 1 hour after dose administration, except for a small volume (30 mL) rinse for taste; otherwise, water is allowed ad libitum. On Day -1 and Day 6, the participants will be fasted (no solid or liquid calories) starting at 10 pm prior to planned dosing on Day 1 and Day 7. On Days 2 through 6, overnight fasting is not required.

[0106] Monitoring will involve vital signs (temperature, heart rate, and blood pressure), physical exam, electrocardiogram (ECG), safety laboratory testing and documentation of adverse events. Blood and urine samples will be collected for determination of drug concentrations.

[0107] If possible, an equal number of male and female participants in total in the hepatically-impaired groups will be enrolled will be enrolled. Eight participants each with mild, moderate, and severe hepatic impairment and 8 healthy participants to match the hepatically-impaired participants by age, weight, and sex will be enrolled in the study. The healthy participants will be enrolled after all the hepatically-impaired participants have been enrolled and completed the study. As the drug has a wide therapeutic index, recruitment of the different groups of hepatically-impaired participants can be done in parallel. The average age and weight as well as the distribution of males and females in the hepatically-impaired participant group will be obtained and used as the basis to recruit the matching healthy participants. The ages and weights of the matching participants will be within 20% of the average age and weight of the hepatically-impaired participants, and the ratio of males to females will be used to determine the number of males and females in the healthy participant group. Eight participants each with mild, moderate, and severe hepatic impairment and eight healthy participants that match the hepatically-impaired participants by age, weight, and sex will be enrolled in the study. The participants will be assigned to one of four groups based on the following scheme using the Child-Pugh scoring system during the Screening Period:

[0108] Study Population

[0109] Participants with Hepatic Impairment

[0110] Inclusion criteria (Participants must meet all the following criteria throughout the Screening Period and at Day -1 to be eligible for enrollment in this study)

[0111] 1. Ability to understand and provide written consent to participate in the study

[0112] 2. Willingness and ability to comply with the study procedures and visit schedule and ability to follow verbal and written instructions.

[0113] 3. Male or female 18 to 80 years of age.

[0114] 4. Must have a minimum body weight of 50 kg and have a BMI << 18 kg / m2 and <30 kg / m2

[0115] 5. Participants must have at screening normal physical examination, vital signs, serum chemistry, hematology, and urinalysis and negative anti-HIV 1 and 2, HBsAg, anti-HCV and RPR / VDRL values. The participants in Groups 2 to 4 must fulfill this criterion with consideration of their hepatic impairment condition.

[0116] 6. With or without a Transjugular Intrahepatic Portosystemic Shunt (TIPS)

[0117] 7. Female participants of childbearing potential must have a negative serum pregnancy test at screening and a negative serum or urine pregnancy test on Day -1 prior to the start of the study.

[0118] 8. Sexually active female participants of childbearing potential must agree to use a double barrier method of contraception. Oral / hormonal contraceptives may not be used for 30 days prior to Day 1 or throughout the study. Female participants who are two-years post-menopausal or surgically sterile are not considered to have childbearing potential.

[0119] 9. If male, agree to use a double-barrier method of contraception throughout the study

[0120] 10. Be nonsmoking or light smoker (<5 cigarettes per day)

[0121] 11. Participants must be willing to comply with dietary and lifestyle restrictions.

[0122] 12. Have a sitting pulse rate of ^ 100 bpm and ^50 bpm at the screening vital sign assessment

[0123] 13. In addition to meeting the Child-Pugh criteria (Section 5.3), have chronic liver disease and / or cirrhosis documented by at least one of the following: a) Liver biopsy results with histological findings consistent with cirrhosis b) Computerized tomographic or ultrasonographic evidence of hepatic fibrosis, with or without portal hypertension c) Physical examination evidence of chronic liver disease d) Colloid shift on a liver-spleen scan

[0124] 14. Have a history of stable cirrhosis and satisfy one or both of the following criteria: a) Clinical and / or laboratory evidence of cirrhosis. Participants with cirrhosis may have any of the following clinical features: hepatosplenomegaly, mild to moderate ascites (a score of 2 or 3 on the Child-Pugh criteria), jaundice, mild pedal edema, spider angiomata, testicular atrophy, palmar erythema, diminished axillary and / or pubic hair, parotid gland enlargement, clubbing of the fingers, or diffuse hyperpigmentation of the skin b) The following laboratory tests pertaining to liver impairment may be abnormal: alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and total bilirubin (all above the upper limit of normal), albumin and platelet count (both below the lower limit of normal), and prolonged prothrombin time

[0125] Exclusion criteria (Participants who meet any of the following criteria will not be eligible to participate in the study):

[0126] 1. Participants who have a known hypersensitivity to AMX0035, or either component, or any of its excipients.

[0127] 2. Participants who have, in the opinion of the examining physician, a clinically significant cardiovascular (e.g., previous myocardial infarction within the last 12 months or history of stroke in the last 12 months), hepatic, endocrine, pulmonary, gastrointestinal, neurologic, psychiatric, immunologic, musculoskeletal, or hematological disease state (other than hepatic function impairment or concomitant conditions for participants in Groups 2 to 4) or are morbidly obese or malnourished.

[0128] 3. Participants who have a sitting systolic blood pressure 100 mmHg and a sitting diastolic blood pressure ^ 100 mmHg or V60 mmHg at screening. Participants in Groups 2 to 4 who may be maintaining their blood pressure with antihypertensive medication, must have their blood pressure reasonably controlled with no history of hospitalization or malignant hypertension.

[0129] 4. Participants with clinically significant ECG abnormalities, in the opinion of the Investigator.

[0130] 5. Acute gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea) at time of screening or admission or a clinical diagnosis of IBS per the Rome IV criteria Recurrent abdominal pain on average at least 1 day / week in the last 3 months, associated with 2 or more of the following criteria: a) Related to defecation b) Associated with a change in the frequency of stool c) Associated with a change in the form (appearance of stool)

[0131] 6. Participants with a history of alcohol or substance abuse within the last 5 years. 7. Test positive for alcohol, benzoyl ecgonine (cocaine), methadone, barbiturates, amphetamines, benzodiazepines, alcohol, cannabinoids, opiates, or phencyclidine

[0132] 8. Participants who have participated in any other clinical investigation using an experimental drug requiring repeated blood draws within the longer of 30 days prior to the start of this study or 5 elimination half-lives of the study drug.

[0133] 9. History of plasma / blood donation within the past 60 days.

[0134] 10. Participants who have consumed xanthine (including caffeine) or Seville oranges and grapefruit containing products within 48 hours or alcohol within 72 hours prior to dosing.

[0135] 11. Participants with any other clinical condition, which might affect the absorption, distribution, metabolism, or excretion of the study drugs (upon discussion and agreement between Sponsor and Investigator) with the exception of previously specified hepatic conditions.

[0136] 12. Participants who are employed by or are family members of employees of the clinical research organization at which the study will be conducted.

[0137] 13. Participants who are currently taking concomitant medications, with the exception of medications that are considered necessary for treatment of the participant’s hepatic disease or concomitant condition, or who have taken medications within 14 days before dosing, including over-the-counter medications. The decision to include or exclude a hepatically-impaired participant will be based on a review of the drugs that participant is taking, for potential interaction with AMX0035.

[0138] 14. Any condition, which compromises ability to give informed consent or to communicate with the Investigator as required for the completion of this study

[0139] 15. Female participants who are currently breast-feeding

[0140] 16. Have a greater than 50% worsening of serum bilirubin concentration or prothrombin time in the preceding 3 months

[0141] 17. Have gastrointestinal hemorrhage due to esophageal varices or peptic ulcers within 6 months before Day 1

[0142] 18. Have severe ascites and / or pleural effusions

[0143] 19. Have a history of febrile illness within 5 days before Day 1 (in participants with physical evidence of ascites) Healthy Participants

[0144] Inclusion criteria (Participants must meet all the following criteria throughout the screening period and at Day -1 to be eligible for enrollment in this study)

[0145] 1. Ability to understand and provide written consent to participate in the study.

[0146] 2. Willingness and ability to comply with the study procedures and visit schedule and ability to follow verbal and written instructions.

[0147] 3. Healthy male or female 18 to 80 years of age.

[0148] 4. Must have a minimum body weight of 50 kg and have a BMI << 18 kg / m2 and <30 kg / m2

[0149] 5. Participants must have at Screening normal physical examination, vital signs, serum chemistry, hematology, and urinalysis and negative anti-HIV 1 and 2, HBsAg, anti-HCV, and RPR / VDRL values.

[0150] 6. Female participants of childbearing potential must have a negative serum pregnancy test during the 21 -day screening period and a negative serum or urine pregnancy test on Day -1 prior to the start of the study.

[0151] 7. Sexually active female participants of childbearing potential must agree to use a double barrier method of contraception. Oral / hormonal contraceptives may not be used for 30 days prior to Day 1 or throughout the study. Female participants who are two-years post-menopausal or surgically sterile are not considered to have childbearing potential.

[0152] 8. If male, agree to use a double-barrier method of contraception throughout the study.

[0153] 9. Be nonsmoking (never smoked or have not smoked within the prior 2 years) or light smoker (<5 cigarettes per day)

[0154] 10. Participants must be willing to comply with dietary and lifestyle.

[0155] 11. Have a sitting pulse rate of ^ 100 bpm and 50 bpm at the screening vital sign assessment

[0156] Exclusion criteria (Participants who meet any of the following criteria will not be eligible to participate in the study):

[0157] 1. Participants with known hypersensitivity to AMX0035, either component, or any of its excipients

[0158] 2. Participants with clinically significant ongoing disease or disorder, including for example: cardiovascular diseases, hypertension, cancer or neoplasia, diabetes, hepatic, endocrine, metabolic, respiratory, renal, gastrointestinal (except appendectomy) including biliary diseases or cholecystectomy, hematological, or Axis I or II psychiatric disorders

[0159] 3. Participants who have a sitting systolic blood pressure 140 mmHg or 100 mmHg and a sitting diastolic blood pressure ^ 100 mmHg or ^60 mmHg at screening

[0160] 4. Participants with clinically significant ECG abnormalities

[0161] 5. Clinically significant, in the opinion of the Investigator, infection or inflammation at time of screening or admission.

[0162] 6. Acute gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea) at time of screening or admission or a clinical diagnosis of IBS per the Rome criteria: Recurrent abdominal pain on average at least 1 day / week in the last 3 months, associated with 2 or more of the following criteria:

[0163] • Related to defecation

[0164] • Associated with a change in the frequency of stool

[0165] • Associated with a change in the form (appearance of stool)

[0166] 7. Participants with a history of alcohol or substance abuse within the last 5 years

[0167] 8. Test positive for alcohol, benzoyl ecgonine (cocaine), methadone, barbiturates, amphetamines, benzodiazepines, alcohol, cannabinoids, opiates, or phencyclidine

[0168] 9. Participants who have participated in any other clinical investigation using an experimental drug requiring repeated blood draws within 30 days of the start of this study.

[0169] 10. History of plasma / blood donation in the last 2 months.

[0170] 11. Participants who have consumed xanthine (including caffeine) or Seville oranges and grapefruit containing products within 48 hours or alcohol within 72 hours prior to the start of the study

[0171] 12. Participants with any other clinical condition, which might affect the absorption, distribution, metabolism, or excretion of the study drugs with the exception of previously specified hepatic conditions

[0172] 13. Participants who are employed by or are family members of employees of the clinical research organization at which the study will be conducted 14. Use of medication (including over the counter [OTC]) within 14 days or 5 elimination half-lives of the medication considered (whichever is longer) of admission.

[0173] 15. Use of prescribed centrally active or psychoactive agents within 28 days from admission.

[0174] 16. Requirement for any medication that would need to be continued during the study.

[0175] 17. History of severe allergies or multiple adverse drug reactions, including penicillin and cephalosporin

[0176] 18. Any condition, which compromises ability to give informed consent or to communicate with the Investigator as required for the completion of this study.

[0177] 19. Female participants who are currently breast-feeding.

[0178] Classification of hepatic participants

[0179] Male and female participants, aged 18 to 80 years, will be eligible to enroll in the study. The participants will be classified according to the following scheme, using the Child-Pugh scoring system:

[0180] Table: Participant Classification Using the Child-Pugh Score

[0181] The Child-Pugh Scores will be determined based on the following characteristics

[0182] Table: Child-Pugh Scoring System

[0183] Note: Grading (total score): Group A = 5 to 6; Group B = 7 to 9; Group C =10 to 15.aAscites will be assessed by an experienced physician by physical examination as well as ultrasound examination at Screening using the following criteria:

[0184] Absent: No ascites is detectable by manual and also not by ultrasound investigation.

[0185] Slight: Ascites palpitation doubtful, but ascites measurable by ultrasound investigation.

[0186] Moderate: Ascites detectable by palpitation and by ultrasound investigation.bEncephalopathy will be assessed by an experienced physician at Screening using the following criteria:

[0187] Grade 0: normal consciousness, personality, neurological examination, el ectroencephal ogram

[0188] Grade 1 : restless, sleep-disturbed, irritable / agitated, tremor, impaired handwriting, 5 cycles per second waves

[0189] Grade 2: lethargic, time-disoriented, inappropriate, asterixis, ataxia, slow triphasic waves

[0190] Grade 3: somnolent, stuporous, place-disoriented, hyper-active reflexes, rigidity, slower waves

[0191] Grade 4: unrousable coma, no personality / behavior, decerebrate, slow 2 to 3 cycles per second delta activity.

[0192] Healthy male and female participants will be age-, weight- and sex-matched to the hepatic-impaired participants (averaged among the recruited hepatic participants) after completion of the hepatic-impaired participants.

[0193] Lifestyle Considerations

[0194] Meals and Dietary Restrictions: Participants will refrain from consumption of grapefruit, grapefruit juice, Seville oranges, Seville orange marmalade, and Seville orange juice or other products containing grapefruit or Seville oranges from 48 hours prior to dose administration and through 24 hours after discharge.

[0195] Caffeine. Alcohol, and Tobacco: Participants will abstain from ingesting caffeine- or xanthine-containing products (e.g., coffee, tea, cola drinks, energy-drinks and chocolate) for 24 hours before dosing until 24 hours after discharge. Participants will abstain from alcohol and tobacco / nicotine product use for 72 hours before dosing until 24 hours after discharge. Concomitant Medications: All healthy participants must abstain from taking prescription or nonprescription drugs (including vitamins and dietary or herbal supplements) within 14 days or 5 half-lives (whichever is longer) before dose administration until the end of study follow-up visit (taken within 7 days of the last blood draw). Hepatic impairment participants will be allowed to take their medications for hypertension, diabetes, anemia, etc. in consultation with the Principal Investigator and Sponsor. Oral / hormonal contraceptives may not be used for 30 days prior to dose administration on Day 1 and throughout the study. As a general rule, no concomitant medication will be permitted, with the exception of medications to treat AEs / SAEs or at the discretion of the Investigator for medical emergencies.

[0196] Study Treatment

[0197] AMX0035 treatment of 1 sachet (oral; 1 sachet = 3g sodium phenylbutyrate [PB] and 1g taurursodiol [TURSO]). Each 10g sachet contains 3g PB and 1 g TURSO as active ingredients and excipients that include: Sodium phosphate dibasic, anhydrous; Dextrates, Hydrates; Sorbitol; Syloid 63FP (colloidal silica); Sucralose; Sodium Stearyl Fumarate; Weber Mixed Berry Flavoring; Kleptose Linecaps (maltodextrin).

[0198] Dosage, Preparation and Administration of AMX0035 to Participant: Authorized pharmacy personnel will prepare the participant’s AMX0035 per the following instruction: Open one sachet of AMX0035 and pour the powder in a cup or other container and add approximately 240 mL (1 cup) of room temperature water and stir vigorously. The participant will consume the drink completely within 2 minutes under supervision. It is normal for a small amount of powder to remain undissolved. Participants should consume within 60 minutes after the powder is added to water. Participants may use a small amount of water (30 mL) to rinse the bitter taste of AMX0035.

[0199] Study assessments and procedures

[0200] Prohibitions and Diet during Clinical Trial Unit Stay

[0201] No water or food is allowed (except for administration of study drug as instructed) between 1 hour prior and 1 hour after dose administration, except for a small volume (30 mL) rinse for taste; otherwise, water is allowed ad libitum. Participants will be encouraged to hydrate regularly during the in-house stay including the fasting period, but no formal volume standard is required. Standard meals will be provided during the CTU stay at pre-defined hours during the stay.

[0202] On Day -1 and Day 6, the participants will be fasted (no solid or liquid calories) starting at 10 pm prior to planned dosing on Day 1 and Day 7. On Days 2 through 6, overnight fasting is not required.

[0203] Study Treatment Administration

[0204] On Day 1, a single dose (1 sachet) of AMX0035 is administered to the participants. Breakfast will be allowed 1 hour after the dose on Day 1. On Days 2 to 6, participants will receive AMX0035 BID (one sachet in the morning and one sachet in the evening). On Day 7, participants will receive a single dose in the morning.

[0205] Pharmacokine tics

[0206] Collection of Samples: Blood samples will be taken on Day 1 at pre-dose, 1-, 2-, 3-, 4-, 5-, 6-, 8-, 10-, 12, and 24 hours post-dose, on Days 4, 5, and 6 at pre-dose of only the first dose, and on Day 7 at pre-dose, 1-, 2-, 3-, 4-, 5-, 6-, 8-, 10-, 12-, 24-, 36-, and 48-hours post-dose. Urine samples will be taken at -2 to 0 (pre-dose), 0 to 4, 4 to 8, 8 to 12, 12 to 16, 16 to 24 hours after dosing on Day 1 and on Day 7 at (predose), 0 to 4, 4 to 8, 8 to 12, 12 to 16, 16 to 24, 24 to 36, and 36 to 48 hours after dosing on Day 7.

[0207] Plasma Pharmacokinetic Parameters: The PK parameters listed in the table below will be determined for PB and metabolites (PA and PAGN), TURSO and metabolites (UDCA and GUDCA), when possible and appropriate.

[0208]

[0209] Pharmacokinetic Analyses: Single-dose and multiple dose PK parameters will be derived from the plasma time concentration. Individual PK concentrations and PK parameters for plasma will be listed. The PK data will be summarized descriptively by severity of hepatic impairment using appropriate statistics (e.g., N, n, arithmetic mean, SD, minimum, median, maximum, geometric mean [PK parameters only, as appropriate], and coefficient of variance [CV%]). Graphical presentations will include by-participant and mean concentrations (±SD) plots which will be presented on linear and semi-logarithmic scales. Scatterplots of individual and geometric mean exposure parameters [AUC(O-inf), AUC(O-t), and Cmax] will be presented by severity of hepatic impairment. Additional graphical presentations of PK data may be added at the discretion of the PK scientist. The renal clearance [(CL(R)], total amount excreted in urine [Ae(O-t)] and total percent excreted in urine [Ae% (total)] will be summarized by severity of hepatic impairment using descriptive statistics: n, mean, SD, CV%, minimum, median, and maximum. Modeling will be used to correlate hepatic functional abnormalities (e.g., Child Pugh scores) and selected PK parameters. The relationship between hepatic function and the pharmacokinetic parameters will be done using a regression approach in which the PK parameters are treated as continuous variables.

[0210] Example 2: Results from clinical study

[0211] 32 subjects (both male and female) were enrolled in the study described in Example 1. Specifically, eight subjects had severe hepatic impairment, eight had moderate hepatic impairment, eight had mild hepatic impairment, and eight were healthy subjects. Subjects were classified based on the Child Pugh criteria described in Example 1.

[0212] A summary of the study schedule is shown below:

[0213] *SD = Single Dose; BID= Twice daily dose

[0214] Safety assessments include, e.g., ECG, vital signs, safety lab, and Adverse

[0215] Events. The PK values for PB, PA, PAGN, TURSO, UDCA, and GUDCA after a single dose on Day 1 are shown in the table below.

[0216] The PK values for PB, PA, PAGN, TURSO, UDCA, and GUDCA after multiple doses (Day 7) are shown in the table below.

[0217] Adverse events are reflected in the table below:

[0218] Applicant found that there were no substantial safety or tolerability differences between subjects with hepatic impairment and heathy subjects when administered AMX0035 at the dosage tested.

[0219] Similar pharmacokinetic profile of PB and PA were observed in subjects with hepatic impairment and normal subjects. However, compared to healthy subjects, subjects with moderate hepatic impairment showed an increase in the Cmax and AUC of TURSO, UDCA and GUDCA by 3-4 fold, 2-3 fold, and 3-fold, respectively. Compared to healthy subjects, subjects with severe hepatic impairment showed an increase in the Cmax and AUC of TURSO, UDCA and GUDCA by 10-13 fold, 2-4 fold, and 6-fold, respectively.

[0220] Accumulation was observed for TURSO, UDCA and GUDCA following multiple dosing (as shown by the Day 7 results).

[0221] These results suggest that the dose of about 1 gram of TURSO and 3 grams of sodium phenylbutyrate twice daily can be used for patients with hepatic impairment. For patients with severe hepatic impairment, a reduction in dosing (e.g., 50%) can be considered.

[0222] Exemplary embodiments

[0223] Embodiment 1. A method comprising administering a combination of TURSO or a pharmaceutically acceptable salt thereof and 4 -phenylbutyric acid (4-PB A) or a pharmaceutically acceptable salt thereof to a subject with hepatic impairment. Embodiment 2. The method of Embodiment 1, wherein the subject has mild hepatic impairment.

[0224] Embodiment 3. The method of Embodiment 1, wherein the subject has moderate hepatic impairment.

[0225] Embodiment 4. The method of Embodiment 1, wherein the subject has severe hepatic impairment.

[0226] Embodiment 5. The method of Embodiment 1, wherein the subject has a Child-Pugh score of about 5-6 points.

[0227] Embodiment 6. The method of Embodiment 1, wherein the subject has a Child-Pugh score of about 7-9 points.

[0228] Embodiment 7. The method of Embodiment 1, wherein the subject has a Child-Pugh score of about 10-15 points.

[0229] Embodiment 8. The method of any one of Embodiments 1-7, comprising administering a combination of TURSO and sodium phenylbutyrate to the subject. Embodiment 9. A method of administering a combination of TURSO and sodium phenylbutyrate to a subject in need thereof, comprising administering about 1 gram of TURSO and about 3 grams of sodium phenylbutyrate once a day for about 3 weeks, followed by administering about 1 gram of TURSO and about 3 grams of sodium phenylbutyrate twice a day, wherein the subject has a Child-Pugh score of about 5-6 points.

[0230] Embodiment 10. A method of administering a combination of TURSO and sodium phenylbutyrate to a subject in need thereof, comprising administering about 1 gram of TURSO and about 3 grams of sodium phenylbutyrate once a day for about 3 weeks, followed by administering about 1 gram of TURSO and about 3 grams of sodium phenylbutyrate twice a day, wherein the subject has a Child-Pugh score of about 7-15 points.

[0231] Embodiment 11. A method of administering a combination of TURSO and sodium phenylbutyrate to a subject in need thereof, comprising administering TURSO at an amount of about 1 gram or less per administration and sodium phenylbutyrate at an amount of about 3 grams or less per administration, wherein the subject has a Child- Pugh score of about 7-15 points. Embodiment 12. A method of administering a combination of TURSO and sodium phenylbutyrate to a subject in need thereof, comprising administering TURSO and sodium phenylbutyrate at a frequency of twice a day or less, wherein the subject has a Child-Pugh score of about 7-15 points.

[0232] Embodiment 13. The method of Embodiment 12, comprising administering TURSO and sodium phenylbutyrate at a frequency of less than once a day.

[0233] Embodiment 14. The method of any one of Embodiments 10-13, wherein the subject has a Child-Pugh score of about 7-9 points.

[0234] Embodiment 15. The method of any one of Embodiments 10-13, wherein the subject has a Child-Pugh score of about 10-15 points.

[0235] Embodiment 16. The method of any one of Embodiments 1-14, wherein the subject has or is suspected as having a neurodegenerative disease.

[0236] Embodiment 17. The method of Embodiment 16, wherein the neurodegenerative disease is selected from the group consisting of Amyotrophic Lateral Sclerosis (ALS), Wolfram Syndrome, and Progressive Supranuclear Palsy (PSP).

[0237] Embodiment 18. A method of treating a neurodegenerative disease in a subject with hepatic impairment, comprising administering a combination of TURSO or a pharmaceutically acceptable salt thereof and 4-PB A or a pharmaceutically acceptable salt thereof to the subject.

[0238] Embodiment 19. The method of Embodiment 18, wherein the subject has mild hepatic impairment.

[0239] Embodiment 20. The method of Embodiment 18, wherein the subject has moderate hepatic impairment.

[0240] Embodiment 21. The method of Embodiment 18, wherein the subject has severe hepatic impairment.

[0241] Embodiment 22. The method of Embodiment 18, wherein the subject has a Child- Pugh score of about 5-6 points.

[0242] Embodiment 23. The method of Embodiment 18, wherein the subject has a Child- Pugh score of about 7-9 points.

[0243] Embodiment 24. The method of Embodiment 18, wherein the subject has a Child- Pugh score of about 10-15 points.

[0244] Embodiment 25. The method of any one of Embodiments 22-24, comprising administering about 1 gram of TURSO and about 3 grams of sodium phenylbutyrate once a day for about 3 weeks, followed by administering about 1 gram of TURSO and about 3 grams of sodium phenylbutyrate twice a day.

[0245] Embodiment 26. The method of Embodiments 23 or 24, comprising administering TURSO at an amount of about 1 gram or less per administration, and administering sodium phenylbutyrate at an amount of about 3 grams or less per administration.

[0246] Embodiment 27. The method of Embodiments 23, 24 or 26, comprising administering TURSO and sodium phenylbutyrate at a frequency of twice a day or less.

[0247] Embodiment 28. The method of Embodiment 27, comprising administering TURSO and sodium phenylbutyrate at a frequency of less than once a day. Embodiment 29. The method of any one of Embodiments 18-28, wherein the neurodegenerative disease is ALS, Wolfram Syndrome, or PSP.

[0248] OTHER EMBODIMENTS

[0249] It is to be understood that while the invention has been described in conjunction with the detailed description thereof, the foregoing description is intended to illustrate and not limit the scope of the invention, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims.

Claims

WHAT IS CLAIMED IS:

1. A method comprising administering a combination of TURSO or a pharmaceutically acceptable salt thereof and 4 -phenylbutyric acid (4-PB A) or a pharmaceutically acceptable salt thereof to a subject with hepatic impairment.

2. The method of claim 1, wherein the subject has a Child-Pugh score of about 5-6 points.

3. The method of claim 1, wherein the subject has a Child-Pugh score of about 7-9 points.

4. The method of claims 2 or 3, comprising administering about 1 gram of TURSO and about 3 grams of sodium phenylbutyrate once a day.

5. The method of claims 2 or 3, comprising administering about 1 gram of TURSO and about 3 grams of sodium phenylbutyrate twice a day.

6. The method of claims 2 or 3, comprising administering about 1 gram of TURSO and about 3 grams of sodium phenylbutyrate once a day for about 14 days or more, followed by administering about 1 gram of TURSO and about 3 grams of sodium phenylbutyrate twice a day.

7. The method of claim 1, wherein the subject has a Child-Pugh score of about 10-15 points.

8. The method of claim 7, comprising administering a combination of TURSO and sodium phenylbutyrate to the subject, wherein TURSO is administered at an amount of less than 1 gram and sodium phenylbutyrate is administered at an amount of less than 3 grams per administration.

9. The method of claim 8, wherein TURSO is administered at an amount of about 0.5 gram and sodium phenylbutyrate is administered at an amount of about 1.5 gram per administration.

10. The method of claim 9, wherein TURSO is administered at an amount of about 0.5 gram and sodium phenylbutyrate is administered at an amount of about 1.5 gram twice a day.

11. The method of any one of claims 1-10, wherein the subject has or is suspected as having a neurodegenerative disease.

12. The method of claim 11, wherein the neurodegenerative disease is selected from the group consisting of Amyotrophic Lateral Sclerosis (ALS), Wolfram Syndrome, and Progressive Supranuclear Palsy (PSP).

13. A method of treating a neurodegenerative disease in a subject with hepatic impairment, comprising administering a combination of TURSO or a pharmaceutically acceptable salt thereof and 4-PB A or a pharmaceutically acceptable salt thereof to the subject.

14. The method of claim 13, wherein the subject has a Child-Pugh score of about 5-6 points.

15. The method of claim 13, wherein the subject has a Child-Pugh score of about 7-9 points.

16. The method of claims 14 or 15, comprising administering about 1 gram of TURSO and about 3 grams of sodium phenylbutyrate once a day.

17. The method of claims 14 or 15, comprising administering about 1 gram of TURSO and about 3 grams of sodium phenylbutyrate twice a day.

18. The method of claims 14 or 15, comprising administering about 1 gram of TURSO and about 3 grams of sodium phenylbutyrate once a day for about 14 days or more, followed by administering about 1 gram of TURSO and about 3 grams of sodium phenylbutyrate twice a day.

19. The method of claim 13, wherein the subject has a Child-Pugh score of about 10- 15 points.

20. The method of claim 19, comprising administering a combination of TURSO and sodium phenylbutyrate to the subject, wherein TURSO is administered at an amount of less than 1 gram and sodium phenylbutyrate is administered at an amount of less than 3 grams per administration.

21. The method of claim 20, wherein TURSO is administered at an amount of about 0.5 gram and sodium phenylbutyrate is administered at an amount of about 1.5 gram per administration.

22. The method of claim 21, wherein TURSO is administered at an amount of about 0.5 gram and sodium phenylbutyrate is administered at an amount of about 1.5 gram twice a day.

23. The method of any one of claims 13-22, wherein the neurodegenerative disease is ALS, Wolfram Syndrome, or PSP.

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