Methods of treating liver and kidney conditions with phenylbutyrate

Abstract

This disclosure relates generally to the use of phenylbutyrate compounds, such as sodium phenylbutyrate (NaPB), in the treatment, prevention, or amelioration of liver- and kidney-related conditions such as pruritis.

Description

METHODS OF TREATING LIVER AND KIDNEY CONDITIONS WITH PHENYLBUTYRATE

[0001] The present application claims priority to U.S. Prov. Appl. No. 63 / 493,688, filed on Mar. 31, 2023, and U.S. Prov. Appl. No. 63 / 519,087, filed on Aug. 11, 2023, each of which is incorporated by reference in its entirety herein.FIELD

[0002] This application relates to the use of phenylbutyrate compounds, such as sodium phenylbutyrate (NaPB), alone or in combination with bile acids, IT AB inhibitors, and other medicaments, in the treatment, prevention, or amelioration of liver- and kidney-related conditions, including chronic cholestatic liver diseases, chronic kidney disease, and symptoms associated with such illnesses in a human subject, particularly in a subject that seeks or receives medical care associated with the illness.BACKGROUND

[0003] Chronic liver disease refers to a disease process of the liver that involves the progressive destruction and regeneration of the liver parenchyma leading to fibrosis and cirrhosis. Causes of chronic liver disease include hepatitis B, hepatitis C, alcoholism, fatty liver disease, cholangitis, liver cancer, and heart failure. The treatment of chronic liver disease depends on the cause. Specific conditions may be treated with medications including corticosteroids, but in the most serious cases a liver transplant is required when the liver fails.

[0004] One condition resulting from chronic liver disease is cholestasis. Cholestasis is defined as hepatocyte and cholangiocyte bile excretion failure or failure of bile transport to the duodenum. Cholestasis may result from chronic progressive diseases occurring in infancy, childhood, or adulthood. While there are a multitude of different diseases and conditions that can lead to cholestasis, each can be characterized in that they damage the biliary epithelium, and manifest clinically with fatigue, pruritus, and jaundice.

[0005] Two particularly serious chronic liver conditions are primary biliary cirrhosis (PBC) or primary sclerosing cholangitis (PSC). Most adult patients with chronic cholestasis have PBC or PSC and these two conditions are the most common causes of cholestatic liver disease. PBC, also called primary biliary cholangitis, is a chronic disease in which the bile ducts in the liver are slowly destroyed. PSC is like PBC, but in PSC inflammation causes scarring within the bile ducts. The scarring makes the ducts hard and narrow and gradually cause serious liver damage. Both PBC and PSC are autoimmune diseases, which are suspected to be triggered by a combination of genetic and environmental factors. While the diseases usually develop slowly, there's currently no cure for either. There are medications to mitigate liver damage, but long-term outcomes often involve liver transplants.

[0006] Current standards of care for patients with cholestasis hinge on identifying the etiology, treating reversible causes, and managing chronic cholestatic processes. Ursodeoxycholic acid (UDCA) has been successfully used in symptomatic treatment of cholestatic liver diseases. Long-term UDCA treatmentimproves survival without liver transplantation in PBC patients. In patients with PBC and rapid progression of the disease, UDCA may be combined with an immunosuppressive substance (i.e., cyclosporin). Unlike PBC, effective medical therapy is more limited in PSC, reflecting the lack of knowledge about the exact pathogenesis of the disease. In PSC, as well as biliary atresia and cholestasis of cystic fibrosis, UDCA at present seems the only treatment of which a benefit for the patients can be expected. Currently, liver transplantation is the only effective therapy for patients with advanced disease, although recurrence of PSC in the graft may occur.

[0007] Much like chronic liver disease, chronic kidney disease is a prolonged disease process of the kidneys that involves progressive loss of function of the renal system. Causes of chronic kidney disease include diabetes, high blood pressure, glomerulonephritis, and polycystic kidney disease. Treatment options for chronic kidney diseases arc primarily directed to mitigating the cause of the disease, and include medications to manage blood pressure, blood sugar, and lower cholesterol, and renal replacement therapy. However, in the most serious cases a kidney is required.

[0008] There continues to be a clear unmet need for additional treatments and medications to address chronic liver and kidney conditions, both regarding the long-term issues as well as the symptoms patients suffer on a day-to-day basis, such as pruritus. The compositions and methods described herein provide needed advancements to address these conditions.SUMMARY

[0009] Phenylbutyrates have been investigated as potential therapeutics for various conditions including urea cycle disorders, maple syrup urine disease, cystic fibrosis, malignant gliomas and sickle-cell anemia. Phenylbutyrates are well-known chemical chaperones, stabilizing denatured proteins. It has been recently hypothesized that sodium phenylbutyrate may act as chemical chaperones to rescue the activity of mutant bile salt export pump (BSEP) in liver cells of patients affected with chronic cholestasis. The present disclosure describes phenylbutyrates, combination therapies, and methods for the treatment of chronic liver conditions.

[0010] Provided herein is a method of treating, preventing, or ameliorating a primary chronic liver or kidney disorder in a subject in need thereof, comprising administering a phenylbutyrate, or a metabolite, prodrug, pharmaceutically acceptable salt, hydrate, solvate, or crystalline form thereof, optionally in combination with a bile acid, an IT AB inhibitor, or other therapeutic compound, or combinations thereof.

[0011] One aspect provided herein is a method of treating, preventing, or ameliorating a pruritus in a subject experiencing primary sclerosing cholangitis (PSC), comprising administering phenylbutyrate, or a metabolite, prodrug, pharmaceutically acceptable salt, hydrate, solvate, or crystalline form thereof and a bile acid.

[0012] Another aspect provided herein is a method of treating, preventing, or ameliorating a pruritus in a subject experiencing chronic kidney disease comprising administering phenylbutyrate, or a metabolite, prodrug, pharmaceutically acceptable salt, hydrate, solvate, or crystalline form thereof and a bile acid.DETAILED DESCRIPTIONDEFINITIONS

[0013] The following description sets forth exemplary embodiments of the present technology. It should be recognized, however, that such description is not intended as a limitation on the scope of the present disclosure but is instead provided as a description of exemplary embodiments.

[0014] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art. As used herein, the below terms have the following meanings unless specified otherwise. Any methods, devices and materials similar or equivalent to those described herein can be used in the practice of the compositions and methods described herein. The following definitions are provided to facilitate understanding of certain terms used frequently herein and are not meant to limit the scope of the present disclosure. All references referred to herein are incorporated by reference in their entirety.

[0015] The term “comprise” and variations thereof, such as, “comprises” and “comprising” are to be construed in an open, inclusive sense, that is, as “including, but not limited to.” Further, the singular forms “a,” “an,” and “the” include plural references unless the context clearly dictates otherwise. Thus, references to “the agent” includes a plurality of such agents.

[0016] Reference to “about” a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se. In certain embodiments, the term “about” includes the indicated amount ± 10%. In other embodiments, the term “about” includes the indicated amount ± 5%. In certain other embodiments, the term “about” includes the indicated amount ± 1%. Also, the term “about X” includes description of “X.”

[0017] “Pharmaceutically acceptable” or “physiologically acceptable” refer to compounds, salts, compositions, dosage forms and other materials which are useful in preparing a pharmaceutical composition that is suitable for human or veterinary pharmaceutical use.

[0018] The term “pharmaceutically acceptable salt” of a given compound refers to salts that retain the biological effectiveness and properties of the given compound, and which are not biologically or otherwise undesirable. “Pharmaceutically acceptable salts” or “physiologically acceptable salts” include, for example, salts with inorganic acids and salts with an organic acid. In addition, if the compounds described herein are obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, an addition salt, particularly a pharmaceutically acceptableaddition salt, may be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds. Those skilled in the art will recognize various synthetic methodologies that may be used to prepare nontoxic pharmaceutically acceptable addition salts. Pharmaceutically acceptable acid addition salts may be prepared from inorganic and organic acids. Pharmaceutically acceptable inorganic salts of phenylbutyrate include sodium, potassium, lithium, calcium, magnesium, and ammonium salts of phenylbutyrate.

[0019] As used herein, “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions.

[0020] As used herein, “metabolite” refers to any substance produced or used during all the physical and chemical processes within the body that create and use energy, such as: digesting food and nutrients, eliminating waste through urine and feces, breathing, circulating blood, and regulating temperature. Metabolites of a compound described herein are substances produced in body’s normal metabolic pathway of that particular substance. Metabolites of phenylbutyrate, for example, are substances produced in the body during the metabolism of phenylbutyrate, including phenylacetate and phenylacetylglutamine. Similarly, metabolites of bile acids are substances produced in the body during the metabolism of bile acids.

[0021] A “stereoisomer” refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures, which are not interchangeable. The present disclosure contemplates various stereoisomers and mixtures thereof and includes “enantiomers,” which refers to two stereoisomers whose molecules are nonsuperimposable mirror images of one another.

[0022] A “prodrug” is any compound which releases an active parent drug according to a structure described herein in vivo when such prodrug is administered to a mammalian subject. Prodrugs of a compound described herein are prepared by modifying functional groups present in the compound described herein in such a way that the modifications may be cleaved in vivo to release the parent compound. Prodrugs may be prepared by modifying functional groups present in the compounds in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compounds. Prodrugs include compounds described herein wherein a hydroxy, amino, carboxyl, or sulfhydryl group in a compound described herein is bonded to any group that may be cleaved in vivo to regenerate the free hydroxy, amino, or sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to esters (e.g., acetate, formate and benzoate derivatives), amides, guanidines, carbamates (e.g., N,N-dimethylaminocarbonyl) of hydroxy functional groups in compounds described herein and the like. Preparation, selection and use of prodrugs is discussed in T. Higuchi and V. Stella, “Pro-drugs as Novel Delivery Systems,” Vol. 14 of the A.C.S. Symposium Series; “Design of Prodrugs,” ed. H. Bundgaard, Elsevier, 1985; and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, each of which are hereby incorporated by reference in their entirety.

[0023] As used herein, the term “solvate” refers to a complex formed by combining a compound and a solvent.

[0024] As used herein, the term “hydrate” refers to a complex formed by combining a compound and water (i.e., a solvate when the solvent is water).

[0025] As used herein, the term “acid salt hydrate” refers to a complex formed by combining an acid salt compound with water.

[0026] As used herein, the term “N-oxide” refers to an oxidized tertiary or pyridinyl amine moiety.

[0027] As used herein, the term “isomorphic crystalline form” refers to two or more crystalline forms that have the same space group, unit-cell dimensions, and types and positions of atoms, with the exception of a replacement of one or more atoms in one isomorphic crystalline form with a different atom in its counterpart isomorphic crystalline form.

[0028] As used herein, the term “administration” refers to introducing an agent into a patient. For example, a therapeutic amount can be administered to the patient, which can be determined by the treating physician, medical professional, or the like. In some embodiments, a therapeutic amount is administered orally, wherein orally may be in a suspension of particles (micro- or nanoparticles) in an aqueous liquid, as a solid on a support vehicle such as a food, or as a liquid. The related terms and phrases “administering” and “administration of,” when used in connection with a compound or tablet (and grammatical equivalents) refer both to direct administration, which may be administration to a patient by a medical professional or by self-administration by the patient, and / or to indirect administration, which may be the act of prescribing a drug. Administration entails delivery to the patient of the drug.

[0029] The term “dose” or “dosage” refers to the total amount of an active agent (e.g., OLPRUVA® or a pharmaceutically acceptable salt thereof) administered to a patient in a single day (24-hour period). The desired dose can be administered once daily. In some embodiments, the desired dose may be administered in one, two, three, four or more sub-doses at appropriate intervals throughout the day, where the cumulative amount of the sub-doses equals the amount of the desired dose administered in a single day. The terms “dose” and “dosage” are used interchangeably herein.

[0030] As used herein, “preprandial” refers to a period of time before ingestion of food, such as a meal or snack, e.g., at least 5 minutes prior to a meal. As used herein, late preprandial refers to a period of time 3, 4, or more hours before ingestion of a meal or snack. As used herein, “postprandial” refers to a period of time after ingestion of food, such as a meal or snack e.g., at least 5 minutes after to a meal. As used herein, late postprandial refers to a period of time 3, 4, or more hours after ingestion of a meal or snack.

[0031] As used herein, “effective amount,” “therapeutically effective amount,” or “therapeutic amount” refers to an amount of a drug or an agent (e.g., sodium phenylbutyrate or an alternative pharmaceutically acceptable salt thereof) that when administered to a patient suffering from a condition, will have the intended therapeutic effect, e.g., alleviation, amelioration, palliation or elimination of one or more manifestations of the condition in the patient. The full therapeutic effect does not necessarily occur by administration of one dose and can occur only after administration of a series of doses and can be administered in one dose form or multiples thereof. For example, 500 mg of the drug can be administered in a single 500 mg strength tablet or two 250 mg strength tablets. Thus, a therapeutically effective amount may be administered in one or more administrations.

[0032] As used herein, the term “patient” or “subject” refers to a mammal, such as a human, bovine, rat, mouse, dog, monkey, ape, goat, sheep, cow, or deer. A patient as described herein can be a human. The patient can be a male or a female.

[0033] As used herein, “treatment,” “treating,” and “treat” are defined as acting upon a disease, disorder, or condition with an agent to reduce or ameliorate the harmful or any other undesired effects of the disease, disorder, or condition and / or its symptoms. Treatment, as used herein, covers the treatment of a human patient, and includes: (a) reducing the risk of occurrence of the condition in a patient determined to be predisposed to the disease but not yet diagnosed as having the condition, (b) impeding the development of the condition, and / or (c) relieving the condition, i.e., causing regression of the condition and / or relieving one or more symptoms of the condition.

[0034] “Prevention” or “preventing” means any treatment of a disease or condition that causes the clinical symptoms of the disease or condition not to develop. Compounds may, in some embodiments, be administered to a subject (including a human) who is at risk or has a family history of the disease or condition.Treatment Methods and UsesChronic Liver Disorders (CLD)

[0035] In a first embodiment, this application relates to the use of phenylbutyrate compounds, such as sodium phenylbutyrate (NaPB), alone or in combination with bile acids and other medicaments, in the treatment, prevention, or amelioration of liver-related conditions, including chronic cholestatic liverdiseases and symptoms associated with such illnesses in a human subject, particularly in a subject that seeks or receives medical care associated with the illness.

[0036] Liver-related conditions are a problem that affects approximately 1 .8% of the population and is responsible for approximately 2 million deaths per year worldwide. In addition, these diseases are a major burden for sufferers as well as public health organizations. Even early cases can lead to symptoms, such as pruritis, that are debilitating and reduce quality of life. Treatment of pruritus in liver diseases can be challenging and requires specific management with early initiation and a stepwise approach using specific drugs. Clinical trials are ongoing with novel agents that demonstrate potential efficacy, but currently there is a continued unmet need for improvements in methods of treating liver-related conditions and the symptoms associated with these conditions.

[0037] One class of compounds that has potential use in treatment of liver-related conditions is bile acids. Bile acids (BAs) are of interest to gastroenterologists and hepatologists due to their role in fat digestion. In recent years, there has been a growing interest in BAs as signaling molecules. Basic and clinical research related to BAs has suggested a physiological role in liver diseases, with potential targets for treating patients with PBC, PSC and NAFLD for which there is currently limited or no effective drug therapy. Ursodeoxycholic acid (UDCA) is currently the only US Food and Drug Administration (FDA) approved drug for PBC and it is the current standard of care for patients with this condition. UDCA has potent anticholestatic, antiapoptotic and anti-inflammatory properties. The optimum dose of UDCA in treating patients with PBC is 13-15 mg / kg / day and guidelines recommend initiating treatment at a low dose and increasing it gradually to the optimum dose.Specific Chronic liver disorders

[0038] Chronic liver disorders are marked by gradual destruction of liver tissue over time. Examples of CLD include alcoholic liver disease, fatty liver disease, liver cirrhosis, hepatitis B or C, autoimmune hepatitis, primary biliary cholangitis, primary sclerosing cholangitis, and obstructive jaundice. Heroin and / or alcohol abuse over an extended period of time can also lead to CLD. Certain genetic disorders such as Wilson's disease and hereditary hemochromatosis, cystic fibrosis, porphyria, and glycogen storage diseases can also lead to CLD.

[0039] In some embodiments, the chronic liver disorder comprises a primary chronic liver disorder. In some embodiments, the chronic liver disorder is selected from one or more of hepatitis, liver cirrhosis, fatty liver disease, primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), progressive familial intrahepatic cholestasis type 1 or 2 (PFIC1 of PFIC2), biliary atresia, Alagille syndrome, Caroli syndrome, and obstructive jaundice.

[0040] In some embodiments, the chronic liver disorder comprises a chronic cholestasis liver disorder. Cholestasis is defined as hepatocyte and cholangiocyte bile excretion failure or failure of bile transport tothe duodenum, resulting in damage to the liver. Two particularly serious chronic liver conditions are primary biliary cirrhosis (PBC) or primary sclerosing cholangitis (PSC). The majority of adult patients with chronic cholestasis have PBC or PSC.Primary’ biliary cirrhosis (PBC)

[0041] In some embodiments, the chronic liver disorder comprises a chronic cholestasis liver disorder. In some embodiments, the chronic cholestasis liver disorder comprises primary biliary cholangitis (PBC). PBC is an autoimmune disease of the liver resulting from slow, progressive destruction of the small bile ducts of the liver, causing buildup of bile and other toxins in the liver. PBC causes slow damage to the liver, eventually leading to fibrosis and cirrhosis.

[0042] Those affected by PBC often experience fatigue, which is a nonspecific symptom and can complicate diagnosis. Dry skin and itching (pruritus) are also common symptoms, and may be mild or severe. Pruritus may also be intermittent and may develop at any stage of the disease. PBC affects up to one in 3,000-4,000 people, with women being much more frequently affected than men. More than 90% of those affected by PBC have antimitochondrial antibodies (AMAs) against pyruvate dehydrogenase complex (PDC-E2), an enzyme found in the mitochondria. A failure of immune tolerance against PDC- E2 is thought to be a primary cause of PBC.Primary sclerosing cholangitis (PSC)

[0043] In some embodiments, the chronic cholestasis liver disorder comprises primary sclerosing cholangitis (PSC). PSC is a long-term progressive disease of the liver and gallbladder leading to inflammation of the bile ducts, eventually leading to scarring and narrowing of the ducts and impeding the flow of bile into the intestines. Similar to PBC, those affected by PSC may experience symptoms such as severe itching and fatigue, though nearly half of those with PSC do not experience any initial symptoms. Progression of the disease can lead to episodes of acute infection of the bile ducts (cholangitis), which can be life-threatening. Additionally, PSC can increase the risk of various cancers such as liver and gallbladder cancer, colorectal cancer, and bile duct cancer (cholangiocarcinoma). Currently the only known effective treatment for PSC is a liver transplant, though PSC can recur even after transplantation.

[0044] PSC is often associated with inflammatory bowel disease (IBD), most often ulcerative colitis. Roughly 3.0-7.5% of patients with ulcerative colitis also have PSC, and 80% of those with PSC have some form of IBD. The underlying cause of PSC is unknown, and it is thought to be a complex, multifactorial disorder wherein genetic factors, immune system dysfunction, and abnormal gut flora may all contribute to the disease.Progressive familial intrahepatic cholestasis (PF1C)

[0045] In some embodiments, the chronic cholestasis liver disorder comprises progressive familial intrahepatic cholestasis (PFIC). PFIC, also known as Byler disease, is a disorder characterized by defects in biliary epithelial transporters which impede the secretion of bile in the liver, eventually leading to bile buildup cirrhosis. Symptoms of PFIC usually begin in infancy, and includes severe itching, jaundice, and failure to thrive.

[0046] In some embodiments, the chronic cholestasis liver disorder comprises progressive familial intrahepatic cholestasis Type 1 (PFIC1). PFIC1 is caused by mutations in the gene coding for an ATPase protein (FIC-1) responsible for phospholipid translocation across membranes. Typically, those with PFIC1 present the earliest symptoms, and may experience additional symptoms beyond those related to liver disease such as pancreatitis and diarrhea. Fat malabsorption may also occur, leading to vitamin deficiencies and other complication such as low bone density.

[0047] In some embodiments, the chronic cholestasis liver disorder comprises progressive familial intrahepatic cholestasis Type 2 (PFIC2). PFIC2 is caused by mutations in the gene that codes for the bile salt export pump (BSEP), leading to retention of bile salts within liver cells. While the symptoms of PFIC2 are typically only related to liver disease itself, they tend to be more severe than those of PFIC1. PFIC2 often lead to liver failure in children in the first few years of life, and those affected with PFIC2 are at increased risk for hepatocellular carcinoma.Drug Induced Liver Injury or Disorder

[0048] The liver plays a central role in transforming and clearing chemicals and is susceptible to the toxicity from these agents. Certain medicinal agents, when taken in overdoses (e.g. paracetamol) and sometimes even when introduced within therapeutic ranges (e.g. halothane), may injure the organ. Drug- induced hepatotoxicity has also been observed in treatment of patients with vaccines. Examples include anti-rabies vaccination-induced hepatotoxicity and autoimmune hepatitis due to influenza virus and hepatitis A and B vaccines. Mechanisms for drug induced liver injury include liver cell necrosis, hepatitis, cholestasis, steatosis, granuloma, vascular lesions, and neoplasms. Ultimately, drug-induced liver injury may cause acute or chronic liver disease.

[0049] Similarly, drug induced hepatotoxicity may be induced by gene therapy treatments, such as use of viral vector-based therapies. Current therapies generally utilize adenoviral, lentiviral, or adeno- associated viral vectors. Viral vectors for use in gene therapy are described in Bulcha et al., Signal Transduction and Targeted Therapy 6:53 (2021), herein incorporated by reference. The underlying problem with use of these viral-based deliver systems is that the human immune system has evolved to recognize infectious agents. In response, viral vector therapies may utilize large vector doses, -1014vector genomes / kg. These large concentrations can induce hepatotoxicity and lead to adverse chronic liver conditions. In some embodiments, drug induced liver injury comprises a hepatocellular injury (wherein three times upper limit of transaminase in comparison to ALP), cholestatic injury (three timesincrease in ALP comparison to transaminase), or mixed pattern (where both ALP and aminotransferase are three times upper limit), as defined in 139 Arch. Pathol. Lab. Med. 876-887 (2015), herein incorporated by reference.Other Liver Disorders

[0050] In some embodiments, the chronic liver disorder comprises hepatitis. Hepatitis is inflammation of the liver tissue and is most commonly caused by the virus hepatovirus A, B, C, and D, though other viruses such as Epstein-Barr virus and yellow fever virus may also cause liver inflammation. Other causes may be due to alcohol abuse, other medications, toxins, and autoimmune diseases.

[0051] In some embodiments, the chronic liver disorder comprises liver cirrhosis. Cirrhosis is impaired liver function caused by the formation of scar tissue (fibrosis). Cirrhosis typically develops slowly over months or years and is most commonly caused by alcoholic liver disease, non-alcoholic steatohepatitis (NASH), and chronic hepatitis.

[0052] In some embodiments, the chronic liver disorder comprises fatty liver disease. Fatty liver disease (steatosis) is excessive fat buildup in the liver, and may be alcohol-induced or non-alcohol related. Nonalcoholic fatty liver disease (NAFLD) is the most common liver disorder in developed countries and is the leading cause of chronic liver disease in the US and Europe.

[0053] In some embodiments, the chronic liver disorder comprises biliary atresia, also known as extrahepatic ductopenia and progressive obliterative cholangiopathy. Biliary atresia is a childhood disease of the liver in which one or more bile ducts are abnormally narrow, blocked, or absent. It can be congenital or acquired. Infants with biliary atresia develop progressive conjugated jaundice, pale white stools, and dark urine. Some infants fail to thrive as there will be a degree of fat and fat-soluble vitamin malabsorption (e.g. Vitamin K), which may cause a bleeding tendency. Eventually, and usually after 2 months, cirrhosis with portal hypertension will develop. If left untreated, biliary atresia can lead to liver failure.

[0054] In some embodiments, the chronic liver disorder comprises Alagille syndrome, also called Alagillc- Watson syndrome, a genetic condition that affects the liver and heart, along with other parts of the body. The condition can cause liver damage and structural heart abnormalities. People diagnosed with this condition can experience bile (digestive fluid) backup in their liver caused by short or narrow bile ducts, or a decreased number of bile ducts. The stored bile damages the liver and may cause one or more of the following symptoms: jaundice, pruritis, xanthomas, weak bones, shortened stature, developmental delays, cirrhosis, blood clots, and dark colored urine. Long terms issues include liver disease and liver failure.

[0055] In some embodiments, the chronic liver disorder comprises Caroli disease, a rare genetic condition that causes the bile ducts in the liver to be wider than normal. Widening (dilation) of the bileducts in the liver (intrahepatic bile ducts) may cause bile duct stones to form, which can lead to yellowing of the skin (jaundice) and flu-like symptoms.

[0056] A subtype of Caroli disease is Caroli syndrome, a disease wherein the subject has scarring on their liver (congenital hepatic fibrosis) that can cause high blood pressure in the veins in the liver (portal hypertension) as well as problems with the bile. In some embodiments, people with Caroli syndrome may develop cysts on their kidneys (polycystic kidney disease). Symptoms of Caroli syndrome are similar to Caroli disease, but may also include blood in the stools, frequent illnesses, and pain in the abdomen.

[0057] In some embodiments, the chronic liver disorder comprises obstructive jaundice. Obstructive jaundice is a specific type of jaundice where symptoms develop due to a narrowed or blocked bile duct of pancreatic duct, thereby preventing drainage of bile from the bloodstream. This leads to a buildup of bilirubin, a pigment which causes the characteristic symptom of yellow eyes and skin in patients.Symptoms of CLD

[0058] Also provided are methods for the treatment of the symptoms of primary chronic liver disorders. Symptoms of CLD may take a long time to develop, which can complicate diagnosis. These symptoms include pruritus, fatigue, jaundice, eyelid xanthoma (xanthelasma), body pigmentation, spider angioma (also known as spider nevus or spider telangiectasia), abdominal discomfort, liver palms (palmar erythema), nausea, diarrhea, or anorexia. Additional symptoms of CLD can include fluid buildup in the abdomen (ascites) and the legs (edema), vomiting blood, increased bruising, and dark urine. At advanced stages of CLD, complications may develop including acute renal failure and hepatic encephalopathy leading to neurological symptoms such as forgetfulness, unresponsiveness, changes in sleep habits, and psychosis.

[0059] In some embodiments, the method of treating, preventing, or ameliorating a primary chronic liver disorder comprises treating a symptom of the disorder. In some embodiments, the symptom of a primary chronic liver disorder comprises one or more of pruritus, fatigue, jaundice, eyelid xanthoma, body pigmentation, spider angioma, abdominal discomfort, liver palms, nausea, diarrhea, or anorexia.

[0060] In some embodiments, the symptom of a primary chronic liver disorder is pruritus. Pruritus is characterized by an unpleasant, itchy sensation of the skin which provokes scratching. The scratching is sometimes severe enough to irritate and inflame the skin. Although usually occurring in the skin, pruritus can also occur in non-cutaneous areas such as mucous membranes. Pruritus is a very common and well- known symptom of CLD. For example, up to 80% of patients suffering from PBC and PSC experience pruritus. Historically, pruritus has been observed to accompany jaundice, but it is not uncommon to see pruritus as the first manifestation of cholestasis even before the onset of jaundice or other symptoms. Pruritus of the extremities (feet and hands) are common, though patients also may experience itching ofthe scalp, face, back, and torso as well, and may be mild to moderate or severe enough in intensity to disturb sleep or cause anxiety and / or depression.Chronic Kidney Disease (CKD)

[0061] In a second embodiment, this application relates to the use of phenylbutyrate compounds, such as sodium phenylbutyrate (NaPB), alone or in combination with bile acids and / or angiotensin converting enzyme inhibitors (ACEIs), angiotensin II receptor antagonists (ARBs), and other medicaments, in the treatment, prevention, or amelioration of kidney-related conditions and symptoms, including pruritis, increased blood pressure, fluid overload, urea or potassium accumulation, hyperphosphatemia, hypocalcemia, anemia, cachexia, cognitive decline or sexual dysfunction.

[0062] Kidney-related conditions are a problem that affects approximately 15% of the population. Approximately 90% of those people do not know they have CKD. CKD is a major burden for sufferers as well as public health organizations. Treatment of pruritus and other kidney-related conditions can be challenging due to the late onset of symptoms and the challenges related to the wide effects on the body. Currently there is a continued unmet need for improvements in methods of treating kidney-related conditions and the symptoms associated with these conditions.

[0063] One class of compounds that has potential use in treatment of kidney-related conditions is bile acids. Renal dysfunction occurs in patients with biliary obstruction. Plasma accumulation of bile acids and oxidative stress have been proposed as contributory factors. Bile acids can alter the renal handling of electrolytes and water by blocking the Na(+)-H+ antiport in the tubule. Oxidative stress, defined as an imbalance between radical generating systems and radical scavenging systems giving rise to free radical induced tissue damage, occurs in patients with liver disease. Bile acids cause oxidative damage to tubular cell membranes by stimulating the generation of oxygen free radicals from mitochondria, as well as promoting their release from neutrophils and macrophages. Oxidative stress can promote the formation of a variety of vasoactive mediators including endothelin-1, cysteinyl leukotrienes, as well as the F2- isoprostanes, endogenous products of lipid peroxidation. These mediators can each affect renal function directly by causing renal vasoconstriction or decreasing the glomerular capillary ultrafiltration coefficient, and thus reduce glomerular filtration rate. Collectively, these factors contribute to the onset of renal failure in patients with biliary obstruction. Bile acid treatments may be useful in the mitigation of biliary obstruction-related renal conditions and improve or mitigate chronic kidney-related diseases.Symptoms of CKD

[0064] Also provided are methods for the treatment of the symptoms of primary chronic kidney disorders (CKD). Symptoms of CKD may not develop until later stages of the disease, making treatment difficult. These symptoms include pruritus, fatigue, nausea, fatigue, high blood pressure, muscle cramps, sexual dysfunction, frequent urination, and sleep problems. Additional symptoms of CLD can include fluidbuildup around the heart and the feet and legs (edema), and shortness of breath due to fluid buildup in the lungs. At advanced stages of CKD, complications may develop including renal failure and cardiovascular disease, impaired central nervous system and decreased immune response.

[0065] In some embodiments, the method of treating, preventing, or ameliorating a primary chronic kidney disorder comprises treating a symptom of the disorder. In some embodiments, the symptom of a primary chronic liver disorder comprises one or more of pruritus, fatigue, nausea, fatigue, high blood pressure, muscle cramps, sexual dysfunction, frequent urination, sleep problems, edema, and shortness of breath.

[0066] In some embodiments, a symptom of a primary chronic kidney disorder comprises pruritus, also called uremic pruritus or chronic kidney disease-associated prCKD-associated pruritus. Uremia refers to excessive urea in the blood and occurs when the kidneys stop working (renal failure). Pruritus (itch) is a common problem for patients with chronic renal failure or end-stage renal disease and is characterized by an unpleasant, itchy sensation of the skin which provokes scratching. The most recent epidemiologic data have suggested that approximately 40% of patients with end-stage renal disease experience moderate to severe pruritus and that uremic pruritus (UP) has a major clinical impact, being associated strongly with poor quality of life, impaired sleep, depression, and increased mortality.Compounds, Pharmaceutical Compositions, and Modes of Administration

[0067] Chemical chaperones are a class of small molecules that function to enhance the folding and / or stability of proteins. Chemical chaperones are a broad and diverse group of molecules, and they can influence protein stability and polypeptide organization through a variety of mechanisms. Chemical chaperones are used for a range of applications, from production of recombinant proteins to treatment of protein misfolding. They have been proposed for the treatment of genetic diseases that are caused by unstable proteins.

[0068] There are many different small molecules that can function to enhance protein stability and folding, many of them can be broadly grouped into large classes based both on their structure and their proposed mechanism of action. The parameters that define these groups are not strictly defined, and many small molecules that exert a chemical chaperoning effect do not readily fall into one of these categories. 4- Phenylbutyrate has been suggested as a possible chemical chaperone that may have advantages in various biological systems. 4-phenylbutyrate contains an aromatic moiety and can bind hydrophobic patches of unfolded or partially folded proteins. For this reason, it acts as a “hydrophobic chaperone.” see, e.g., 21 Int. J. Mol. Sci.489 (2020), herein incorporated by reference.)

[0069] Potential treatment of systemic diseases has been shown with short-chain fatty acid derivatives of 2 to 6 carbons in length. Embodied examples include those short chain fatty acid derivatives selected from the group consisting of butyric acid, butyrate, 2.2 dimethylbutyric acid, a-methylhydrocinnamic acid,3.5 dimethoxy-4-hydrocinnamic acid, cinnamic acid, butyryl hydroxamate, propionate, bromopropionate, E-3-3 pyridyl-2-propenoic acid, levulinic acid, Kemp triacid, isovalerate, valerate, butyramide, isobutyramide, valproic acid, and valproate (U.S. 8,846,039, herein incorporated by reference). However, such examples comprised topical formulations and focused on the effects of these short-chain fatty acid derivatives on cytokine systems.

[0070] Based on novel understandings of the chaperone nature of phenylbutyrate and its interactions with proteins in the liver and kidneys, along with its synergistic interaction with bile acids, such as TUDC A, and other active ingredients, the disclosure provides methods for the treatment, prevention, or amelioration of liver- and kidney -related conditions and symptoms. In particular, one aspect comprises treating chronic cholestatic liver diseases and symptoms such as pruritis. Another aspect comprises treating chronic kidney disease and symptoms such as pruritis. Further advantages arc seen in some embodiments from particular dosing schedules of one or both of the phenylbutyrate and bile acid, such as preprandial dosing.

[0071] Provided herein are compounds, compositions and methods for the treatment, prevention, or amelioration of liver- and kidney-related conditions, including chronic cholestatic liver diseases, chronic kidney disease and symptoms associated with such illnesses. Also provided herein is a method of treating, preventing, or ameliorating a primary chronic liver disorder in a subject in need thereof, comprising administering a phenylbutyrate, or a metabolite, prodrug, pharmaceutically acceptable salt, hydrate, solvate, or crystalline form thereof, alone or in combination with bile acids and other medicaments.

[0072] Also provided herein is a method of treating a symptom of a primary chronic liver disorder in a subject in need thereof, comprising administering a phenylbutyrate, or a metabolite, prodrug, pharmaceutically acceptable salt, hydrate, solvate, or crystalline form thereof, in combination with a bile acid, alone or in combination with other pharmaceuticals. In some embodiments, the phenylbutyrate is coadministered with a bile acid or a prodrug, pharmaceutically acceptable salt, hydrate, solvate, or crystalline form thereof.

[0073] Also provided herein is a method of treating, preventing, or ameliorating a pruritus in a subject experiencing primary sclerosing cholangitis (PSC), comprising administering sodium 4-phenylbutyrate, or a metabolite, prodrug, pharmaceutically acceptable salt, hydrate, solvate, or crystalline form thereof with a bile acid or a prodrug, pharmaceutically acceptable salt, hydrate, solvate, or crystalline form thereof.

[0074] Also provided herein is a method of treating a symptom of a chronic kidney disorder in a subject in need thereof, comprising administering a phenylbutyrate, or a metabolite, prodrug, pharmaceutically acceptable salt, hydrate, solvate, or crystalline form thereof, in combination with a bile acid or a prodrug, pharmaceutically acceptable salt, hydrate, solvate, or crystalline form thereof. In some embodiments, the phenylbutyrate is co-administered with a bile acid along with one or more additional compounds, such as ACE inhibitors, ARBs, or other compounds.Phenylbutyrates

[0075] 4-phenylbutyrate is an aromatic, small molecule fatty acid made up of an aromatic ring and butyric acid, having the following structure:

[0076] It is commercially available as the sodium salt, sodium phenylbutyrate (NaPB). The chemical name for sodium phenylbutyrate is 4-phenylbutyric acid, sodium salt. It forms water-soluble off-white crystals and has the following chemical structure:

[0077] In another embodiment, 4-phenylbutyrate can be converted into a glycerol analog, glycerol phenylbutyrate. Glycerol phenylbutyrate is a room temperature triglyceride containing three phenylbutyrate molecules, having the following structure:

[0078] In some embodiments described herein, the phenylbutyrate comprises a sodium 4-phenylbutyrate or equivalent salt. In some embodiments described herein, the phenylbutyrate comprises an alkali 4- phenylbutyrate salt. In some embodiments, the phenylbutyrate comprises an organic salt of 4- phenylbutyrate. In some embodiments, the phenylbutyrate comprises a glycerol phenylbutyrate.Sodium Phenylbutyrate

[0079] In some embodiments, the phenylbutyric acid is a sodium salt. Sodium salts of butyric acid, or sodium phenylbutyrate, is sold commercially under the brand name BUPHENYL®, which is an FDA- approved product for the treatment of urea cycle disorders. Sodium phenylbutyrate is also sold under the brand name PHEBURANE® and AMMONAPS®. The commercially available formulations of immediate release sodium phenylbutyrate are unpalatable due to its highly bitter taste that is highly unpleasant. Noncompliance due to the poor taste can lead to insufficient dosing and suboptimal outcomes. Palatable formulations of sodium phenylbutyrate can be made via applying layered coatings to the active drug to mask the unpleasant taste and is available commercially under the brand name OLPRUVA®.

[0080] Sodium phenylbutyrate has found several actual and potential uses for treating conditions in human subjects. It has been approved for treating urea cycle disorders, genetic diseases in which nitrogen waste builds up in the blood plasma as ammonia glutamine (a state called hyperammonemia) due to deficiencies in the enzymes carbamoyl phosphate synthetase I, ornithine transcarbamylase, or argininosuccinic acid synthetase. Further, it is being investigated as a potential treatment option for maple syrup urine disease, cystic fibrosis, malignant gliomas and sickle-cell anemia.

[0081] Sodium phenylbutyrate has several possible mechanisms of action in the body. In treatment of UCD, phenylbutyrate acts as a prodrug, being first converted to phenylbutyryl-CoA and then metabolized by mitochondrial beta-oxidation to the active form, phenylacetate. Phenylacetate conjugates with glutamine to phenylacetylglutamine, which is eliminated with the urine. Phenylacetate is commercially sold under the brand name AMMONUL® (a mixture of sodium phcnylacctatc / sodium benzoate) for the treatment of acute hyperammonemia.

[0082] Other mechanisms of action of sodium phenylbutyrate include inhibition of histone deacetylase, activation of certain genes that protect neurons, and as a chemical chaperone, stabilizing denatured proteins and thereby improve conditions such as cystic fibrosis.

[0083] Sodium phenylbutyrate has been shown rescue the activity of mutant bile salt export pump (BSEP) in hepatocytes and improve clinical symptoms in patients with PFIC. Sodium phenylbutyrate was found to noticeably improve pruritus symptoms in patients with both PFIC2 and PFIC1, though no beneficial effects on liver functions were observed (Malatack et al, Pediatrics 2018, 141 : 1 and Hasegawa et al. Orphanet Journal of Rare Diseases 2014, 9:89).Other salts of phenylbutyrate

[0084] In some embodiments, the phenylbutyrate is an inorganic salt. In some embodiments, the phenylbutyrate is an ammonium salt. In some embodiments the phenylbutyrate is a lithium, sodium, or potassium, calcium, or magnesium salt.

[0085] In some embodiments, the phenylbutyrate is an organic salt. Salts and mixture of phenylbutyric acid are described in European Pat. Application No. EP2397458A1, which is incorporated by reference in its entirety.

[0086] In some embodiments, the organic salt of phenylbutyrate is an amine 4-phenylbutyrate salt. In some embodiments, the amine is selected from the group consisting of 2-(diethylamino)-ethanol, benethamine, benzathine, benzylamine, betaine (trimethylglycine), choline, deanol, diethanolamine, diethylamine (2,2'-iminobis(ethanol)), ethanolamine (2-aminoethanol), ethylenediamine, glucamines such as N-methyl-glucamine, hydrabramine, tromethamine, and triethanolamine (2,2',2"-nitrolitris(ethanol)). In some embodiments, the amine is selected from the group consisting of imidazoles such as 1 H-Imidazole,morpholines such as 4-(2-hydroxyethyl)-morpholine, piperazines, and pyrrolidines, such as l-(2- hydroxyethyl)-pyrrolidine.

[0087] In some embodiments, the organic salt of phenylbutyrate is a 4-phenylbutyrate salt of an amino acid. In some embodiments, the amino acid is selected from the group consisting of D-amino acids such as D-alanine, and L-amino acids such as L-lysine and L-arginine.Glycerol phenylbutyrate ( GPB )

[0088] In some embodiments, the phenylbutyrate is glycerol phenylbutyrate. Glycerol phenylbutyrate (GPB) is administered orally as with sodium phenylbutyrate but requires action of pancreatic lipases in the gastrointestinal tract to metabolize into phenylbutyrate, essentially acting as a slow-releasing form of sodium phenylbutyrate. GPB has been shown to achieve more stable control of ammonia levels over a 24- hour period due to its slow-release mechanism. Glycerol phenylbutyrate is used with dietary protein restriction and, in some cases, dietary supplements (e.g., essential amino acids, arginine, citrulline, or protein-free calorie supplements). Glycerol phenylbutyrate is administered orally in the form of a liquid.

[0089] Glycerol phenylbutyrate (GPB) is commercially available under the trade name RAVICTI®, an FDA-approved medication for the treatment of urea cycle disorders. RAVICTI® is contraindicated in patients less than 2 months of age, as they may have immature pancreatic exocrine function which could impair hydrolysis of RAVICTI®, leading to impaired absorption of phenylbutyrate and hyperammonemia; and in patients with known hypersensitivity to phenylbutyrate.Dosages of phenylbutyrate

[0090] Typical dosages of phenylbutyrate are described in U.S. Pat. Nos. 6,372,938 and 11,433,041, and French Pat. No. 2959129B1, each of which is incorporated by reference in its entirety.

[0091] In some embodiments, the phenylbutyrate is administered to the subject at a dosage of 100-1000 mg / kg / day. In some embodiments, the phenylbutyrate is administered to the subject at a dosage of 125- 800 mg / kg / day. In some embodiments, the phenylbutyrate is administered to the subject at a dosage of 150-600 mg / kg / day. In some embodiments, the phenylbutyrate is administered to the subject at a dosage of 250-500 mg / kg / day.

[0092] In some embodiments, the phenylbutyrate is administered to the subject at a dosage of 6-20 g / m2 / day. In some embodiments, the phenylbutyrate is administered to the subject at a dosage of 8-15 g / m2 / day. In some embodiments, the phenylbutyrate is administered to the subject at a dosage of 9.9-13.0 g / m2 / day. In some embodiments, the phenylbutyrate is administered for chronic management of adult and pediatric patients weighing 20 kg or greater and with a body surface area (BSA) of 1.2 m2or greater, with urea cycle disorders (UCDs) involving deficiencies of carbamylphosphate synthetase (CPS), ornithinetranscarbamylase (OTC), or argininosuccinic acid synthetase (AS) at a recommended dosage of 9.9 -13 g / m2 / day orally divided into three to six doses.

[0093] In some embodiments the total daily dosage of phenylhutyrate is to be taken in equally divided amounts with each meal or feeding (i.e., three to six times per day). In some embodiments, the phenylbutyrate is taken with each meal. In other embodiments, the dose is adjusted according to the time of day or ammonia levels, e.g., fasting ammonia levels. In some embodiments, the phenylbutyrate and / or bile acid is taken preprandial. In some embodiments, the phenylbutyrate is taken up to one hour preprandial. In some embodiments, the phenylbutyrate is taken up to 30 minutes preprandial. Administration, e.g., preprandial, may be once, twice, three times, or more per day, such as once or twice, meaning, in some embodiments, that not all dosages per day need to be preprandial.

[0094] In certain embodiments, the amount of phenylbutyrate (e.g., NaPB) administered preprandially is at least 5% less than that required to produce the same Cmax when phenylbutyrate (e.g., NaPB) is administered with food, e.g., up to about 10%, 15%, 20, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, or 75% less, such as about 20%, 25%, 30%, 35%, 40%, or 45% less. In certain embodiments, the administration of phenylbutyrate, e.g., preprandial taste masked phenylbutyrate, e.g., 5 g NaPB or equivalent, results in a Cmax of phenylbutyrate, e.g., NaPB, greater than 100 pg / mL, e.g., 100-500 pg / mL, 100-300 pg / mL, 200-300 pg / mL at least 125 pg / mL, 150 pg / mL, 175 pg / mL, or 200 pg / mL, e.g., up to 500 pg / mL or 300 pg / mL. In certain embodiments, the administration of phenylbutyrate, e.g., preprandial taste masked phenylbutyrate, e.g., 5 g NaPB or equivalent, results in an AUCo-24 of phenylbutyrate, e.g., NaPB, approximately equal to that of 14.1 g NaPB that is not taste masked (BUPHNEYL®) administered in a fed stated TID.

[0095] In some embodiments, the total dosage of the phenylbutyrate comprises 50 grams per day or less. In some embodiments, the total dosage of the phenylbutyrate comprises 30 grams per day or less. In some embodiments, the total dosage of the phenylbutyrate comprises 20 grams per day or less.Bile acids

[0096] In some embodiments, the phenylbutyrate is administered in combination with a bile acid or a prodrug, pharmaceutically acceptable salt, hydrate, solvate, or crystalline form thereof. Bile acids are steroid acids found predominantly in the bile of mammals and other vertebrates. Bile acid is an important component of bile, accounting for about 85% of the solid composition of bile. Bile acids are conjugated with taurine or glycine residues to give anions called bile salts. Primary bile acids are those synthesized by the liver while secondary bile acids result from bacterial actions in the colon. Bile acids aid in lipid digestion by solubilizing fats. Synthesis of bile acids is also a major route of cholesterol metabolism in humans and other species.

[0097] Examples of bile acids include, but are not limited to, taursodeoxycholic acid (TUDCA), ursodeoxycholic acid (UDCA), chenodeoxycholic acid (also referred to as “chenodiol” or “chenic acid”), cholic acid, hyodeoxycholic acid, deoxy cholic acid, 7-oxolithocholic acid, lithocholic acid, iododeoxycholic acid, iocholic acid, taurochenodeoxycholic acid, taurodeoxycholic acid, glycoursodeoxycholic acid, taurocholic acid, glycocholic acid, obeticholic (INT-747), 6a-ethyl-3a,7a- dihydroxy-50-cholan-23-sulfate (INT-767), 6a-ethyl-23(S)-methyl-3a,7a,12a-trihydroxy-5|3-cholan-24- oic acid (INT-777). Bile acids further include other synthetically derived bile acids, either naturally occurring or human-modified, see, e.g., Sarenac and Mikov, Front. Pharmacol. 9:939 (2018) doi: 10.3389 / fphar.2O18.00939, herein incorporated by reference in its entirety.

[0098] In some embodiments, the bile acid comprises cholic acid, taurochenodeoxycholic acid, taurocholic acid, glycocholic acid, glycochcnodcoxycholic acid, dcoxycholic acid, lithocholic acid, chenodeoxycholic acid, and ursodeoxycholic acid. In some embodiments the bile acid comprises taurochenodeoxycholic acid, tauroursodeoxycholic acid, or ursodeoxycholic acid.

[0099] In some embodiments the bile acid comprises ursodeoxycholic acid (UDCA). Ursodeoxycholic acid (UDCA), also known as ursodiol, is a secondary bile acid produced by intestinal bacteria in humans and other species. UDCA has been evaluated as a therapeutic for the treatment of PBC and PSC. It is thought that UDCA is able to form mixed micelles with hepatotoxic hydrophobic bile acids, thereby attenuating damage to the liver and bile ducts. It has also been suggested that UDCA may stimulate hepatocellular excretion of bile acids, thereby preventing their toxic buildup which leads to liver damage.

[0100] In some embodiments, the bile acid comprises tauroursodeoxycholic acid (TUDCA). Tauroursodeoxycholic acid (TUDCA), also known as ursodoxicoltaurinc or taurursodiol, is the taurine - conjugated form and primary metabolite of UDCA. TUDCA has been shown to inhibit apoptosis, attenuate oxidative stress, and reduce endoplasmic reticulum stress in neurodegenerative diseases, particularly for retinal degenerative disorders. TUDCA is more hydrophilic than UDCA and has been shown to be equally effective and safe as UDCA in a study with patients suffering from PBC.

[0101] In some embodiments, the bile acid comprises taurochenodeoxycholic acid. Taurochenodeoxycholic acid, also known as 12-deoxycholyltaurine, is the taurine-conjugated form of chenodeoxycholic acid. It is an epimer of tauroursodeoxycholic acid and acts as a detergent to solubilize fats in the small intestine and is itself absorbed by active transport in the terminal ileum.

[0102] In some embodiments the bile acid is administered to the subject at a dosage of 50-1500 mg / day. In some embodiments the bile acid is administered to the subject at a dosage of 100-1200 mg / day. In some embodiments the bile acid is administered to the subject at a dosage of 200-1000 mg / day. In some embodiments the bile acid is administered to the subject at a dosage of 300-900 mg / day. In some embodiments the bile acid is administered to the subject at a dosage of 400-800 mg / day.

[0103] In some embodiments the total daily dosage of phenylbutyrate and / or bile acid is to be taken in equally divided amounts with each meal or feeding (i.e., three to six times per day). In some embodiments, the phenylbutyrate and / or bile acid is taken with each meal. In other embodiments, the dose is adjusted according to the time of day or ammonia levels, e.g., fasting ammonia levels. In some embodiments, the phenylbutyrate and / or bile acid is taken preprandial. In some embodiments, the phenylbutyrate and / or bile acid is taken up to one hour preprandial. In some embodiments, the phenylbutyrate and / or bile acid is taken up to 30 minutes preprandial. Administration, e.g., preprandial, may be once, twice, three times, or more per day, such as once or twice, meaning, in some embodiments, that not all dosages per day need to be preprandial.

[0104] Alternatively, in some embodiments, the phenylbutyrate and / or bile acid is taken postprandial. In some embodiments, the phenylbutyrate and / or bile acid is taken up to one hour postprandial. In some embodiments, the phenylbutyrate and / or bile acid is taken up to 30 minutes postprandial.

[0105] In some embodiments, the method of treating, preventing, or ameliorating a primary chronic liver disorder in a subject in need thereof comprises administering sodium phenylbutyrate in combination with a bile acid. In some embodiments, the sodium phenylbutyrate is administered in combination with TUDCA. Sodium phenylbutyrate / ursodoxicoltaurine, also known as sodium phenylbutyrate / taurursodiol, is a fixed-dose combination medication used for the treatment of amyotrophic lateral sclerosis (ALS), commercially available under the trade name RELYVRIO / ALBRIOZA®. It contains 3 grams of sodium phenylbutyrate and 1 gram ursodoxicoltaurine (taurursodiol) per packet with dosing of 1 packet / day for 3 weeks, then 1 packet twice daily thereafter. Sodium phenylbutyrate / ursodoxicoltaurine is suspected to act by blocking cell death pathways in mitochondria and in the endoplasmic reticulum. Sodium phenylbutyrate acts as a chemical chaperone that helps proteins maintain their normal conformation, preventing aggregation that may lead to cell death. Ursodoxicoltaurine improves mitochondrial energy production. Compositions containing sodium phenylbutyrate / taurursodiol are described in U.S. Pat. No. 11,559,533.

[0106] In some embodiments, provided is a method of treating, preventing, or ameliorating a primary chronic liver disorder in a subject in need thereof, comprising administering a dosage of 100-1000 mg / kg / day of phenylbutyrate, or a metabolite, prodrug, pharmaceutically acceptable salt, hydrate, solvate, or crystalline form thereof, in combination with a dosage of 100-2000 mg / day of a bile acid or a prodrug, pharmaceutically acceptable salt, hydrate, solvate, or crystalline form thereof. In some embodiments, the phenylbutyrate is sodium 4-phenylbutytate, or a metabolite, prodrug, pharmaceutically acceptable salt, hydrate, solvate, or crystalline form thereof. In some embodiments, the bile acid is ursodeoxycholic acid, taurochenodeoxycholic acid, tauroursodeoxycholic acid, or a prodrug, pharmaceutically acceptable salt, hydrate, solvate, or crystalline form thereof.

[0107] In some embodiments, provided is a method of treating, preventing, or ameliorating a pruritus in a subject experiencing a primary liver disorder comprising administering a dosage of 100-1000 mg / kg / dayof sodium 4-phenylbutyrate, or a metabolite, prodrug, pharmaceutically acceptable salt, hydrate, solvate, or crystalline form thereof, in combination with a dosage of 100-2000 mg / day of taurochenodeoxy cholic acid, tauroursodeoxycholic acid, or a prodrug, pharmaceutically acceptable salt, hydrate, solvate, or crystalline form thereof. In some embodiments, the primary liver disorder comprises primary sclerosing cholangitis (PSC).Ileal Bile Acid Transporter Inhibitors

[0108] Ileal bile acid transporter (IB AT) inhibitors modulate protein function directed to bile acid uptake from blood plasma, a process mediated by co-transport of Na+. Example embodiments of IBAT inhibitors include, but are not limited to, elobixibat, lopixibat, maralixibat, and odevixibat. In some embodiments, the phenylbutyrate is administered in combination with an IBAT inhibitor (or a prodrug, pharmaceutically acceptable salt, hydrate, solvate, or crystalline form thereof) or, alternatively, in combination with an IBAT inhibitor and a bile acid.

[0109] In some embodiments the IBAT inhibitor is administered to the subject at a dosage of 5-50 mg / day. In some embodiments the IBAT inhibitor is administered to the subject at a dosage of 10-40 mg / day. In some embodiments the IBAT inhibitor is administered to the subject at a dosage of 5-30 mg / day. In some embodiments the IBAT inhibitor is administered to the subject at a dosage of 5-15 mg / day.

[0110] In some embodiments, the total daily dosage of phenylbutyrate and / or IBAT inhibitor is to be taken in equally divided amounts with each meal or feeding (i.e., three to six times per day). In some embodiments, the phenylbutyrate and / or IBAT inhibitor is taken with each meal. In other embodiments, the dose is adjusted according to the time of day or ammonia levels, e.g., fasting ammonia levels. In some embodiments, the phenylbutyrate and / or IBAT inhibitor is taken preprandial. In some embodiments, the phenylbutyrate and / or IBAT inhibitor is taken up to one hour preprandial. In some embodiments, the phenylbutyrate and / or IBAT inhibitor is taken up to 30 minutes preprandial. Administration, e.g., preprandial, may be once, twice, three times, or more per day, such as once or twice, meaning, in some embodiments, that not all dosages per day need to be preprandial. In one embodiment, the phenylbutyrate is taken preprandially three times a day and the IBAT inhibitor is taken preprandially in the morning. Some embodiments further comprise pre- or postprandial dosing of one or more bile acids.

[0111] Some embodiments provide a method of treating, preventing, or ameliorating a primary chronic liver disorder in a subject in need thereof, comprising administering a dosage of phenylbutyrate is in combination with an IBAT inhibitor and, optionally, a bile acid.

[0112] Some embodiments provide a method of treating, preventing, or ameliorating a primary chronic liver disorder in a subject in need thereof, comprising administering a dosage of 100-1000 mg / kg / day of phenylbutyrate, or a metabolite, prodrug, pharmaceutically acceptable salt, hydrate, solvate, or crystallineform thereof, in combination with a dosage of 5-50 mg / day of a IBAT inhibitor or a prodrug, pharmaceutically acceptable salt, hydrate, solvate, or crystalline form thereof. In some embodiments, the phenylbutyrate comprises sodium 4-phenylbutytate, or a metabolite, prodrug, pharmaceutically acceptable salt, hydrate, solvate, or crystalline form thereof. In some embodiments, the IBAT inhibitor comprises elobixibat, lopixibat, maralixibat, and odevixibat, or a prodrug, pharmaceutically acceptable salt, hydrate, solvate, or crystalline form thereof. In some embodiments, the method further comprises administering a dosage of 100-2000 mg / day of a bile acid. In some embodiments, the bile acid comprises ursodeoxycholic acid, taurochenodeoxycholic acid, tauroursodeoxycholic acid, or a prodrug, pharmaceutically acceptable salt, hydrate, solvate, or crystalline form thereof.

[0113] Some embodiments provide a method of treating, preventing, or ameliorating a pruritus in a subject experiencing a primary liver disorder comprising administering a dosage of 100-1000 mg / kg / day of sodium 4-phenylbutyrate, or a metabolite, prodrug, pharmaceutically acceptable salt, hydrate, solvate, or crystalline form thereof, in combination with a dosage of 5-50 mg / day of a IBAT inhibitor or a prodrug, pharmaceutically acceptable salt, hydrate, solvate, or crystalline form thereof. In some embodiments, the IBAT inhibitor comprises elobixibat, lopixibat, maralixibat, and odevixibat, or a prodrug, pharmaceutically acceptable salt, hydrate, solvate, or crystalline form thereof. In some embodiments, the method further comprises administering a dosage of 100-2000 mg / day of a bile acid. In some embodiments, the bile acid comprises ursodeoxycholic acid, taurochenodeoxycholic acid, tauroursodeoxycholic acid, or a prodrug, pharmaceutically acceptable salt, hydrate, solvate, or crystalline form thereof. In some embodiments, the primary liver disorder comprises primary sclerosing cholangitis (PSC).High Blood Pressure Medication

[0114] In some embodiments directed to chronic kidney conditions and other renal diseases, the phenylbutyrate may be administered in combination with an angiotensin converting enzyme (ACE) inhibitor or an angiotensin II receptor blocker (ARB) or a prodrug, pharmaceutically acceptable salt, hydrate, solvate, or crystalline form thereof. ACE inhibitors inhibit the activity of angiotensin-converting enzyme, an important component of the renin-angiotensin system which converts angiotensin I to angiotensin II and hydrolyses bradykinin. Therefore, ACE inhibitors decrease the formation of angiotensin II, a vasoconstrictor, and increase the level of bradykinin, a peptide vasodilator. This combination is synergistic in lowering blood pressure. In some embodiments, the ACE inhibitor comprises one or more of alacepril, quinapril, imidapril, cilazapril, fosinopril, arfalasin, benazepril, zofenopril, perindopril, trandolapril, captopril, enalapril, lisinopril, and ramipril.

[0115] Angiotensin II receptor blockers (ARBs) are a group of pharmaceuticals that bind to and inhibit the angiotensin II receptor type 1 (ATT) and thereby block the arteriolar contraction and sodium retention effects of renin-angiotensin system. Their main uses are in the treatment of hypertension (high blood pressure), diabetic nephropathy (kidney damage due to diabetes) and congestive heart failure. Theyselectively block the activation of the ATI receptor, preventing the binding of angiotensin II compared to ACE inhibitors. ARBs and the similar-attributed ACE inhibitors are both indicated as the first line antihypertensives in patients developing hypertension along with left-sided heart failure. In some embodiments, the ACE inhibitor comprises one or more of valsartan, telmisartan, losartan, irbesartan, azilsartan, olmesartan, candesartan, saprisartan, eprosartan, and fimasartan.

[0116] In some embodiments, provided is a method of treating a symptom of a chronic kidney and / or liver disorder in a subject in need thereof, comprising administering a dosage of 100-800 mg / kg / day of sodium 4-phenylbutyrate, glycerol phenylbutyrate, or a metabolite, prodrug, pharmaceutically acceptable salt, hydrate, solvate, or crystalline form thereof, in combination with an ACE inhibitor or ARB drug, optionally with a bile acid.Anemia Medication

[0117] In some embodiments directed to chronic kidney conditions and other renal diseases, the phenylbutyrate may be administered in combination with a medication for treating anemia. Anemia is a common complication of chronic kidney disease because the kidneys are involved in signaling the body to produce red blood cells. In particular, the kidneys produce erythropoietin in response to cellular hypoxia, which stimulates red blood cell production in the bone marrow. In subjects with chronic kidney disease, this signaling pathway is restricted. Medications for treating anemia include, but are not limited to, erythropoietin along with exogenous erythropoietin, recombinant human erythropoietin (rhEPO), produced by recombinant DNA technology in cell culture (collectively called erythropoiesis-stimulating agents (ESA), for example epoetin alfa (Procrit, Epogen), epoetin beta (NeoRecrmon), epoetin zeta (Silapo, Rctacrit).

[0118] In some embodiments, provided is a method of treating a symptom of a chronic kidney and / or liver disorder in a subject in need thereof, comprising administering a dosage of 100-800 mg / kg / day of sodium 4-phenylbutyrate, glycerol phenylbutyrate, or a metabolite, prodrug, pharmaceutically acceptable salt, hydrate, solvate, or crystalline form thereof, in combination with an anemia medication, optionally with a bile acid.Other Co-Administered Kidney Treatments

[0119] In some embodiments directed to chronic kidney conditions and other renal diseases, the phenylbutyrate may be administered in combination with a medication for treating a vitamin D deficiency or metabolic bone disease, phosphodiesterase-5 inhibitors for sexual dysfunction, a phosphate binder to control serum phosphate levels, or a loop diuretic. Example embodiments of medications for vitamin D deficiency include calcitriol. Example embodiments of medications for treating serum phosphate levels include sevelamer hydrochloride or carbonate (Renagel, Renvela), aluminum salts (Alucaps, Basaljel), calcium carbonate (Calcichew, Titralac), calcium acetate (Lenal Ace, PhosLo), lanthanum carbonate(Fosrenol), ferric citrate (Auryxia). Example embodiments of medications for sexual dysfunction include erectile dysfunction drugs, such as Viagra (sildenafil), Levitra (vardenafil), Cialis (tadalafil), and Stendra (avanafil). Example embodiments of medications for controlling edema include furosemide, azosemi de, bumetanide, piretanide, torasemide, ethacrynic acid and etozolin.

[0120] In some embodiments, provided is a method of treating a symptom of a chronic kidney and / or liver disorder in a subject in need thereof, comprising administering a dosage of 100-800 mg / kg / day of sodium 4-phenylbutyrate, glycerol phenylbutyrate, or a metabolite, prodrug, pharmaceutically acceptable salt, hydrate, solvate, or crystalline form thereof, in combination with a medication for treating vitamin D deficiency or metabolic bone disease, a phosphodiesterase-5 inhibitor, a phosphate binder, or a loop diuretic, optionally with a bile acid.Immunosuppressive agents

[0121] Many of the conditions described herein may have at least some component that is influenced by one or more autoimmune disorders of the subject. In such embodiments, further treatment with an immunosuppressant can provide synergistic advantages to said subject. Immunosuppressants can be classified into glucocorticoids, cytostatics, antibodies, drugs acting on immunophilins, and other drugs.

[0122] In pharmacologic (supraphysiologic) doses, glucocorticoids, such as prednisone, dexamethasone, and hydrocortisone are used to suppress various allergic, inflammatory, and autoimmune disorders. Glucocorticoids suppress cell-mediated immunity. They act by inhibiting genes that code for the cytokines Interleukin 1 (IL-1), IL-2, IL-3, IL-4, IL-5, IL-6, IL-8, and TNF-alpha, the most important of which is IL- 2. Smaller cytokine production reduces T cell proliferation. Glucocorticoids also suppress the humoral immunity, causing B cells to express smaller amounts of IL-2 and IL-2 receptors. This diminishes both B cell clone expansion and antibody synthesis.

[0123] Cytostatics inhibit cell division. In immunotherapy, they are used in smaller doses than in the treatment of malignant diseases. They affect the proliferation of both T cells and B cells. Due to their highest effectiveness, purine analogs are most frequently administered. The alkylating agents used in immunotherapy are nitrogen mustards (cyclophosphamide), nitrosoureas, platinum compounds, and others. Antimetabolites interfere with the synthesis of nucleic acids and include folic acid, purine, pyrimidine, and protein synthesis inhibitors. Further cytostatics include methotrexate, azathioprine, dactinomycin, anthracyclines, mitomycin C, bleomycin, and mithramycin.

[0124] Poly- and monoclonal antibodies are sometimes used as a targeted treatment of lymphoproliferative or autoimmune disorders. Antibodies for immunosuppression include batacept, adalimumab, anakinra, certolizumab, etanercept, golimumab, infliximab, ixekizumab, natalizumab, rituximab, secukinumab, tocilizumab, ustekinumab, vedolizumab, basiliximab, and daclizumab.

[0125] Drugs acting on immunophilins include a variety of complex compounds that inhibit immunophilin activity. Compounds include ciclosporin, tacrolimus, sirolimus, everolimus, and zatarolimus. Other drugs that may act as immunosuppressors include interferons (e.g., IFN-b), opioids, mycophenolate, and fingolimod.Anti-pruritis agents

[0126] Pruritus is a common symptom among the spectrum of chronic liver disorders that can severely impact a patient’s quality of life. In some embodiments, additional anti-pruritus agents may be administered to the subject for additional synergistic benefits. Antipruritics consist of a large group of drugs belonging to different classes with varying mechanisms to treat itch and may work directly or indirectly to relieve itch. Topical treatments generally treat localized itch whereas systemic drugs are designed to treat generalized itch across the whole body.

[0127] In some embodiments the anti-pruritus agent includes moisturizers, corticosteroids, calcineurin inhibitors, vitamin D analogs, antihistamines, and anesthetics. In some embodiments any of the following anti-pruritus agents may be administered topically or orally. In some embodiments, the anti-pruritus agent is a systemic drug such as an antibiotic, for example, rifampicin.Moisturizers

[0128] Moisturizers have long been used to maintain the integrity of the epidermal barrier and promote its protective function against dehydration, irritants, allergens, and infectious pathogens, all of which may precipitate itch and / or pain. Increases in transepidermal water loss (TEWL), which suggest decreased barrier function, are associated with increased intensity of pruritus in atopic dermatitis (AD) and other itchy dermatoses. Moisturizing is aimed at replenishing the cornified layer in order restore normal barrier function, in part by rehydrating or ‘plumping’ the corneocytes and by restoring the structure of the lipid bilayer of corneocytes within the lower stratum corneum. All commercially available moisturizer formulations contain a combination of humectants (which attract and hold water in the skin, e.g. glycerol, lactate, urea), occlusives (which prevent evaporation, e.g. petrolatum, mineral oil), and emollients (oils or lipids that provide partial hydration and occlusion, e.g. sterols, lanolin, glycol and glyceryl stearates). In general, moisturizers should be applied once or three times daily to xerotic skin, and especially within minutes of bathing for optimal occlusion of a hydrated stratum corneum.

[0129] No particular moisturizer formulation has consistently proven superior to others for improving skin barrier function. In general, ointments or thick creams containing high lipid content are preferred over lotions or gels. Glycerol-based moisturizers have been shown to increase stratum corneum hydration and thickness and can alleviate inflammation and itch in atopic skin. Several nonsteroidal barrier creams, recently introduced on the market as ‘medical devices’ for the treatment of AD, are thought to incorporate directly into the structural framework of the skin and are safe and effective in treating atopic pediatric andadult patients. These formulations contain various combinations of lipids such as triglycerides and free fatty acids, cholesterol, phospholipids, ceramides, squalene, and phytosterol, all of which are thought to reinforce the cornified layer scaffold. Barrier cream preparations may also contain hyaluronic acid or various humectants to hydrate corneocytes, as well as anti-inflammatory agents such as glycyrrhetinic acid, N-palmitoylthanolamine and antioxidants. Although more comparative clinical trials are needed, several studies suggest that pure petrolatum and lipid-containing creams are equally effective in repairing the skin barrier after experimental perturbation and in the setting of chronic dermatitis. Emollients rich in ceramides have also been shown to be effective in blocking TEWL and improving clinical disease scores.

[0130] In addition to hydration and structurally barrier reinforcement, emerging agents may accelerate recovery from barrier damage via yet unknown mechanisms. Application of capesazepine, a transient receptor potential vanilloid type 1 (TRPV1) antagonist, accelerates recovery from barrier damage in humans and can attenuate dermatitis-associated barrier damage in mouse models. Similarly, a newly developed prostanoid (DPI) receptor agonist known as TS-022 can significantly accelerate the repair of the cutaneous barrier disruption caused by mechanical scratching. The exact mechanism by which these agents act to improve barrier repair is unknown, but such agents may soon be incorporated into moisturizers and may prove helpful in preventing exacerbations in various pruritic skin disorders.Corticosteroids

[0131] Corticosteroids are a class of steroid hormones that are produced in the adrenal cortex of vertebrates, as well as the synthetic analogues of these hormones. Topical corticosteroids are first line therapy for a variety of conditions associated with pruritus. While the exact mechanism of action is not known, topical corticosteroids arc thought to activate glucocorticoid receptors that inhibit cytokine activation, thereby decreasing local inflammation and indirectly controlling pruritus. Thus, while frequently employed by health practitioners to treat patients with pruritus of unknown etiology, it must be emphasized that topical corticosteroids are of limited to no benefit in patients with non-inflammatory itch.

[0132] There are over 30 different topical steroid formulations available in the United States and these are prepared in different bases (e.g. solution, lotion, cream or ointment). Topical corticosteroids range in potency from low (Class VII) to high or ultra-potent (Class I). It is generally accepted that the clinical efficacy to treat inflammation, and indirectly pruritus, correlates with steroid potency.

[0133] Optimal use of topical corticosteroids usually involves using medium to ultra-potent formulations on a daily to twice daily basis for short courses lasting 1-3 weeks to pruritic areas or dermatitis on the trunk or extremities, and lower potency agents on the face or intertriginous areas. One study demonstrated that twice daily application of fluocinonidc 0.1% cream for 3 days was well tolerated by atopic patients and resulted in a 79% decrease in pruritus from baseline using the pruritus visual analog scale.14 A small pilot study in patients with pruritus from undefined etiologies demonstrated that topical application of hydrocortisone acetate 2.5% and pramoxine hydrochloride 1% in a hydrolipid lotion reduced pruritus by30% from baseline as rated by patients using the visual analog scale within 24 hours of initiation of therapy.15

[0134] In some embodiments, prolonged use of medium to ultra-potent topical steroids with close clinical monitoring may be indicated. Ultra-potent topical steroids, such as betamethasone dipropionate, are often used as first line agents and when combined with occlusive bandages, are thought to be particularly useful to interrupt the itch-scratch cycle. The use of topical steroids should be limited in cases of generalized cutaneous disease or prolonged daily treatment duration due to the risk of local side effects including atrophy, striae, pigment alteration, acne, petechiae, telangiectasia and the potential risk from systemic absorption including hypothalamus-pituitary axis suppression. While tachyphylaxis, defined as a decreasing response after administration of a few doses, has been demonstrated with use of topical steroids in several experimental settings, the clinical significance of this in pruritic disorders such as AD and psoriasis is unclear.Calcineurin inhibitors

[0135] Topical calcineurin inhibitors (TCIs), tacrolimus and pimecrolimus, are immunomodulators that have been shown to be effective in reducing pruritus in patients with pruritus symptoms. The underlying mechanisms of the ability of TCIs to reduce pruritus are unclear and may be multi-factorial. TCIs regulate T-cell activation and inhibit release of various inflammatory cytokines. While initially thought to act solely via their anti-inflammatory properties, TCIs may also mediate their anti-pruritic effects by activating and then desensitizing TRPV 1 located on peripheral nerve fibers.Vitamin D analogs

[0136] Topical vitamin D3 or its analogues, such as calcipotriol that has been used widely for the treatment of psoriasis, may also be useful to treat pruritus in some clinical scenarios. Vitamin D3 downregulates cellular adhesion molecule expression by inhibiting TNF-a mRNA expression and influences keratinocyte proliferation and differentiation. In two randomized, double-blind clinical trials, twice-daily application of calcitriol ointment for 8 weeks resulted in significant improvements in pruritus compared to vehicle ointment, in addition to reducing other symptoms of psoriasis. Topical vitamin D3 has also been reported to be effective in the treating the intensely pruritic lesions of prurigo nodularis. A double-blind, right / left comparison of calcipotriol 50 mg / gm ointment and betamethasone valerate 0.1% ointment in the treatment of prurigo nodularis demonstrated that calcipotriol was more effective in reducing the size and number of prurigo nodules.

[0137] Topical vitamin D3 analogues have been shown to be safe and well-tolerated in a number of short-term and long-term clinical trials. Pharmacokinetic studies in both healthy and psoriasis patients have demonstrated that topical calcitriol ointment produces little systemic absorption and does not alter systemiccalcium or phosphorous metabolism significantly even when applied to approximately one third of the body surface area.Antihistamines

[0138] Topical or oral antihistamines, while widely used to treat itch and available without a prescription, offer limited benefit in the treatment of pruritic conditions. In general, studies on antihistamines, including topical diphenhydramine, have been inconsistent, inconclusive or limited in design (small patient number, no placebo group, non-randomized). Only topical doxepin, a tricyclic antidepressant and potent Hl and H2 antagonist, has been shown to significantly reduce pruritus in patients with AD, lichen simplex chronicus, contact dermatitis and nummular dermatitis. However, topical doxepin may cause localized burning, allergic contact dermatitis, and has been reported to cause drowsiness due to systemic absorption in up to 25% of patients. Thus, despite its potential benefit, use of topical doxepin is limited by its side effect profile.Topical anesthetics

[0139] Topical anesthetics such as lidocaine 5% or the eutectic mixture of lidocaine 2.5% - prilocaine 2.5%, pramoxine 1%, and polidocanol 3%, have all been shown to have anti-pruritic effects and have been used successfully in several pruritic conditions. Lidocaine and prilocaine are both aminoamide anesthetics which inhibit sodium flux through voltage-gated sodium channels and thereby stabilize sensory fibers and block itch and pain sensation. Topical lidocaine alone or as a eutectic mixture with prilocaine has been used to effectively treat pruritus in patients with notalgia paresthetica, pruritus ani, and postburn pruritus. Potential side effects of ‘caine’ anesthetics include parasthesias, allergic contact dermatitis (usually due to metabolites of aminoester formulations), and methemoglobinemia necessitating avoidance in infant and pregnant patients.

[0140] Pramoxine, which is thought to exert anti-pruritic effects by stabilizing membranes of sensory nerves, effectively decreases itch in patients with xerosis, uremic pruritus, and psoriasis and has been used as a single agent or in combination with mild potency topical steroids or lactic acid lotion. In a randomized, double-blind, comparative trial in patients suffering from uremic pruritus, twice daily application of pramoxine 1% lotion for 4 weeks significantly reduced pruritus compared to a control lotion and was generally well-tolerated.

[0141] Polidocanol is a non-ionic surfactant with both local anesthetic properties and moisturizing effects. In an open-label, multi-center, drug monitoring survey of 1611 pediatric and adult patients, a combination of 5% urea and 3% polidocanol was found to significantly reduce or completely alleviate pruritus in 50% of patients with AD, contact dermatitis, psoriasis, or idiopathic pruritus. Anti-pruritic effects were evident in 25% of patients as early as 2 weeks, the first time point of evaluation, and themixture was well-tolerated with only 2.8% of cases reporting adverse events, including mild burning or itching.

[0142] Topical capsaicin, which activates TRPV1 on cutaneous sensory nerves triggering release and then depletion of neuropeptides such as substance P, and thereby limiting neural transmission from these fibers over time, has been used to treat itching in various pruritic disorders. Numerous reports and clinical studies have described successful treatment of symptoms in patients with notalgia paresthetica, brachioradial pruritus, pruritus ani, prurigo nodularis, aquagenic pruritus and uremic pruritus. In one study of 33 patients with prurigo nodularis, application of topical capsaicin 4 to 6 times daily demonstrated complete remission of itch in all patients within 2 weeks. Control of pruritus with topical capsaicin lasted for up to as long as 10 months with continued use but recurred soon after treatment discontinuation. However, a recent systematic review of existing controlled trials to test the efficacy of capsaicin as an antipruritic found numerous methodological concerns with these trials and concluded that there is no convincing evidence for the use of capsaicin to treat pruritus in any medical condition. A common side effect of topical capsaicin is a transient burning sensation and local erythema with initial application. Patients should be warned about this effect and may benefit from simultaneous application of a topical anesthetic for the first few days of use to improve overall compliance. Limited hyperalgesia and neurogenic inflammation have been reported in African American patients in response to topical capsaicin.

[0143] Topical menthol, a monoterpene isolated from the essential oils of Menthe piperita and M. arvesis, has been used since ancient times for its anti-pruritic and analgesic effects. Menthol elicits a cool sensation via activation of TRPM8, a temperature- sensitive member of the melastatin transient receptor potential subfamily expressed on cutaneous sensory fibers.66 The anti-pruritic effect of menthol has been described for lichen amyloidosis, as well as hydroxyethyl starch-induced, histamine-induced, and mustard gas-induced pruritus. Of note, menthol at concentrations of 1 to 3% have been reported to relieve pruritus, while higher dose preparations such as 10% solutions can induce irritation.Other agents

[0144] Rifampicin (RFP), also known as rifampin, is an ansamycin antibiotic used to treat several types of bacterial infections, including tuberculosis (TB), Mycobacterium avium complex, leprosy, and Legionnaires’ disease. There is evidence to suggest that rifampicin is an effective second line therapy for controlling pruritus in patients with chronic cholestatic liver disease. It is most widely used as an antipruritic agent in the autoimmune cholestatic liver disease, primary biliary cirrhosis (PBC). However, Rifampicin may potentially cause hepatitis or other significant impairment of liver synthetic function in patients. Before treating a person for a long period of time, measurements of liver enzymes and blood counts are recommended. Rifampicin may be given either by mouth or intravenously.

[0145] Rifampicin is the most powerful known inducer of the hepatic cytochrome P450 enzyme system, including isoenzymes CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP3A4, CYP3A5, and CYP3A7. Itincreases metabolism of many drugs and consequently, can make them less effective, or even ineffective, by decreasing their levels. For instance, patients undergoing long-term anticoagulation therapy with warfarin must increase their dosage of warfarin and have their clotting time checked frequently because failure to do so could lead to inadequate anticoagulation, resulting in serious consequences of thromboembolism .

[0146] Rifampicin often induces cholestatic liver injury and hyperbilirubinemia which limits its clinical use. Administration of sodium phenylbutyrate was shown to alleviate the negative effects of RFP on HepG2 cell viability reduction, apoptosis, and MRP2 ubiquitination degradation in mice, indicating that sodium phenylbutyrate may alleviate RFP-indued cholestatic liver damage.

[0147] In some embodiments, dosages of sodium phenylbutyrate need to be modified when taken with Rifampicin. In some embodiments, sodium phenylbutyrate is administered to the subject at a dosage of 400 mg / kg / day. In some embodiments, sodium phenylbutyrate is administered to the subject at a dosage of 300 mg / kg / day. In some embodiments, sodium phenylbutyrate is administered to the subject at a dosage of 240 mg / kg / day.

[0148] Orally administered rifampicin results in peak plasma concentrations in about 2-4 hours. The half-life of rifampicin ranges from 1.5 to 5.0 hours, though hepatic impairment significantly increases it. Food consumption inhibits its absorption from the GI tract, and the drug is more quickly eliminated. When rifampicin is taken with a meal, its peak blood concentration falls by 36%. Distribution of the drug is high throughout the body and reaches effective concentrations in many organs and body fluids, including the cerebrospinal fluid. Since the substance itself is red, this high distribution is the reason for the orange -red color of the saliva, tears, sweat, urine, and feces. About 60% to 90% of the drug is bound to plasma proteins.EXAMPLES

[0149] Example 1: In a multicenter, double-blind, randomized trial study, a 24-week treatment with TUDCA or UDCA shows similar biochemical improvement (decline in ALP levels from baseline in 76% and 81% patients for TUDCA and UDCA groups, respectively) in PBC patients, demonstrating that TUDCA is not inferior to UDCA for this disease (Ma et al., Medicine 2016, 95:47, herein incorporated by reference).

[0150] Among all the symptoms / signs, 48.57% in TUDCA group improves after treatment, while only 25.58% in UDCA group improves (P=0.035). It is noteworthy that the proportion of patients with pruritus / scratch increase from 1.43% to 10.00% in UDCA group, while there’ s no change in TUDCA group (P=0.023). In terms of jaundice / scleral yellow dye, the proportion of patients decrease from 8.53% to 1.55% in TUDCA group, and from 17.14% to 10.00% in UDCA group (P=0.049).

[0151] It is also noteworthy that the same amount (750mg) of TUDCA and UDCA per day is not bioequivalent because of their different molecular weight, and 500mg TUDCA is approximately 375mg UDCA in terms of bioequivalence. So, it could be anticipated that TUDCA could be more effective than UDCA if given the same bioequivalent amount of drugs for PBC patients. Thus, patients in the TUDCA group receive smaller molar amounts of the drug and this may partially explain why TUDCA is not superior to UDCA in this study, since it is known that low-dose (<10mg / kg / d) UDCA does not work well in patients with PBC.

[0152] Example 2: One or more subjects suffering from a chronic liver condition are entered into a study to determine the effectiveness of an oral sodium 4-phenylbutyrate (NaPB) composition in the treatment of the liver condition and / or symptoms related thereto. Enrolled subjects are screened and genetically tested, with those having genetically inherited liver conditions being analyzed separately. Dosing is 250-500 mg / kg / day (orally) of NaPB and treatment is done for a period of at least 2 weeks. Subjects treated have one or more of the following conditions: hepatitis, liver cirrhosis, fatty liver disease, primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), progressive familial intrahepatic cholestasis type 1 or 2 (PFIC1 of PFIC2), or obstructive jaundice.

[0153] NaPB shows effective improvement on liver function or symptoms related to the noted liver diseases. In particular, therapy with NaPB at a dosage of 350 or 500 mg / kg / day significantly relieves the pruritis. In addition, hemorrhage and eschar on the patients’ skin is diminished, and areas of fresh normal skin appear as the frequency and intensity of skin scratching decreases, and sleep quality is improved.

[0154] Example 3: While a monotherapy of either TUDCA or UDCA alone or NaPB alone has shown promise, it is contemplated that a combination therapy of a bile acid with phenylbutyrates would be effective in treating chronic liver disorders and its symptoms such as pruritus. It is also contemplated that bile acids may be more effective in treating chronic liver disorders when co- administered with a phenylbutyrate. It is further contemplated that different forms of phenylbutyrate (such as sodium phenylbutyrate or glycerol phenylbutyrate) in combination with a bile acid may result in different efficacies when administered to a patient with a chronic liver disorder.

[0155] The test subjects described in Example 2 are further treated with a combination therapy comprising NaPB and a bile acid. For example, sodium phenylbutyrate is administered in combination with a bile acid such as UDCA, TUDCA, or taurochenodeoxycholic acid. Subjects with chronic liver disorders, for example, PBC or PSC, are administered sodium phenylbutyrate at a dosage of, for example, 250 mg / kg / day or 500 mg / kg / day along with a bile acid at a dosage of, for example, 400 mg / day or 800 mg / day. The dosage is administered 3 times a day either before, with, or after a meal. Routine blood tests are conducted at 4, 12, and 24 weeks after the first dose to measure changes in serum markers and bile acid concentrations compared with baseline levels. Qualitative assessment of symptoms such as fatigue, nausea,and abdominal discomfort / pain are also carried out. Pruritus is quantified using a visual analog scale (graduated from 0 to 10) during daytime and nighttime, with a score of 0 indicating no pruritus and a score of 0 indicating unremitting pruritus with severely impaired quality of life.

[0156] In a similar example study, subjects are administered glycerol phenylbutyrate in combination with a bile acid such as UDCA, TUDCA, or taurochenodeoxycholic acid. In another study, subjects are administered sodium phenylacetate / sodium benzoate in combination with a bile acid such as UDCA, TUDCA, or taurochenodeoxycholic acid.

[0157] The combination therapy shows effective improvement on liver function or symptoms related to the noted liver diseases. Qualitative assessments show improved liver function or reduction of symptoms. Pruritis scores are reduced by 1 , 2, 3 or more points, with scores improving inline with the time of treatment.

[0158] Additionally, dosing of NaPB relative to meal timing significantly impacts treatment effectiveness. NaPB (150 mg / kg) is administered orally 30 min before, just before, and just after meal(s) following overnight fasting. Compared with postprandial administration, preprandial administration significantly increases the peak plasma concentration and area under the plasma concentration-time curve of NaPB by 2.5-fold (95% confidential interval (CI), 2.0-3.0;P = 0.003) and 2.4-fold (95% CI, 1.7- 3.2;P = 0.005). Further, preprandial administration shows markedly better improved liver function and reduction of clinical symptoms.

[0159] Example 4: One or more subjects suffering from a chronic kidney condition are entered into a study to determine the effectiveness of an oral sodium 4-phenylbutyrate (NaPB) composition in the treatment of the kidney condition and / or symptoms related thereto. Enrolled subjects are screened. Dosing is 250-500 mg / kg / day (orally) of NaPB and treatment is done for a period of at least 2 weeks. Subjects treated have reduced renal function along with one or more of the following conditions: pruritus, fatigue, nausea, fatigue, high blood pressure, muscle cramps, sexual dysfunction, frequent urination, sleep problems, edema, and shortness of breath.

[0160] NaPB shows effective improvement on kidney function or symptoms related to the noted symptoms diseases. In particular, therapy with NaPB at a dosage of 350 or 500 mg / kg / day significantly relieves the pruritis. In addition, hemorrhage and eschar on the patients’ skin is diminished, and areas of fresh normal skin appear as the frequency and intensity of skin scratching decreases, and sleep quality is improved.

[0161] Example 5: A combination therapy of a bile acid (either TUDCA or UDCA) and NaPB is tried to look for synergistic effects in treating chronic renal disorders and symptoms, such as pruritus. It is also contemplated that bile acids may be more effective in treating chronic kidney disorders when coadministered with a phenylbutyrate. It is further contemplated that different forms of phenylbutyrate (suchas sodium phenylbutyrate or glycerol phenylbutyrate) in combination with a bile acid may result in different efficacies when administered to a patient with a chronic kidney disorder.

[0162] The test subjects described in Example 4are further treated with a combination therapy comprising NaPB and a bile acid. For example, sodium phenylbutyrate is administered in combination with a bile acid such as UDCA, TUDCA, or taurochenodeoxycholic acid. Subjects with chronic kidney conditions are administered sodium phenylbutyrate at a dosage of, for example, 250 mg / kg / day or 500 mg / kg / day along with a bile acid at a dosage of, for example, 400 mg / day or 800 mg / day. The dosage is administered 3 times a day either before, with, or after a meal. Routine blood tests are conducted at 4, 12, and 24 weeks after the first dose to measure changes in serum markers compared with baseline levels. Qualitative assessment of symptoms such as fatigue, nausea, and blood and protein content in urine are also carried out. Pruritus is quantified using a visual analog scale (graduated from 0 to 10) during daytime and nighttime, with a score of 0 indicating no pruritus and a score of 0 indicating unremitting pruritus with severely impaired quality of life.

[0163] In a similar example study, subjects are administered glycerol phenylbutyrate in combination with a bile acid such as UDCA, TUDCA, or taurochenodeoxycholic acid. In another study, subjects are administered sodium phenylacetate / sodium benzoate in combination with a bile acid such as UDCA, TUDCA, or taurochenodeoxycholic acid.

[0164] The combination therapy shows effective improvement on kidney function or symptoms related to chronic kidney disease. Qualitative assessments show improved kidney function or reduction of symptoms. Pruritis scores are reduced by 1, 2, 3 or more points, with scores improving inline with the time of treatment.

[0165] Additionally, dosing of NaPB relative to meal timing significantly impacts treatment effectiveness. NaPB (150 mg / kg) is administered orally 30 min before, just before, and just after meal(s) following overnight fasting. Compared with postprandial administration, preprandial administration significantly increases the peak plasma concentration and area under the plasma concentration-time curve of NaPB by 2.5-fold (95% confidential interval (CI), 2.0-3.0;P = 0.003) and 2.4-fold (95% CI, 1.7- 3.2;P = 0.005). Further, preprandial administration shows markedly better improved kidney function and reduction of clinical symptoms.

Claims

CLAIMS1. A method of treating, preventing, or ameliorating a primary chronic liver or kidney disorder in a subject in need thereof, comprising orally administering to the subject a dosage of a phenylbutyrate, or a metabolite, prodrug, pharmaceutically acceptable salt, hydrate, solvate, or crystalline form thereof.

2. The method of claim 1, wherein the treating, preventing, or ameliorating a primary chronic liver or kidney disorder comprises treating a symptom of the disorder.

3. The method of claim 2, wherein the disorder is a primary chronic liver disorder and the symptom comprises one or more of pruritus, fatiguejaundice, eyelid xanthoma, body pigmentation, spider angioma, abdominal discomfort, liver palms, nausea, diarrhea, and anorexia.

4. The method of claim 2, wherein the disorder is a primary chronic kidney disorder and the symptom comprises one or more of pruritus, fatigue, nausea, fatigue, high blood pressure, muscle cramps, sexual dysfunction, frequent urination, sleep problems, edema, and shortness of breath5. The method of claim 3 or claim 4, wherein the symptom comprises pruritus.

6. The method of any one of claims 1-3 or 5, wherein the chronic liver disorder is selected from hepatitis, liver cirrhosis, fatty liver disease, primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), progressive familial intrahepatic cholestasis type 1 or 2 (PFIC1 or PFIC2), biliary atresia, Alagille syndrome, Caroli syndrome, drug induced liver injury, or obstructive jaundice.

7. The method of any one of claims 1-3 or 5, wherein the chronic liver disorder is a chronic cholestasis liver disorder.

8. The method of claim 7, wherein the chronic cholestasis liver disorder is selected from primary biliary cholangitis (PBC) or primary sclerosing cholangitis (PSC).

9. The method of any one of the preceding claims, wherein the phenylbutyrate is selected from an alkali 4-phenylbutyrate salt or glycerol phenylbutyrate.

10. The method of claim 9, wherein the phenylbutyrate is sodium 4-phcnylbutyratc.

11. The method of any one of the preceding claims, wherein the dosage of the phenylbutyrate or metabolite, prodrug, pharmaceutically acceptable salt, hydrate, solvate, or crystalline form thereof administered to the subject is from 100-800 mg / kg / day of phenylbutyrate.

12. The method of claim 10, wherein the phenylbutyrate is administered to the subject at a dosage of 150-600 mg / kg / day.

13. The method of claim 10, wherein the phenyl butyrate is administered to the subject at a dosage of 250-500 mg / kg / day.

14. The method of any one of the preceding claims, wherein the phenylbutyrate is administered to the subject at a dosage of 9.9 -13 g / m2 / day.

15. The method of claim 10, wherein the dosage of the phenylbutyrate is 30 grams or less per day.

16. The method of claim 10, wherein the dosage of the phenylbutyrate is 20 grams or less per day.

17. The method of any one of the preceding claims, wherein the phenylbutyrate is administered preprandial.

18. The method of any one of the preceding claims, further comprising administering a bile acid or a prodrug, pharmaceutically acceptable salt, hydrate, solvate, or crystalline form thereof.

19. The method of claim 17, wherein the bile acid is selected from cholic acid, taurochenodeoxycholic acid, taurocholic acid, glycocholic acid, glycochenodeoxycholic acid, deoxycholic acid, lithocholic acid, chenodeoxycholic acid, tauroursodeoxycholic acid, obeticholic acid, or ursodeoxycholic acid.

20. The method of claim 18, wherein the bile acid is selected from taurochenodeoxycholic acid, tauroursodeoxycholic acid, or ursodeoxycholic acid.

21. The method of claim 17, wherein the bile acid is administered to the subject at a dosage of 100- 2000 mg / day.

22. The method of claim 20, wherein the bile acid is administered to the subject at a dosage of 400- 1500 mg / day.

23. The method of any one of the preceding claims, wherein the subject is further administered a therapeutically effective amount of an additional therapeutic agent.

24. The method of claim 23, wherein the additional therapeutic agent comprises an ileal bile acid transporter inhibitor, an ACE inhibitor, an ARB, an immunosuppressive agent, an anti-pruritis agent, anansamycin antibiotic, an erythropoietin, calcitriol, an agent for moderating serum phosphate levels, an erectile dysfunction drug, or a drug for controlling edema.

25. The method of claim 24, wherein the additional therapeutic agent is selected from one or more of elobixibat, lopixibat, maralixibat, and odevixibat, alacepril, quinapril, imidapril, cilazapril, fosinopril, arfalasin, benazepril, zofenopril, perindopril, trandolapril, captopril, enalapril, lisinopril, ramipril, valsartan, telmisartan, losartan, irbesartan, azilsartan, olmesartan, candesartan, saprisartan, eprosartan, fimasartan, erythropoietin, recombinant human erythropoietin, sevelamer hydrochloride or carbonate, an aluminum salt, calcium carbonate, calcium acetate, lanthanum carbonate, ferric citrate, sildenafil, vardenafil, tadalafil, avanafil, urosemide, azosemide, bumetanide, piretanide, torasemide, ethacrynic acid etozolin, batacept, adalimumab, anakinra, certolizumab, etanercept, golimumab, infliximab, ixekizumab, natalizumab, rituximab, secukinumab, tocilizumab, ustekinumab, vedolizumab, basiliximab, and daclizumab, ciclosporin, tacrolimus, sirolimus, everolimus, zatarolimus, prednisone, dexamethasone, hydrocortisone, vitamin D or a vitamin D analog, diphenhydramine, doxepin, lidocaine, prilocaine, pramoxine, polidocanol, capsaicin, menthol, and rifampicin.

26. A method of treating, preventing, or ameliorating a pruritus in a subject experiencing primary sclerosing cholangitis (PSC), comprising administering sodium 4-phenylbutyrate, or a metabolite, prodrug, pharmaceutically acceptable salt, hydrate, solvate, or crystalline form thereof.

27. A method of treating, preventing, or ameliorating a pruritus in a subject experiencing chronic kidney disease, comprising administering sodium 4-phenylbutyrate, or a metabolite, prodrug, pharmaceutically acceptable salt, hydrate, solvate, or crystalline form thereof.

28. The method of claim 26 or claim 27, further comprising administering sodium 4-phenylbutyrate in combination with taurochenodeoxycholic acid, tauroursodeoxycholic acid, or a prodrug, pharmaceutically acceptable salt, hydrate, solvate, or crystalline form thereof.

29. The method of claim 28, wherein the sodium 4-phenylbutyrate, or a metabolite, prodrug, pharmaceutically acceptable salt, hydrate, solvate, or crystalline form thereof is administered at a dosage of 100-800 mg / kg / day and the taurochenodeoxycholic acid, tauroursodeoxycholic acid, or a prodrug, pharmaceutically acceptable salt, hydrate, solvate, or crystalline form thereof is administered at a dosage of 100-1000 mg / day.

30. The method of any one of the preceding claims, wherein the subject is between 2-12 years of age.

31. The method of claim 23, wherein the additional therapeutic agent comprises a viral vector-based therapeutic agent.

32. The method of claim 31, wherein the viral- vector based therapeutic agent comprises a gene therapy.

33. The method of claim 32, wherein the viral- vector based therapeutic agent comprises an adenovirus, a lentivirus, or an adeno-associate virus as the vector.

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