Compositions and methods for treating subjects with renal 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 renal impairment. Also provided are methods of treating a neurodegenerative disease in a subject with renal 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] Attorney Docket No.38709-0070WO1 COMPOSITIONS AND METHODS FOR TREATING SUBJECTS WITH RENAL IMPAIRMENT CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Application No. 63 / 536,534, filed on September 5, 2023, the contents of which are hereby incorporated by reference in its entirety. BACKGROUND Renal impairment may affect 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 renal impairment. SUMMARY Subjects with renal function impairment, including those with moderate or severe renal impairment, may be more sensitive to salt intake and may experience different drug pharmacokinetics and pharmacodynamics as compared to subjects that do not have renal function impairment. Applicant found that administration of similar dosages of TURSO and sodium phenylbutyrate to subjects with renal impairment and subjects with normal renal function provide similar safety and tolerability profiles. The pharmacokinetic profiles in subjects with renal impairment suggest that dosing regimens that are similar to those in subjects with normal renal function would be safe. Provided herein, in some embodiments, 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 renal impairment. In some embodiments, the subject has mild renal impairment. In some embodiments, the subject has moderate renal impairment. In some embodiments, the subject has severe renal impairment. In some embodiments, the subject has an estimated glomerular filtration rate (eGFR) of about 60 to about 89 mL / min / 1.73 m2. In some embodiments, the subject has an estimated glomerular filtration rate (eGFR) of less than about 60 mL / min / 1.73 m2. In some embodiments, the subject has Attorney Docket No.38709-0070WO1 an eGFR of about 30 to about 59 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of about 15 to about 29 mL / min / 1.73 m2. In some embodiments, the methods described above comprise administering a combination of TURSO and sodium phenylbutyrate to the subject. In some embodiments, the methods include administering to the subject about 1 gram of TURSO and about 3 grams of sodium phenylbutyrate once a day. In some embodiments, the methods include administering to the subject about 1 gram of TURSO and about 3 grams of sodium phenylbutyrate twice a day. In some embodiments of any of the methods described herein, the methods include administering to the subject 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. For example, in some embodiments, provided herein are methods 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 an eGFR of about 60 mL / min / 1.73 m2or higher. In some embodiments, provided herein are methods 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 an eGFR of 15 to about 59 mL / min / 1.73 m2. In some aspects, the methods described herein include administering to the subject less than 1 gram of TURSO and less than 3 grams of sodium phenylbutyrate once a day. In some embodiments, the methods include administering to the subject less than 1 gram of TURSO and less than 3 grams of sodium phenylbutyrate twice a day. In some embodiments of any of the methods described herein, the methods include administering to the subject less than 1 gram of TURSO and less than 3 grams of sodium phenylbutyrate once a day for about 14 days or more, followed by Attorney Docket No.38709-0070WO1 administering less than about 1 gram of TURSO and less than about 3 grams of sodium phenylbutyrate twice a day. For example, in some embodiments, provided herein are methods 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 an eGFR of about 15 to about 59 mL / min / 1.73 m2. In some aspects, the methods described herein include administering to the subject TURSO or a pharmaceutically acceptable salt thereof and 4-PBA or a pharmaceutically acceptable salt thereof at a frequence of once twice a day or less (e.g., once a day, once every two days etc.) For example, in some embodiments, provided are methods 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 an eGFR of about 15 to about 59 mL / min / 1.73 m2. In some embodiments, the method comprises administering TURSO and sodium phenylbutyrate at a frequency of less than once a day. In some embodiments, the subject has an eGFR of about 15 to about 29 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of about 30 to about 59 mL / min / 1.73 m2. In some 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). Also provided herein, in some embodiments, are methods of treating a neurodegenerative diseases in a subject with renal 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. In some embodiments, the subject has mild renal impairment. In some embodiments, the subject has moderate renal impairment. In some embodiments, the subject has severe renal impairment. Attorney Docket No.38709-0070WO1 In some embodiments, the subject has an estimated glomerular filtration rate (eGFR) of about 60 to about 89 mL / min / 1.73 m2. In some embodiments, the subject has an estimated glomerular filtration rate (eGFR) of less than about 60 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of about 30 to about 59 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of about 15 to about 29 mL / min / 1.73 m2. In some embodiments, the methods described herein comprise 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. In some embodiments, the methods described herein comprise 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. In some embodiments, the methods described herein comprise administering TURSO and sodium phenylbutyrate at a frequency of twice a day or less. In some embodiments, the methods described herein comprise administering TURSO and sodium phenylbutyrate at a frequency of less than once a day. In some embodiments, the neurodegenerative disease is ALS, Wolfram Syndrome, or PSP. 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. Other features and advantages of the invention will be apparent from the following detailed description and figures, and from the claims. DETAILED DESCRIPTION Provided herein are methods of administering a combination of (1) taurursodiol (TURSO), ursodeoxycholic acid (UDCA), or pharmaceutically Attorney Docket No.38709-0070WO1 acceptable salts thereof and (2) 4-phenylbutyric acid (4-PBA) or pharmaceutically acceptable salts thereof to a subject with renal impairment. In some embodiments, the methods comprising administering a combination of TURSO or a pharmaceutically acceptable salt thereof (e.g., TURSO) and 4-PBA or a pharmaceutically acceptable salt thereof (e.g., sodium phenylbutyrate). Subjects with renal function impairment, including those with moderate or severe renal impairment, may be more sensitive to salt intake and may experience different drug pharmacokinetics and pharmacodynamics as compared to subjects that do not have renal function impairment. Applicant found that administration of similar dosages of TURSO and sodium phenylbutyrate to subjects with renal impairment and subjects with normal renal function provide similar safety and tolerability profiles. The pharmacokinetic profiles in subjects with renal impairment suggest that dosing regimens that are similar to those in subjects with normal renal function would be safe. 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 renal impairment. 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 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 renal impairment. In some embodiments, the subject has an eGFR of about 60 mL / min / 1.73 m2or higher. 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 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 Attorney Docket No.38709-0070WO1 moderate or severe renal impairment. In some embodiments, the subject has an eGFR of 15 to about 59 mL / min / 1.73 m2. 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 renal impairment. In some embodiments, the subject has an eGFR of about 15 to about 59 mL / min / 1.73 m2. 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, wherein the subject has moderate or severe renal impairment. In some embodiments, the subject has an eGFR of about 15 to about 59 mL / min / 1.73 m2. In a further aspect, provided herein are methods of treating a neurodegenerative diseases in a subject with renal 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. Compounds Taurursodiol Taurursodiol (TURSO) or pharmaceutically acceptable salts thereof can be utilized in the methods disclosed herein. Taurursodiol (also called ursodoxicoltaurine or tauroursodeoxycholic acid) is a naturally occurring hydrophilic bile acid which is the taurine conjugated form of ursodeoxycholic acid (UDCA). TURSO has the following structure: 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: Attorney Docket No.38709-0070WO1 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-(C1-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. 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 hydroxyl- substituted mono-, di-, or tri-alkylamines, dicyclohexylamine; tributyl amine; pyridine; N-methyl, N-ethylamine; diethylamine; triethylamine; mono-, bis-, or tris- (2-OH-(C1-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. Attorney Docket No.38709-0070WO1 4-Phenylbutyric acid 4-Phenylbutyric acid (4-PBA) or pharmaceutically acceptable salts thereof can be utilized in the methods disclosed herein. 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: 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. In some embodiments, the pharmaceutically acceptable salt of 4-PBA is sodium phenylbutyrate with the following structure: 4-PBA is metabolized to phenylacetate, an active metabolite, that conjugates with glutamine via acetylation to form phenylacetylglutamine (PAGN), which is finally excreted by kidneys. PAGN has the following structure: Methods of Treatment 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 renal impairment. In some embodiments, the subject has mild renal impairment. In some embodiments, the subject has moderate renal Attorney Docket No.38709-0070WO1 impairment. In some embodiments, the subject has severe renal impairment. The severity of renal impairment can be determined using methods known in the art. For example, the estimated glomerular filtration rate (eGFR) can be used to determine whether a subject has mild, moderate or severe renal impairment. See. e.g., Levey et al., Nature Reviews Nephrology, 16, 51-64 (2020). The eGFR of a subject can be determined using methods known in the art. In some embodiments, eGFR is determined using the CKD-EPI Creatinine equation. For example, eGFR can be determined using the following equation: Serum creatinine (Scr) can be measured with an essay known in the art (e.g., a standardized assay). In some embodiments, mild renal impairment corresponds with an estimated glomerular filtration rate (eGFR) of about 60 to about 89 mL / min / 1.73 m2. In some embodiments, moderate renal impairment corresponds with an eGFR of about 30 to about 59 mL / min / 1.73 m2. In some embodiments, severe renal impairment corresponds with an eGFR of about 15 to about 29 mL / min / 1.73 m2. In some embodiments, the subject has had a stable level of impaired renal function for at least about 3 months (e.g., at least about 4, 5, or 6 months or more). In some embodiments, the subject’s eGFR has had no more than 20% change for at least about 3 months. The methods described herein can include selecting a subject with mild, moderate, or severe renal impairment, prior to administration of a combination of TURSO or a pharmaceutically acceptable salt thereof and 4-PBA or a pharmaceutically acceptable salt thereof.. In some embodiments, the methods include selecting a subject that has an eGFR of about 60 to about 89 mL / min / 1.73 m2. In some embodiments, the methods include selecting a subject that has an eGFR of about 30 to about 59 mL / min / 1.73 m2. In some embodiments, the methods include selecting a subject that has an eGFR of about 15 to about 29 mL / min / 1.73 m2. Methods of the present disclosure are useful for patients with chronic kidney disease (CKD). CKD can be characterized by the presence of kidney damage or an eGFR of less than 60 mL / min / 1.73 m², persisting for 3 months or more. Kidney Attorney Docket No.38709-0070WO1 damage can be determined based on pathologic abnormalities suggested by imaging studies or renal biopsy, abnormalities in urinary sediment, increased urinary albumin excretion rates, electrolyte and other abnormalities due to tubular disorders, or history of kidney transplantation. In some embodiments, the methods of the present disclosure are useful for patients with CKD at any of the following stages: G1: GFR 90 mL / min / 1.73 m2and above with evidence of kidney disease, such as hematuria or proteinuria G2: GFR 60 to 89 mL / min / 1.73 m2G3a: GFR 45 to 59 mL / min / 1.73 m2G3b: GFR 30 to 44 mL / min / 1.73 m2G4: GFR 15 to 29 mL / min / 1.73 m2G5: GFR less than 15 mL / min / 1.73 m2or treatment by dialysis In some embodiments, stages of CKD can be further based on 3 levels of albuminuria (A1, A2, and A3), with each stage of CKD subcategorized according to the urinary albumin-creatinine ratio (ACR; mg / g or mg / mmol). Additional classification criteria for kidney impairment or chronic kidney disease are known in the art, and can be found at least in e.g., Kidney Int Suppl (2011). 2013 Jan; 3(1): 19–62. In some embodiments, the methods include administering a combination of TURSO and sodium phenylbutyrate to the subject. 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 Attorney Docket No.38709-0070WO1 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. Some embodiments provide methods of treating one or more neurodegenerative diseases in a subject with renal impairment, comprising administering TURSO or a pharmaceutically acceptable salt thereof and phenylbutyric acid or a pharmaceutically acceptable salt thereof to the subject. 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. 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 Attorney Docket No.38709-0070WO1 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. 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. 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. Following administration, the subject can be evaluated to detect, assess, or Attorney Docket No.38709-0070WO1 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. Upon improvement of a patient's condition (e.g., a change (e.g., decrease) in the level of disease in the subject), a maintenance dose of a compound, composition or combination of this disclosure may be administered, if necessary. Subsequently, the dosage or frequency of administration, or both, may be reduced, as a function of the symptoms, to a level at which the improved condition is retained. Patients may, however, require intermittent treatment on a long-term basis upon any recurrence of disease symptoms. The 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). 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.

[0002] Attorney Docket No.38709-0070WO1 The pharmacokinetic parameters can include one or more of the following: 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 The compounds of the present disclosure can generally be administered in a therapeutically effective amount. An “effective amount” is an amount sufficient to Attorney Docket No.38709-0070WO1 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. 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. 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 Attorney Docket No.38709-0070WO1 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. 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 Attorney Docket No.38709-0070WO1 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. 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). 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). 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). Attorney Docket No.38709-0070WO1 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). 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. The present disclosure provides methods, including e.g., administration dosages and frequencies, for 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 renal impairment. Kidneys are expected to play a significant role in drug elimination. Here, Applicant found that administration of similar dosages of TURSO and sodium phenylbutyrate to subjects with renal impairment and subjects with normal renal function provided similar safety and tolerability profiles. In some embodiments, the dosage and frequency of administration for a subject with mild renal impairment or a subject having an eGFR of about 60 mL / min / 1.73 m2or higher is the same as those for a subject without renal impairment. In some embodiments, the dosage and frequency of administration for a subject with moderate or severe renal impairment or a subject having an eGFR of about 15 to about 59 mL / min / 1.73 m2is the same as those for a subject without renal impairment. The present disclosure provides methods of administering to a subject with renal impairment about 1 gram of TURSO and about 3 grams of sodium phenylbutyrate once a day or twice a day. In some embodiments, the subject has an estimated glomerular filtration rate (eGFR) of about 60 to about 89 mL / min / 1.73 m2. In some embodiments, the subject has an estimated glomerular filtration rate (eGFR) Attorney Docket No.38709-0070WO1 of less than about 60 mL / min / 1.73 m2. For example, the subject can have an eGFR of about 30 to about 59 mL / min / 1.73 m2. In another example, the subject has an eGFR of about 15 to about 29 mL / min / 1.73 m2. 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 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 (e.g., for about weeks, months, or years), wherein the subject has mild renal impairment. In some embodiments, the subject has an eGFR of about 60 mL / min / 1.73 m2or higher. 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 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 (e.g., for about weeks, months, or years), wherein the subject has moderate or severe renal impairment. In some embodiments, the subject has an eGFR of about 15 to about 59 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of about 15 to about 29 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of about 30 to about 59 mL / min / 1.73 m2. In another aspect, the present disclosure provides methods of administering to a subject with renal impairment (e.g., mild, moderate, or severe renal impairment) a combination of TURSO or a pharmaceutically acceptable salt thereof and 4- phenylbutyric acid (4-PBA) or a pharmaceutically acceptable salt thereof, wherein the amount of the compounds administered to thesubject is less than that administered to a subject without renal impairment, or whereinthe frequency of administration is less frequent as compared to a subject without renal impairment. In some embodiments, the subject has an eGFR of about 15 to about 59 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of about 15 to about 29 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of about 30 to about 59 mL / min / 1.73 m2. For example, the present disclosure also provides methods of administering TURSO and sodium phenylbutyrate to a subject with renal impairment, at an amount Attorney Docket No.38709-0070WO1 of less than 1 gram of TURSO and less than 3 grams of sodium phenylbutyrate once or twice a day. In some embodiments, the methods include administering TURSO and sodium phenylbutyrate to the subject at an amount of less than 1 gram of TURSO and less than 3 grams of sodium phenylbutyrate once a day for about 14 days or more (e.g., about 3 weeks), followed by an amount of less than about 1 gram of TURSO and less than about 3 grams of sodium phenylbutyrate twice a day (e.g., for about weeks, months, or years). 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, 1.11, 0.9, 0.8, 0.7, or 0.6 grams per administration), wherein the subject has moderate or severe renal impairment. In some embodiments, the subject has an eGFR of about 15 to about 59 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of about 15 to about 29 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of about 30 to about 59 mL / min / 1.73 m2. In some embodiments, the methods comprise administering about 0.5 gram of TURSO and about 1.5 grams of sodium phenylbutyrate to the subject twice a day. 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 renal impairment. In some embodiments, the subject has an eGFR of about 15 to about 59 mL / min / 1.73 m2. 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 an eGFR of about 15 to about 29 mL / min / 1.73 m2. In some embodiments, the subject has an eGFR of about 30 to about 59 mL / min / 1.73 m2. Attorney Docket No.38709-0070WO1 Pharmaceutical Composition 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. 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. 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. 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 Attorney Docket No.38709-0070WO1 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. 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 corn starch. When aqueous suspensions and / or emulsions are administered orally, the active ingredient may be suspended or dissolved in an oily phase is combined with emulsifying and / or suspending agents. If desired, certain sweetening, flavoring, or coloring agents may be added. 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. 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 Attorney Docket No.38709-0070WO1 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. 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). 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. 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 Attorney Docket No.38709-0070WO1 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, corn, and potato. In some embodiments, the maltodextrin is pea maltodextrin. In some embodiments, the composition includes about 28.3% w / w of pea maltodextrin. For example, pea maltodextrin obtained from Roquette (KLEPTOSE® LINECAPS) can be used. 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. 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. Attorney Docket No.38709-0070WO1 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 anti- caking 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 µm to about 10 µm (e.g. about 3 µm to about 9 µm, about 4 µm to about 8 µm, about 5 µm to about 8 µm, or about 7.5 µm). In some embodiments, the porous silica have an average pore volume of about 0.1 cc / gm to about 2.0 cc / gm (e.g., about 0.1 cc / gm to about 1.5 cc / gm, about 0.1 cc / gm to about 1 cc / gm, about 0.2 cc / gm to about 0.8 cc / gm, about 0.3 cc / gm to about 0.6 cc / gm, or about 0.4 cc / gm). In some embodiments, the porous silica have a bulk density of about 50 g / L to about 700 g / L (e.g. about 100 g / L to about 600 g / L, about 200 g / L to about 600 g / L, about 400 g / L to about 600 g / L, about 500 g / L to about 600 g / L, about 540 g / L to about 580 g / L, or about 560 g / L). In some embodiments, the compositions described herein include about 0.05% to about 2% w / w (e.g., any subranges of this range described herein) of Syloid® 63FP (WR Grace). 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 Attorney Docket No.38709-0070WO1 sodium phosphate (e.g., sodium phosphate dibasic anhydrous). For example, the pharmaceutical composition can include about 2.7% w / w of sodium phosphate dibasic. 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. 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. In some embodiments, the pharmaceutical composition further includes one or both of acacia and medium-chain triglycerides. EXAMPLES The invention is further described in the following examples, which do not limit the scope of the invention described in the claims. Example 1: Clinical study 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 renal function impairment and in healthy participants. Attorney Docket No.38709-0070WO1 Study Objectives The primary objective of the study is to evaluate the PK characteristics of PB and its major metabolites, phenylacetic acid (PAA) and phenylacetylglutamine (PAGN), and 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 renal function impairment and in healthy participants. The secondary objective of the study is to evaluate the safety and tolerability of AMX0035 in participants with impaired renal function and in healthy participants. Endpoints 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 PB, PAA, and PAGN between healthy participants and participants with disease severities (mild, moderate, and severe). Secondary endpoints include: · Frequency of TEAEs in healthy participants and participants with disease severities (mild, moderate, and severe) · Frequency of TEAEs in healthy participants and participants with disease severities (mild, moderate, and severe) Study design A phase I, open label, multiple dose study in participants with impaired renal function and in healthy participants is conducted since renal impairment has the potential to alter the PK of AMX0035 as the kidneys play a significant role in its elimination. 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. 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 serum creatinine test, a urine pregnancy test (females only), and an assessment of prior and concomitant medication. On Day 1, participants will receive a single dose of Attorney Docket No.38709-0070WO1 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 Day 748-hour post-dose PK blood sample is collected and exit procedures are performed on Day 9 . 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. 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. If possible, an equal number of male and female participants will be enrolled. Eight participants each with mild, moderate, and severe renal impairment and 8 healthy participants to match the renally-impaired participants by age, weight, and sex will be enrolled in the study. The healthy participants will be enrolled after all the renally-impaired participants have been enrolled and completed the study. As the drug has a wide therapeutic index, recruitment of the different groups of renally-impaired participants can be done in parallel. The average age and weight as well as the distribution of males and females in the renally-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 renally-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. The participants will be assigned to one of four groups based on their estimated Glomerular Filtration Rate (eGFR) during the Screening Period as follows: Group I: Eight (n=8) healthy participants with normal renal function (eGFR ≥90 mL / min / 1.73 m2) will be matched as closely as possible by age, weight, and sex Attorney Docket No.38709-0070WO1 (based on percentage ratio of male: female) to the 8 participants in Groups II, III, and IV Group II: Eight (n=8) non-dialyzed participants with mild decrease in GFR (eGFR = 60 to 89 mL / min / 1.73 m2) Group III: Eight (n=8) non-dialyzed participants with moderate decrease in GFR (eGFR = 30 to 59 mL / min / 1.73 m2) Group IV: Eight (n=8) non-dialyzed participants with severe decrease in GFR (eGFR = 15 to 29 mL / min / 1.73 m2) Study Population Participants with Renal Impairment 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) 1. Ability to understand and provide written consent to participate in the study 2. Willingness and ability to comply with the study procedures and visit schedule and ability to follow verbal and written instructions. 3. Male or female 18 to 80 years of age. 4. Must have a minimum body weight of 50 kg and have a BMI ≥18 kg / m2 and <30 kg / m2 5. Participants must have at screening, negative anti-HIV 1 and 2, HBsAg, anti-HCV and RPR / VDRL values. 6. The medical history of the participants with impaired renal function should document a stable level of impaired renal function (no more than 20% change of GFR) for at least 3 months prior to Screening (e.g., a recently resolved acute event over chronic impairment). The severity of renal function will be based on the calculation of eGFR using the CKD-EPI Creatinine equation. 7. Female participants 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. 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. Attorney Docket No.38709-0070WO1 9. If male, agree to use a double-barrier method of contraception throughout the study 10. Be nonsmoking or light smoker (<5 cigarettes per day) 11. Participants must be willing to comply with dietary and lifestyle restrictions. 12. Have a sitting pulse rate of not greater than 100 bpm and not less than 50 bpm at the screening vital sign assessment. Exclusion criteria (Participants who meet any of the following criteria at screening or at the timepoint otherwise specified, will be excluded from enrolment in the study) 1. Participants who have a known hypersensitivity to AMX0035, or either component or any of its excipients. 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 renal function impairment or concomitant conditions) or are morbidly obese or malnourished. 3. Participants who have a sitting systolic blood pressure greater than or equal to 160 mmHg or less than or equal to 100 mmHg and a sitting diastolic blood pressure greater than or equal to 100 mmHg or less than or equal to 60 mmHg at screening. Participants in Groups II-IV 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. 4. Participants with clinically significant ECG abnormalities, in the opinion of the Investigator. 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: o Related to defecation o Associated with a change in the frequency of stool Attorney Docket No.38709-0070WO1 o Associated with a change in the form (appearance of stool) 6. Participants with a history of alcohol or substance abuse within the last 5 years. 7. Test positive for alcohol, benzoylecgonine (cocaine), methadone, barbiturates, amphetamines, benzodiazepines, alcohol, cannabinoids, opiates, or phencyclidine 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. 9. History of plasma / blood donation within the past 60 days. 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. 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 renal conditions. 12. Participants who are employed by or are family members of employees of the clinical research organization at which the study will be conducted. 13. Participants who are currently taking concomitant medications, with the exception of medications that are considered necessary for treatment of the participant’s renal 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 renally-impaired participant will be based on a review of the drugs that participant is taking, for potential interaction with AMX0035. 14. Any condition, which compromises ability to give informed consent or to communicate with the Investigator as required for the completion of this study 15. Female participants who are currently breast-feeding. Healthy Participants 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) 1. Ability to understand and provide written consent to participate in the study. Attorney Docket No.38709-0070WO1 2. Willingness and ability to comply with the study procedures and visit schedule and ability to follow verbal and written instructions. 3. Healthy male or female 18 to 80 years of age. 4. Must have a minimum body weight of 50 kg and have a BMI ≥18 kg / m2 and <30 kg / m2 5. Participants must have at Screening, normal physical examination, vital signs, serum chemistry, hematology, urinalysis, negative anti-HIV 1 and 2, HBsAg, anti-HCV and RPR / VDRL values. 6. Group I (normal renal function) participants must be matched as closely as possible to the range of age and weight of the participants in Groups II-IV. In addition, these participants must meet the sex requirement based on the percentage ratio of male:female participants in the 3 renal impaired groups. 7. Female participants 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. 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. 9. If male, agree to use a double-barrier method of contraception throughout the study. 10. Be nonsmoking (never smoked or have not smoked within the prior 2 years) or light smoker (<5 cigarettes per day) 11. Participants must be willing to comply with dietary and lifestyle restrictions as outlined in Section 8.4. 12. Have a sitting pulse rate of ≤100 bpm and ≥50 bpm at the screening vital sign assessment Exclusion criteria (Participants who meet any of the following criteria will not be eligible to participate in the study) 1. Participants with known hypersensitivity to AMX0035, either component, or any of its excipients. Attorney Docket No.38709-0070WO1 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. 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. 4. Participants with clinically significant ECG abnormalities. 5. Clinically significant, in the opinion of the Investigator, infection or inflammation at time of screening or admission. 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: o Related to defecation o Associated with a change in the frequency of stool o Associated with a change in the form (appearance of stool) 7. Participants with a history of alcohol or substance abuse within the last 5 years. 8. Test positive for alcohol, benzoylecgonine (cocaine), methadone, barbiturates, amphetamines, benzodiazepines, alcohol, cannabinoids, opiates, or phencyclidine. 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. 10. History of plasma / blood donation in the last 2 months. 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. 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 renal conditions. Attorney Docket No.38709-0070WO1 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. 15. Use of prescribed centrally active or psychoactive agents within 28 days from admission. 16. Requirement for any medication that would need to be continued during the study. 17. History of severe allergies or multiple adverse drug reactions, including penicillin and cephalosporin 18. Any condition, which compromises ability to give informed consent or to communicate with the Investigator as required for the completion of this study. 19. Female participants who are currently breast-feeding. Classification of Renal Participants Male and female participants, aged 18 to 80 years, will be eligible to enroll in the study. Participants will be enrolled on the basis of their renal function and based on the calculation of eGFR using the CKD-EPI Creatinine equation using serum creatinine measured with a standardized assay (Scr, std, mg / dL), and age determined during the Screening Period. Healthy male and female participants will be age-, weight-, and sex-matched to the renal-impaired participants (averaged among the recruited renal participants) after recruitment of the renal-impaired participants is complete. Lifestyle Considerations Meals and Dietary Restrictions: Participants will refrain from consumption of grapefruit, grapefruit juice, Seville oranges, Seville orange marmalade, and Seville Attorney Docket No.38709-0070WO1 orange juice or other products containing grapefruit or Seville oranges from 48 hours prior to dose administration and through 24 hours after discharge. Caffeine, Alcohol, and Tobacco: During the dose administration session, participants will abstain from ingesting caffeine- or xanthine-containing products (e.g., coffee, tea, cola drinks, energy-drinks, and chocolate) for 24 hours before the dose administration until 24 hours after discharge. During the dose administration session, participants will abstain from alcohol and tobacco / nicotine product use for 72 hours before the dose administration 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). Renal impairment participants will be allowed to take their medications for hypertension, diabetes, anemia, renal osteodystrophy, etc. in consultation with the Principal Investigator and Sponsor. Oral / hormonal contraceptives may not be used for 30 days prior to Day -1 and throughout the study. As a general rule, no concomitant medication will be permitted, with the exception of medications to treat adverse events (AEs) / serious adverse events (SAEs) or at the discretion of the Investigator for medical emergencies. Study Treatment 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). Duration of Treatment: On Day 1, study participants will receive a single dose (1 sachet) of AMX0035 in the morning. 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. 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 Attorney Docket No.38709-0070WO1 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. Study assessments and procedures Prohibitions and Diet During Clinical Trial Unit Stay 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. Study Treatment Administration 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. Pharmacokinetics Collection of Samples: Blood samples are taken on Day 1 at pre-dose, 1-, 2-, 3-, 4-, 5-, 6-, 8-, 10-, and 12-hours post-dose, on Days 2 to 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 are 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 at (pre-dose), 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. Plasma and Urine Pharmacokinetic Parameters: The PK parameters listed in the table below are determined for PB and metabolites (phenylacetate-PA) and phenylacetyl glutamine (PAGN), TURSO and metabolites (urodeoxycholate-UDCA and glycourodeoxycholate-GUDCA), when possible and appropriate. Attorney Docket No.38709-0070WO1 Pharmacokinetic Analyses: Single-dose and multiple-dose PK parameters are derived from the plasma time concentration. Individual PK concentrations and PK parameters for plasma will be listed. The PK data are summarized descriptively by severity of renal 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 include by- participant and mean concentrations (±SD) plots which are presented on linear and semi-logarithmic scales. Scatterplots of individual and geometric mean exposure Attorney Docket No.38709-0070WO1 parameters [AUC(0-inf), AUC(0-t), and Cmax] are presented by severity of renal impairment. The renal clearance [(CL(R)], total amount excreted in urine [Ae(0-t)] and total percent excreted in urine [Ae% (total)] are summarized by severity of renal impairment using descriptive statistics: n, mean, SD, CV%, minimum, median, and maximum. The relationship between renal function and the pharmacokinetic parameters is done using a regression approach in which the PK parameters are treated as continuous variables. The effect of different baseline variables that can affect the PK of AMX0035 (age, sex, weight, and age) are evaluated. Example 2: Results from clinical study 32 subjects (both male and female) were enrolled in the study described in Example 1. Specifically, eight subjects had severe renal impairment, eight had moderate renal impairment, eight had mild renal impairment, and eight were healthy subjects. Subjects were classified based on their renal function calculated by their eGFR as described in Example 1: Group I: Eight (n=8) healthy participants with normal renal function (eGFR ≥90 mL / min / 1.73 m2) will be matched as closely as possible by age, weight, and sex (based on percentage ratio of male: female) to the 8 participants in Groups II, III, and IV Group II: Eight (n=8) non-dialyzed participants with mild decrease in GFR (eGFR = 60 to 89 mL / min / 1.73 m2) Group III: Eight (n=8) non-dialyzed participants with moderate decrease in GFR (eGFR = 30 to 59 mL / min / 1.73 m2) Group IV: Eight (n=8) non-dialyzed participants with severe decrease in GFR (eGFR = 15 to 29 mL / min / 1.73 m2) A summary of the study schedule is shown below: Attorney Docket No.38709-0070WO1 *SD = Single Dose; BID= Twice daily dose Safety assessments include, e.g., ECG, vital signs, safety lab, and Adverse 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. multiple doses (Day 7) are shown in the table below. Attorney Docket No.38709-0070WO1 Adverse events are reflected in the table below: Kidney function is thought to play a significant role in the elimination of AMX0035. Here, Applicant found no substantial safety or tolerability differences between participants with renal impairment (across the mild, moderate and severe severity levels) compared to those with normal renal function. Further, administration of AMX0035 did not significantly affect the PK of PB, PAA, TURSO, UDCA and GUDCA in patients with renal impairment. There was a doubling of the PAGN Cmax and a 4-fold increase of the PAGN AUC in patients with severe renal function. Accumulation was observed for TURSO (2-fold), UDCA (3-6 fold) and GUDCA (10 fold) following multiple dosing (as shown by the Day 7 results). 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 renal impairment in a safe manner. OTHER EMBODIMENTS 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

Attorney Docket No.38709-0070WO1 WHAT IS CLAIMED IS:

1. A method 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 renal impairment.

2. The method of claim 1, wherein the subject has an estimated glomerular filtration rate (eGFR) of about 60 to about 89 mL / min / 1.73 m2.

3. The method of claim 1, wherein the subject has an estimated glomerular filtration rate (eGFR) of less than about 60 mL / min / 1.73 m2.

4. The method of claim 3, wherein the subject has an eGFR of about 30 to about 59 mL / min / 1.73 m2.

5. The method of claim 3, wherein the subject has an eGFR of about 15 to about 29 mL / min / 1.73 m2.

6. The method of any one of claims 1-5, comprising administering a combination of TURSO and sodium phenylbutyrate to the subject.

7. The method of any one of claims 1-6, comprising administering to the subject about 1 gram of TURSO and about 3 grams of sodium phenylbutyrate once a day.

8. The method of any one of claims 1-6, comprising administering to the subject about 1 gram of TURSO and about 3 grams of sodium phenylbutyrate twice a day.

9. The method of any one of claims 1-6, comprising administering to the subject 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.

10. The method of any one of claims 1-6, comprising administering to the subject less than 1 gram of TURSO and less than 3 grams of sodium phenylbutyrate once a day.Attorney Docket No.38709-0070WO1 11. The method of any one of claims 1-6, comprising administering to the subject less than 1 gram of TURSO and less than 3 grams of sodium phenylbutyrate twice a day.

12. The method of any one of claims 1-6, comprising administering to the subject less than 1 gram of TURSO and less than 3 grams of sodium phenylbutyrate once a day for about 14 days or more, followed by administering less than about 1 gram of TURSO and less than about 3 grams of sodium phenylbutyrate twice a day.

13. The method of any one of claims 1-6, comprising administering to the subject TURSO and sodium phenylbutyrate at a frequency of less than once a day.

14. The method of any one of claims 1-13, wherein the subject has or is suspected as having a neurodegenerative disease.

15. The method of claim 14, wherein the neurodegenerative disease is selected from the group consisting of Amyotrophic Lateral Sclerosis (ALS), Wolfram Syndrome, and Progressive Supranuclear Palsy (PSP).

16. A method of treating a neurodegenerative disease in a subject with renal 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.

17. The method of claim 16, wherein the subject has an estimated glomerular filtration rate (eGFR) of about 60 to about 89 mL / min / 1.73 m2.

18. The method of claim 16, wherein the subject has an estimated glomerular filtration rate (eGFR) of less than about 60 mL / min / 1.73 m2.

19. The method of claim 18, wherein the subject has an eGFR of about 30 to about 59 mL / min / 1.73 m2.Attorney Docket No.38709-0070WO1 20. The method of claim 18, wherein the subject has an eGFR of about 15 to about 29 mL / min / 1.73 m2.

21. The method of any one of claims 16-20, comprising administering a combination of TURSO and sodium phenylbutyrate to the subject.

22. The method of any one of claims 16-21, comprising administering to the subject about 1 gram of TURSO and about 3 grams of sodium phenylbutyrate once a day.

23. The method of any one of claims 16-21, comprising administering to the subject about 1 gram of TURSO and about 3 grams of sodium phenylbutyrate twice a day.

24. The method of any one of claims 16-21, comprising administering to the subject 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.

25. The method of any one of claims 16-21, comprising administering to the subject less than 1 gram of TURSO and less than 3 grams of sodium phenylbutyrate once a day.

26. The method of any one of claims 16-21, comprising administering to the subject less than 1 gram of TURSO and less than 3 grams of sodium phenylbutyrate twice a day.

27. The method of any one of claims 16-21, comprising administering to the subject less than 1 gram of TURSO and less than 3 grams of sodium phenylbutyrate once a day for about 14 days or more, followed by administering less than about 1 gram of TURSO and less than about 3 grams of sodium phenylbutyrate twice a day.

28. The method of any one of claims 16-21, comprising administering to the subject TURSO and sodium phenylbutyrate at a frequency of less than once a day.Attorney Docket No.38709-0070WO1 29. The method of any one of claims 16-28, wherein the neurodegenerative disease is ALS, Wolfram Syndrome, or PSP.