Treatment of cholangiopathy

Abstract

To provide a method for treating cholangiopathy in a subject who is intolerant or has insufficient response to obeticholic acid and / or fibrate.SOLUTION: Seladelpar and salt thereof are useful for treatment of cholangiopathy in a subject who is intolerant or has insufficient response to obeticholic acid and / or fibrate.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to the treatment of cholangiopathy in subjects who are intolerant to or have an inadequate response to obeticholic acid and / or fibrates. [Background technology]

[0002] cholangiopathy

[0003] Cholangiocytes are epithelial cells lining the intrahepatic and extrahepatic bile ducts, and they are involved in bile production and homeostasis. In a healthy liver, cholangiocytes contribute to bile secretion via net release of bicarbonate and water. Cholangiocytes operate through a bile acid-independent bile flow driven by active transport of electrolytes. Cholangiocytes are damaged in a variety of human diseases called cholangiopathies. Cholestasis is a disease in which the flow of bile from the liver to the duodenum is slowed or blocked; in cholestasis, bile accumulates in the liver parenchyma. Cholestasis can be conveniently divided into two types: intrahepatic cholestasis, which occurs inside the liver, where bile formation is prevented by illnesses such as various diseases, prolonged parenteral nutrition, or side effects of certain medications (such as some antibiotics); and extrahepatic cholestasis, which occurs outside the liver and typically occurs when bile flow is prevented by mechanical partial or complete blockage of the bile duct, such as by bile duct tumors, cysts, bile duct stones, strictures, or pressure on the bile duct; however, primary sclerosing cholangitis (PSC) can be intrahepatic or extrahepatic. Common symptoms of cholestasis include fatigue, pruritus (itching), jaundice, and xanthomas (deposits of cholesterol-rich material under the skin). The effects of cholestasis can be severe and widespread, leading to worsening liver disease with systemic illness, liver failure, and the need for liver transplants. As a group, cholangiopathies account for approximately 18% of adult liver transplants and the majority of pediatric liver transplants.

[0004] Intrahepatic cholangiopathies include, in order of decreasing frequency, primary biliary cholangitis (PBC, formerly known as primary biliary cirrhosis); primary sclerosing cholangitis (PSC, which may be extrahepatic, as described above); progressive familial intrahepatic cholestasis (PFIC); and Alagille syndrome (AS). Other cholangiopathies include cystic fibrosis-associated cholangiopathies, immune-mediated cholangiopathies autoimmune cholangitis, and graft-versus-host disease involving the liver. Other cholangiopathies are described, for example, in Box 1: Selected cholangiopaties at page 272 in Banales et al., "Cholangiocyte pathobiology", Nature Rev. Gastroenterol. Hepatol., vol. 16, pages 269-281 (2019), or other cholangiopathies literature.

[0005] PBC is an autoimmune disease of the liver characterized by the slow progressive destruction of the small bile ducts of the liver, with the interlobular ducts being affected early in the disease. When these ducts are damaged, bile is produced in the liver (cholestasis) and over time, can cause tissue damage, scarring, fibrosis and cirrhosis. Recent studies have shown that it may affect up to 1 in 3,000-4,000 people, with a male:female gender ratio of at least 9:1. There is no cure for PBC, so liver transplants are often required; however, medications (e.g., ursodeoxycholic acid (UDCA, ursodeol) to reduce cholestasis and improve liver function), cholestyramine to absorb bile acids, modafinil for fatigue, and fat-soluble vitamins (vitamins A, D, E and K; reduced bile flow makes it difficult to absorb these vitamins) can moderate progression to allow for a normal life span and quality of life. UDCA is approved in the United States to treat PBC, but it has been reported that approximately 40% of patients have an inadequate response to UDCA, and approximately 5% are intolerant to UDCA treatment. Japanese researchers have reported that the addition of bezafibrate, a pan-agonist of peroxisome proliferator-activated receptors (PRARs) and a pregnane X receptor agonist, to UDCA is useful in treating patients in whom treatment with UDCA monotherapy is ineffective, and in improving serum biliary enzymes, cholesterol, and triglycerides. Korean researchers have reported studies of the addition of fenofibrate or bezafibrate to UDCA; and BEZURSO, which adds bezafibrate to UDCA. Obeticholic acid (OCA, 6α-ethylchenodeoxycholic acid, Intercept's OCALIVA), a semisynthetic bile acid analogue that is a highly potent farnesoid X receptor agonist, was approved in the US in 2016 for the treatment of PBC, either as an add-on to UDCA or as monotherapy when UDCA is intolerant.However, approximately 50% of patients have been reported to have an inadequate response to OCA, and OCA is widely known to exacerbate pruritus, one of the symptoms of PBC. According to the OCALIVA package insert, severe pruritus was reported in 23% of patients in the OCALIVA 10 mg arm, 19% of patients in the OCALIVA infusion arm, and 7% of patients in the placebo arm in a 12-month double-blind, randomized controlled trial of 216 patients. Prospective observational multicenter studies have reported OCA discontinuation rates of 12% to 17%, with a significant proportion of patients (45% to 71%) discontinuing due to treatment-induced pruritus.

[0006] PSC is a chronic cholestatic liver disease characterized by inflammation and fibrosis (eventually resulting in cirrhosis) of the bile ducts, either intrahepatic or extrahepatic. The underlying cause of the inflammation is believed to be autoimmune; and approximately three-quarters of patients with PSC suffer from inflammatory bowel disease, usually ulcerative colitis, although the prevalence (generally reported to be approximately 1 in 10,000) and sex ratio (generally reported to be male dominated) are reported to vary by country. Standard treatments include UDCA, which has been shown to reduce elevated liver enzymes in people with PSC, but have not improved liver or overall survival; and also include antipruritics, cholestyramine, fat-soluble vitamins, and antibiotics to treat infections (bacterial cholangitis). A study reported in 2009 found that long-term high-dose UDCA therapy was associated with improved serum liver tests in PSC, but not improved survival, and was associated with a higher incidence of serious adverse events. Fenofibrate alone has been tested in PSC (NCT01142323); and the addition of fenofibrate or bezafibrate to UDCA has been reported in patients with an inadequate response to UDCA. Liver transplantation is the only proven long-term treatment.

[0007] PFIC refers to a group of three types of autosomal recessive disorders of childhood associated with intrahepatic cholestasis: familial intrahepatic cholestasis 1 (PFIC-1) deficiency, bile salt export pump (PFIC-2) deficiency, and multidrug resistance protein 3 (PFIC-3) deficiency. Together, their incidence is 1 in 50,000 to 100,000. Onset of the disease is usually before age 2 years, with PFIC-3 usually presenting earliest, but patients may be diagnosed with PFIC as early as adolescence. Patients usually present with cholestasis, jaundice, failure to thrive, and severe pruritus. Fat malabsorption and deficiencies of fat-soluble vitamins may be present. Biochemical markers include normal gamma-glutamyl transpeptidase (GGT) in PFIC-1 and PFIC-2, but markedly elevated GGT in PFIC-3; whereas serum bile acid levels are greatly elevated. However, because the disease is due to transporters rather than anatomical problems with the bile duct cells, serum cholesterol levels are not typically elevated as is usually seen with cholestasis. The disease is typically progressive, without organ transplantation, leading to liver failure and death in childhood. Hepatocellular carcinoma can also develop at a very early age in PFIC-2. UDCA-based medications are common. Fat-soluble vitamins, cholestyramine, and pancreatic enzymes are combined in PFIC-1.

[0008] AS, also known as Alagille-Watson syndrome, syndromic cholangiopancreas, and arteriohepatic dysplasia, is an autosomal dominant disorder associated with liver, heart, eye, and skeletal abnormalities, as well as characteristic facial features; incidence is approximately 1 in 100,000. Liver abnormalities involve narrowing and malformation of the bile ducts within the liver, which can result in obstruction of bile flow and lead to cirrhosis (scarring). AS is primarily caused by changes in the Jagged1 gene, located on chromosome 20. In 3-5% of cases, the entire gene is missing (deleted) from one copy of chromosome 20. In the remainder, there is an alteration or mutation in the Jagged1 DNA sequence. In a very small number of cases, less than 1%, changes in another gene, Notch2, cause AS. In about one-third of cases, the mutation is inherited. In about two-thirds, the mutation is de novo. There is no cure for AS, but the severity of liver disease typically peaks by age 3-5 years and often resolves by age 7-8 years. In some people, liver disease may progress to end-stage liver disease and require a liver transplant; approximately 15% of people with AS will require a liver transplant. A number of different medications, such as UDCA, are used to improve bile flow and reduce itching, and many patients are given high doses of fat-soluble vitamins.

[0009] Cystic fibrosis-associated cholangiopathy, more commonly known as cystic fibrosis liver disease or CFLD, affects approximately 30% of patients with cystic fibrosis and is reported to be the third most common cause of death in patients with cystic fibrosis. CFLD can progress to focal biliary cirrhosis and multilobar cirrhosis, with occasional hepatitis. In some adult patients with CFLD, the syndrome resembles that of PSC. UDCA is a common treatment, as is supplementation with fat-soluble vitamins.

[0010] According to Heathcote, "Autoimmune cholangitis", Clinics Liver Dis., vol. 2(2), pp. 303-311 (1998), "The term 'autoimmune cholangitis' refers to patients whose chronic liver disease has a biliary pattern typical of primary biliary cirrhosis (PBC) but is associated with non-organ-specific antibodies typical of autoimmune hepatitis. Some consider the disease to be a variant of classical type I autoimmune hepatitis. Others consider it a variant of PBC because of the absence of serum mitochondrial antibodies. UDCA, and immunosuppressants such as azathioprine or corticosteroids such as prednisolone have been proposed for treatment,

[0011] Graft-versus-host disease (GVHD) is a common complication after allogeneic hematopoietic cell transplantation (HCT) and typically manifests as damage to the skin, gastrointestinal mucosa, and liver. Chronic GVHD of the liver is more typically an indolent cholestatic syndrome with abnormalities of the skin, oral mucosa, and lacrimal glands that appears 100 days after allogeneic HCT. The common treatment is immunosuppressive therapy.

[0012] Alkaline phosphatase (ALP) and GGT are important markers of cholestasis. Although an elevation of only one of them is not indicative of cholestasis and other parameters are required for confirmation, an elevation of both ALP and GGT is indicative of cholestasis and a decrease in both indicates improvement of cholestasis. Thus, ALP and GGT levels serve as biochemical markers indicating the presence of bile pathophysiology present in intrahepatic cholangiopathies, and ALP levels have been used as a primary outcome marker in clinical studies of intrahepatic cholangiopathies such as PBC, including the study leading to the US approval of OCA. Other relevant markers may include biomarkers of bile duct degeneration such as CK19, miR 506 (e.g., Baghdasaryan et al., "Inhibition of intestinal bile acid absorption improves cholestatic liver and bile duct injury in a mouse model of sclerosing cholangitis"; J. Hepatology, vol. 64, pp. 674-681 (2016) and Erice et al., "MiRNA-506 promotes primary biliary cholangitis-like features in cholangiocytes and immune activation"; Hepatology, vol. 67(4), pp. 1420-1440 (2018)), markers of liver injury such as aspartate aminotransferase (AST) and alanine aminotransferase (ALT), and markers of fibrosis such as Col1α1. Fibrosis is more commonly seen in extrahepatic cholangiopathies than in intrahepatic cholangiopathies. Clinical markers reflecting treatment include the biomarkers listed above, lack of progression of fibrosis or progression to cirrhosis; and reduction in blood-based fibrosis markers such as ELF, Pro-C3, and Pro-C5.These may include the absence of liver-related adverse events such as cholangitis, ascites, variceal bleeding, and progression of MELD.

[0013] Treatment of cholangitis

[0014] As mentioned above, UDCA is a common treatment for cholangiopathies due to its ability to reduce cholestasis and improve liver function. However, a 2012 Cochrane Review of UDCA in PBC found that although UDCA demonstrated a reduction in biomarkers of liver pathology, jaundice, and ascites, there was no evidence in the medical literature demonstrating the benefit of UDCA over mortality or liver transplantation. Its use was associated with weight gain and costs. Although UDCA is used in other cholangiopathies, liver transplantation is the only long-term treatment for many patients with cholangiopathies.

[0015] Also, as mentioned above, OCA was approved in the United States in 2016 for the treatment of PBC, either in addition to UDCA or as monotherapy when UDCA is not tolerated. Fibrates, such as fenofibrate and bezafibrate, are also used in addition to UDCA or as monotherapy when UDCA is not tolerated or responds inadequately, as is OCA. Other drugs, such as the PPARα / delta agonist elafibranor, have been tested in PBC, and both fenofibrate and bezafibrate have also been tested in PSC. Other cholangiopathy drugs, particularly those for PFIC and AS, target the cholestatic pruritus associated with these diseases by inhibiting the apical sodium bile acid transporter ASBT [also called bile acid transporter (IBAT)]. These include odevixibat, approved in the United States as BYLVAY by Albireo for the treatment of PFIC, and maralixabat, approved in the United States as LIVMARLI by Mirum for the treatment of AS.

[0016] However, the current U.S. label for OCALIVA includes a "black box" warning against use in PBC patients with decompensated cirrhosis (e.g., Child-Pugh class B or C) or compensated cirrhosis with evidence of a previous decompensated event or portal hypertension. Meanwhile, the current U.S. label for fenofibrate (AbbVie's TRICOR) states that it is contraindicated in patients with active liver disease, including primary biliary cirrhosis and persistent liver dysfunction of unknown etiology. Although bezafibrate is not approved in the U.S., the current Canadian labeling for extended-release bezafibrate (Allergan's BEZALIP SR) states that it is contraindicated in patients with liver impairment, including primary biliary cirrhosis.

[0017] It would be desirable to develop a pharmacological treatment for cholangiopathy in subjects who are intolerant to or have an inadequate response to obeticholic acid and / or fibrates.

[0018] Seladelpar

[0019] Serradelpal (International Nonproprietary Name - INN) has the chemical name [4-({(2R)-2 ethoxy-3-[4-(trifluoromethyl)phenoxy]propyl}sulfanyl)-2-methylphenoxy]acetic acid [IUPAC name from WHO recommended INN: List 77], and the code number MBX 8025. Serradelpal, and its synthesis, composition, and use are disclosed, for example, in U.S. Pat. No. 7,301,050 (compound 15 in Table 1, Example M, claim 49), U.S. Pat. No. 7,635,718 (compound 15 in Table 1, Example M), and U.S. Pat. No. 8,106,095 (compound 15 in Table 1, Example M, claim 14). The lysine (L-lysine) salt of serradelpal and related compounds are disclosed in U.S. Pat. No. 7,709,682 (serradelpal L-lysine salt, crystalline form claimed throughout the examples).

[0020] Serradelpal is an orally active, potent (2 nM) PPARδ agonist. It is specific (>600-fold and >2500-fold compared to PPARα and PPARγ receptors). Activation of PPARδ stimulates fatty acid oxidation and utilization, improves plasma lipid and lipoprotein metabolism, glucose utilization, and mitochondrial respiration, and maintains stem cell homeostasis. According to U.S. Pat. No. 7,301,050, PPARδ agonists such as Serradelpal are suggested to treat PPARδ-mediated conditions, including "diabetes, cardiovascular disease, metabolic X syndrome, hypercholesterolemia, low-high-density lipoprotein (HDL)-cholesterolemia, high-low-density lipoprotein (LDL)-cholesterolemia, dyslipidemia, atherosclerosis, and obesity," where dyslipidemia is said to include hypertriglyceridemia and mixed hyperlipidemia.

[0021] US Patent No. 9486428 and PCT International Publication No. WO 2015 / 143178 disclose the treatment of intrahepatic cholestatic diseases such as primary biliary cholangitis, primary sclerosing cholangitis, progressive familial intrahepatic cholestasis, and Alagille syndrome. US Patent No. 10272058 and PCT International Publication No. 2017 / 209865 disclose the treatment of the same diseases with lower doses of seradelpal and its salts, such as 5 and 10 mg / day of seradelpal. US Patent Application Publication No. 2019 / 0105291 and PCT International Publication No. 2019 / 06373 disclose the treatment of cholestatic pruritus with seradelpal and its salts.

[0022] Seldelpar has been studied in primary biliary cholangitis (PBC) with results reported at 50 mg / day and 200 mg / day in "Seldelpar (MBX-8025), a selective PPAR-δ agonist, in patients with primary biliary cholanditis with an inadequate response to ursodeoxychloric acid: a double-blind, randomised, placebo-controlled, phase 2, proof-of-concept study" by Jones et al.Lancet Gastroenterol. Hepatol., 2(10), 716 726 (2017) and at The International Liver Congress®, organized by the European Association for the Study of Liver Diseases (EASL), Paris, France (April 11-15, 2018): Poster LBP-2 (Hirschfield et al., "Treatment Efficacy and Safety of Seldelpar, a Selective Peroxisome Proliferator Activated Receptor Delta agonist, in Primary Biliary Cholangitis Patients; 12- and 26-Week Analyses of an Ongoing, International, Randomized, Dose Ranging Phase 2 Study") "Treatment Efficacy and Safety of Seldelpar, a Delta Agonist; 12- and 26-Week Analyses of an Ongoing International Randomized Dose-Ranging Phase 2 Study"; and poster THU-239 by Boudes et al., "Seldelpar's Mechanism of Action as a Potential Treatment for Primary Biliary Cholangitis and Non-Alcoholic Steatohepatitis" (both available at https: / / ir.cymabay.com / presentations; and in subsequent presentations). In a Phase 2b study, Seldelpar was found to cause statistically significant reductions in ALP and GGT, along with statistically significant reductions in ALT levels and stable total bilirubin levels, over 52 weeks.However, similar results were seen in the subgroup with Child-Pugh A cirrhosis. Serradelpar has also been proposed for other cholangiopathies. Summary of the Invention

[0023] The present invention is a method for treating cholangiopathy in a subject who is intolerant to or has an inadequate response to obeticholic acid and / or ficollic acid by administration of seradelpal or a salt thereof.

[0024] In various aspects, the present invention includes the following. Seradelpal or a salt thereof for use in the treatment of cholangitis in a subject who is intolerant to or has responded inadequately to obeticholic acid and / or a fibrate. Use of seradelpal or a salt thereof for treating cholangitis in a subject who is intolerant to or has responded inadequately to obeticholic acid and / or fibrates, or in the manufacture of a medicament for treating cholangitis; a pharmaceutical composition or medicament comprising seradelpal or a salt thereof for treating cholangitis in a subject who is intolerant to or has responded inadequately to obeticholic acid and / or fibrates.

[0025] Given the demonstrated efficacy of seradelpal in treating primary biliary cholangitis in subjects who are intolerant or inadequately responsive to obeticholic acid and / or fibrates, as shown in Example 1, and the common factors of cholangiopathies, seradelpal is expected to be active in treating other cholangiopathies in subjects who are intolerant or inadequately responsive to obeticholic acid and / or fibrates. This activity is considered particularly advantageous in light of the warnings and contraindications for the use of these agents in cholangiopathies such as PBC. This activity is expected whether the subject is naive, intolerant, or inadequately responsive to ursodeoxycholic acid.

[0026] Preferred embodiments of the present invention are characterized by the features of the description and claims 1 to 20 of the present application as filed.

[0027] (Detailed Description) definition

[0028] Cholangiopathies and their treatment are described in the Background section entitled "Choleductosis" and "Treatment of Choleductosis."

[0029] Seradelpal is described in the Background section entitled "Seradelpal."

[0030] Salts (e.g., pharma- ceutically acceptable salts) of seradelpal are included in the present invention and are useful in the methods described in this application. These salts are preferably formed with pharma- ceutically acceptable acids. For an extensive discussion of pharmaceutical salts, their selection, preparation, and use, see, for example, "Handbook of Pharmaceutically Acceptable Salts," Stahl and Wermuth, eds., Verlag Helvetica Chimica Acta, Zurich, Switzerland. Unless the context requires otherwise, a reference to seradelpal is a reference to both the compound and its salts.

[0031] Seradelpal contains a carboxyl group, so that the acidic protons present can form salts when reacted with inorganic or organic bases. Typically, Seradelpal is treated with an excess of an alkaline reagent, such as a hydroxide, carbonate, or alkoxide, containing the appropriate cation. Na + , K + , Ca 2+ , Mg 2+ , N.H. 4 +Cations such as are examples of cations present in pharma- ceutically acceptable salts. Suitable inorganic bases thus include calcium hydroxide, potassium hydroxide, sodium carbonate and sodium hydroxide. Salts can also be prepared using organic bases such as salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, and cyclic amines including isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, tromethamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, N-alkylglucamines, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, and the like. Useful salts are expected to include L-lysine salts. And, as noted in the "Serradelpal" subsection, Serradelpal is currently formulated as its L-lysine dihydrate salt.

[0032] "Another anticholestatic agent" refers to an agent used to treat cholangiopathy that is not seradelpar or seradelpar salts, nor is it obeticholic acid or a fibrate. Such agents include ursodeoxycholic acid (UDCA), as described in the Background section.

[0033] The term "fibrate" includes both derivatives of fibric acid, such as gemfibrozil, clofibrate, fenofibrate, bezafibrate, clofibrate, ciprofibrate, clinofibrate, lonifibrate, simfibrate, and non-fibric acid derivative compounds that are PPARα agonists (including mixed agonists only if they have significant PPARα agonism), such as elafibranor, lanifibranor, and saroglitazar, among others, fenofibrate, bezafibrate, and elafibrate.

[0034] "Intolerant" or "intolerance", or similar terms, with respect to obeticholic acid and / or a fibrate, means that a subject administered obeticholic acid and / or a fibrate for the treatment of cholangiopathy experiences side effects, such as discontinuing treatment with obeticholic acid and / or a fibrate. Examples of side effects that would cause a subject to be considered intolerant to obeticholic acid include liver-related adverse reactions, pruritus, and reduced HDL-C, as described, for example, in the current labeling for OCALIVA, which is incorporated herein by reference. Examples of side effects that may cause a subject to be considered intolerant to a fibrate include muscle toxicity / myalgia, elevated creatinine, rhabdomyolysis, nephrotoxicity (elevated serum creatinine or blood urea nitrogen, decreased glomerular filtration rate, and elevated ALT, AST, or total bilirubin (TBIL). "Obeticholic acid and / or a fibrate" and "obeticholic acid and at least one of a fibrate" refer to all of obeticholic acid, a single fibrate, multiple fibrates, obeticholic acid and a single fibrate, and obeticholic acid and multiple fibrates.

[0035] An "inadequate response," "incomplete response," or similar terms with respect to obeticholic acid and / or a fibrate means that a subject administered obeticholic acid and / or a fibrate for the treatment of cholangiopathy fails to experience adequate treatment of the cholangiopathy. An inadequate response can be assessed by the subject's failure to achieve an adequate reduction in biochemical markers of cholangiopathy, for example, by the subject's failure to achieve at least one of ALP less than 1.67 times the upper limit of normal, a sufficient (e.g., at least 15%) reduction in ALP, and / or total bilirubin less than the upper limit of normal.

[0036] Because ursodeoxycholic acid is considered first-line treatment for many cholangiopathies, it is typically necessary to test other therapies, such as obeticholic acid, in patients who are intolerant or inadequately responsive to ursodeoxycholic acid; or as an add-on to ursodeoxycholic acid, as in the BEZURSO and POISE studies. Thus, experience with ursodeoxycholic acid-naïve, i.e., treatment-naïve subjects, is essentially unavailable. However, it is expected that Delcerapar will be similarly effective in subjects who are intolerant or inadequately responsive to ursodeoxycholic acid, as well as in subjects who are ursodeoxycholic acid-naïve.

[0037] "Co-administration" of seradelpal and another anti-cholestatic agent (such as ursodeoxycholic acid) refers to administration of seradelpal and another anti-cholestatic agent during the course of treatment of cholangitis. Such co-administration may include administration of another anti-cholestatic agent before, during, and / or after administration of seradelpal, such that therapeutically effective levels of each compound are maintained. Co-administration may be accomplished by administering seradelpal and another anti-cholestatic agent at their usual doses, respectively. However, co-administration may also include administration of a combined dosage form, where both are orally bioavailable and conveniently administered orally daily. "Combined therapy" of seradelpal and another anti-cholestatic agent is synonymous with "co-administration."

[0038] A "therapeutically effective amount" of seradelpal or a salt thereof is an amount that, when administered for the treatment of cholangitis in a subject (i.e., a human) who is intolerant to or has an inadequate response to obeticholic acid and / or a fibrate, is sufficient to effect treatment of the cholangitis. "Treatment" or "treatment" of cholangitis in a subject includes one or more of the following: (1) To prevent or reduce the risk of developing cholangiopathy, i.e., to prevent clinical symptoms of cholangiopathy from developing in subjects who may be predisposed to cholangiopathy but have not yet experienced or exhibited symptoms of cholangiopathy (i.e., prevention); (2) inhibiting cholangiopathy, i.e., arresting or reducing the progression of cholangiopathy or its clinical symptoms; and (3) alleviating cholangiopathy, i.e., causing regression, reversal, or improvement of cholangiopathy or reducing the number, frequency, duration, or severity of its clinical symptoms. Although "treatment" may include "cure," "treatment" does not necessarily mean a "cure" or complete treatment, e.g., treatment of all clinical symptoms of cholangiopathy. Rather, "treatment" refers to the provision of a clinical benefit from administration of seradelpal as compared to non-administration of seradelpal; and treatment may also be assessed by improvement in biological markers of cholangiopathy during treatment. The therapeutically effective amount for a particular subject will vary depending on the health and physical condition of the subject being treated, the extent of the bile duct disorder, an evaluation of the medical condition, and other relevant factors. It is expected that the therapeutically effective amount will fall in a relatively broad range that can be determined through routine clinical trials. When seradelpar is administered concomitantly with another anti-cholestasis agent that is not obeticholic acid or a fibrate, a "therapeutically effective amount" of seradelpar, or of the other anti-cholestasis agent administered concomitantly with seradelpar, means an amount of each sufficient to be effective in treating cholangitis when seradelpar and the other anti-cholangitis agent are co-administered to a subject to treat cholangitis.

[0039] "Comprising" or "containing" and grammatical variations thereof are words of inclusion, not of limitation, and are meant to specify the presence of the stated components, groups, steps, etc., but not to exclude the presence or addition of other components, groups, steps, etc. Thus, "comprising" does not mean "consisting of," "consisting essentially of," or "consisting only of; and, for example, a formulation "comprising" a compound must include the compound, but may also include other active ingredients and / or excipients. Unless the context requires otherwise, the singular forms "a," "an," and "the" include plural references. Thus, for example, "another anticholestatic agent" refers to one or more other anticholestatic agents; and "a compound selected from seradelpal and salts thereof" refers to one or more compounds selected from the group consisting of seradelpal and salts of seradelpal.

[0040] Formulation and Administration

[0041] Seradelpal may be administered by any route appropriate to the subject to be treated and the nature of the subject's illness. Routes of administration include oral administration (if possible, generally preferred); administration by injection, including intravenous, intraperitoneal, intramuscular, subcutaneous injection; transmucosal (e.g., intranasal, oral, sublingual, rectal, or vaginal) or transdermal (topical) delivery; and the like. Formulations may be oral formulations (e.g., tablets, capsules, or oral solutions or suspensions); injectable formulations (e.g., liquids); and formulations designed to administer drugs across mucous membranes or transdermally. Formulations suitable for each of these methods of administration can be found, for example, in "Remington: The Science and Practice of Pharmacy", 20th Edition, edited by Gennaro, Lippincott Williams & Wilkins, Philadelphia, Pa., USA. Seradelpal is orally available, with typical formulations being oral, and typical dosage forms being tablets or capsules for oral administration. As noted in the "Seradelpal" subsection, Seradelpal has been formulated into capsules for clinical trials. Intravenous formulations are particularly applicable for administration to acutely ill subjects, such as those suffering from acute alcoholic hepatitis or alcoholic fibrosis or cirrhosis, who may be hospitalized for treatment.

[0042] Depending on the intended mode of administration, the pharmaceutical composition may be in solid, semi-solid, or liquid dosage form, preferably in a unit dosage form suitable for single administration of a precise dose. In addition to an effective amount of seradelpal, the composition may contain suitable pharmaceutically acceptable excipients, including adjuvants that facilitate processing of the active compound into a pharmaceutically usable preparation. "Pharmaceutically acceptable excipient" refers to an excipient or mixture of excipients that does not interfere with the effectiveness of the biological activity of the active compound and is not toxic or otherwise undesirable to the subject to which it is administered.

[0043] For solid compositions, conventional excipients include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose, magnesium carbonate, and the like. Pharmacologically administrable liquid compositions can be prepared, for example, by dissolving, dispersing, etc., the active compound described herein and any pharmaceutical adjuvants in water or aqueous excipients, such as water, saline, aqueous dextrose, and aqueous excipients, to form a solution or suspension. If necessary, the pharmaceutical composition to be administered may also contain minor amounts of non-toxic auxiliary excipients, such as wetting or emulsifying agents, pH buffering agents, and the like, such as sodium acetate, sorbitan monolaurate, sodium triethanolamine acetate, triethanolamine oleate, and the like.

[0044] For oral administration, the composition generally takes the form of a tablet or capsule. Or, especially for children, it may be an aqueous or non-aqueous liquid, suspension, or syrup. Tablets and capsules are the preferred oral dosage forms. Tablets and capsules for oral use usually contain one or more commonly used excipients, such as lactose and cornstarch. Lubricants, such as magnesium stearate, are also typically added. When liquid suspensions are used, the active agent can be combined with emulsifying and suspending excipients. Flavoring, coloring, and / or sweetening agents can be added as well, if necessary. Other optional excipients for incorporation into oral formulations include preservatives, suspending agents, thickening agents, etc.

[0045] Typically, the seradelpal pharmaceutical composition, or a kit containing the seradelpal composition, is packaged in a container with a label, instructions, or both, indicating use of the pharmaceutical composition or kit in the treatment of alcoholic liver disease.

[0046] One skilled in the art of pharmaceutical formulations will be able to prepare suitable pharmaceutical compositions of Seradelpal by selecting appropriate dosage forms, excipients, packaging, etc., to achieve a therapeutically effective formulation without undue experimentation and relying on personal knowledge and the disclosure of this application.

[0047] A suitable (i.e., therapeutically effective) amount of seradelpar or a salt thereof for oral administration is at least 0.5 mg / day, e.g., at least 1 mg / day, e.g., at least 2 mg / day, or an amount equivalent to at least 5 mg / day of seradelpar; but an amount equivalent to 50 mg / day or less, e.g., 25 mg / day or less, e.g., 15 mg / day or less, or 10 mg / day or less of seradelpar; for example, in an adult subject who is intolerant to or has an inadequate response to obeticholic acid and / or fibrates, the amount may be within any range defined by one of the values ​​"at least" and one of the values ​​"or less", e.g., at least 1 mg / day and not more than 25 mg / day (i.e., 1 to 25 mg / day), or at least 2 mg / day and not more than 10 mg / day, 2 mg / day, 5 mg / day, or 10 mg / day, depending on factors such as the degree and severity of the cholangiopathy and hepatic and renal function. That is, the amount of Seradelpal suitable for oral administration to treat conditions such as PBC in adults is expected to be approximately the same as for similar subjects who are intolerant or have an inadequate response to obeticholic acid and / or obeticholic acid. Appropriate dose reductions towards or below the lower end of the outer ranges above will be made for pediatric subjects suffering from diseases such as PFIC and AS, depending on additional factors such as age and weight; and also for subjects with significant hepatic impairment, such as those in Child-Pugh classes B and C, depending on the degree of impairment. These amounts represent average daily doses, not necessarily single doses. The frequency of administration may be more than once a day (if the amount or daily dose is divided by the number of doses per day), but more typically once a day (if the amount is administered in a single dose). Optionally, particularly in cases of severe liver impairment, administration may be less frequent than once a day, such as between once a week and every other day, for example once a week, twice a week (particularly where the interval between doses is at least 3 days), three times a week (particularly where the interval between doses is at least 2 days), or every other day; thus, as an example, a subject may receive 5 mg twice a week in an amount of 1.4 mg / day (daily dose).An amount of a serradelpal salt "equivalent" to a particular amount of serradelpal refers to the amount of the particular amount of salt multiplied by the ratio of the formula weight of the salt to the formula weight of serradelpal. For example, when serradelpal L-lysine dihydrate is used, the formula weight of serradelpal L-lysine dihydrate is about 1.41 times the formula weight of serradelpal, so that about 1.41 mg / day of serradelpal L-lysine dihydrate is equivalent to 10 mg / day of serradelpal.

[0048] When seradelpal or seradelpal salt is administered in combination with another anticholestasis agent, the appropriate amount of seradelpal or seradelpal salt is expected to be the same amount as when seradelpal or seradelpal salt is administered alone; however, the appropriate amount of another anticholestasis agent is expected to be the same as the amount approved or used in clinical trials, as described in the background art. That is, the appropriate amount of seradelpal or seradelpal salt and another anticholestasis agent to achieve a therapeutically effective amount of combination therapy is the same as the amount used in clinical trials. However, since both are expected to be effective in treating cholangitis, the therapeutically effective amount of combination therapy may be less than that of monotherapy.

[0049] Those skilled in the art of treating cholangiopathy will be able to ascertain a therapeutically effective amount of seradelpar or seradelpar salts when used alone or in combination with another anti-cholestatic agent, and when used in combination with another cholestatic agent, will achieve a therapeutically effective amount for a particular patient and stage of cholangiopathy without undue experimentation, relying on personal knowledge and the disclosures of this application.

[0050] (Example)

[0051] Example 1: Primary biliary cholangitis

[0052] Subjects with primary biliary cholangitis enrolled in an open-label phase 2 study (NCT02955602, EudraCT 2016-002996-91) or a randomized placebo-controlled phase 3 study (NCT03602560, EudraCT 2018-001171-20) who were intolerant to or had an inadequate response to ursodeoxycholic acid were recruited and subjects who were intolerant to or had an inadequate response to obeticholic acid and / or fibrates were selected for analysis. Study subjects were adult males or females diagnosed with PBC by at least two of the following three criteria: (a) a history of ALP above the upper limit of normal (ULN) for at least 6 months; (b) a positive antimitochondrial antibody titer >1 / 40 by immunofluorescence or positive M2 or PBC-specific antinuclear antibodies by enzyme-linked immunosorbent assay; and (c) documented liver biopsy results consistent with PBC, stable recommended dose of UDCA for the past 12 months, or UDCA intolerance, ALP. > 1.67 ULN. Exclusion criteria included AST or ALT > 3×ULN, TBIL > Subjects were excluded from the study if they had: history of autoimmune or chronic viral hepatitis, PSC, current use of fibrates or simvastatin, use of colchicine, methotrexate, azathioprine, or systemic steroids in the past 2 months; use of experimental treatments for PBC, and use of experimental or unapproved immunosuppressants. Subjects received either Seradelpal (S) 10 mg / day or 5 mg / day of Seradelpal L-lysine dihydrate or placebo orally once daily in capsule form. Efficacy was evaluated in subjects treated for 3 months. The composite endpoint was ALP 1.67 < × ULN, ALP reduction of > 15%, and TBIL < The response rate in subjects who achieved the ULN was 1. Additional endpoints were ALP < The ULN, change from baseline in alkaline phosphatase, and other markers of liver function were assessed. Safety was assessed over 1 year.

[0053] Of the 384 subjects enrolled in the two studies, a total of 71 subjects were intolerant or had an inadequate response to OCA (47 subjects), fibrates (16 subjects), or both (8 subjects). Fifty-one subjects received treatment for 3 months. Thirty-seven cases were evaluated. The results are shown in the table below. [Table 1]

[0054] Safety analyses were performed on all 71 subjects. Four subjects experienced serious adverse events (three receiving seradelpal 5 mg / day and one receiving placebo), none of which were related to seradelpal. Two subjects discontinued treatment due to adverse events; one for ALT / AST elevation and one for gastroesophageal reflux disease, both taking seradelpal 5 mg / day. In patients with PBC who were intolerant to or had an inadequate response to obeticholic acid and / or fibrates, seradelpal appeared to be safe and well tolerated and showed significant improvements in biochemical markers of cholestasis.

[0055] Example 2: Primary sclerosing cholangitis

[0056] Study subjects were adult males or females with a diagnosis of PSC by at least two of the following three criteria: (a) historical evidence of AP>ULN elevation from previous laboratory results, (b) liver biopsy consistent with PSC, and (c) abnormal cholangiogram consistent with PSC as measured by MRCP, ERCP, or percutaneous transhepatic cholangiography; stable recommended dose of UDCA for the past six months. < 20 mg / Kg / day or discontinue UDCA treatment for at least 12 weeks. Intolerance to or inadequate response to obeticholic acid and / or fibrates. Other criteria include ALP > 1.5×ULN, TBIL < 2 × ULN, both ALT and AST < 5×ULN, eGFR > 60mL / min / 1.73m 2,platelet > 140×103 / μL, INR < 1.3 (in the absence of warfarin or other anticoagulant therapy), and albumin > 3.5 g / dL. Exclusion criteria included clinically significant acute or chronic liver disease from an etiology other than PSC, a diagnosis of overlapping autoimmune hepatitis (AIH) and PSC, secondary or IgG4-related sclerosing cholangitis, small-duct PSC, presence of cholangiocarcinoma on cholangiography or MRI, biliary stent placement, history, evidence, or high suspicion of cholangiocarcinoma or other hepatobiliary malignancies, presumed or diagnosed acute cholangitis within 12 weeks, and evidence of compensated or decompensated cirrhosis. The primary endpoint of the study was the relative change in baseline serum ALP at week 24; secondary endpoints were the incidence of treatment-emergent adverse events, the incidence and severity of PSC-related syndromes or procedures, and the incidence of liver disease progression events. Subjects were randomly assigned to receive either placebo or seradelpal or its salts orally once daily for 24 weeks in doses equivalent to 5, 10, or 20 mg / day of seradelpal. Subjects demonstrated a dose-related decrease in ALP and improvement in PSC-related symptoms.

Claims

1. A drug for treating cholangiopathy in a subject who is intolerant or has an insufficient response to at least one of obeticholic acid and fibrate, comprising a compound selected from ceradelpar and its salts.

2. The drug according to claim 1, wherein the compound is ceradelpar L-lysine salt.

3. The drug according to claim 2, wherein the compound is ceradelpar L-lysine dihydrate salt.

4. The drug according to any one of claims 1 to 3, wherein the compound is administered orally.

5. The drug according to any one of claims 1 to 4, wherein the amount of the compound corresponds to an amount of 0.5 to 50 mg / day of ceradelpar.

6. The drug according to claim 5, wherein the amount of the compound corresponds to an amount of 1 to 25 mg / day of ceradelpar.

7. The drug according to claim 6, wherein the amount of the compound corresponds to an amount of 2 to 10 mg / day of ceradelpar.

8. The drug according to claim 7, wherein the amount of the compound corresponds to an amount of 5 mg / day or 10 mg / day of ceradelpar.

9. The drug according to any one of claims 1 to 8, wherein the compound is administered once a day.

10. The drug according to any one of claims 1 to 9, wherein the cholangiopathy is primary biliary cholangitis.

11. The drug according to any one of claims 1 to 9, wherein the cholangiopathy is primary sclerosing cholangitis.

12. The drug according to any one of claims 1 to 9, wherein the cholangiopathy is progressive familial intrahepatic cholestasis.

13. The drug according to any one of claims 1 to 9, wherein the cholangiopathy is Alagille syndrome.

14. The drug according to any one of claims 1 to 9, wherein the cholangiopathy is cystic fibrosis-related cholangiopathy.

15. The drug according to any one of claims 1 to 9, wherein the cholangiopathy is autoimmune cholangitis.

16. The drug according to any one of claims 1 to 9, wherein the cholangiopathy is graft-versus-host disease involving the liver.

17. The drug according to any one of claims 1 to 16, wherein the subject is naive to ursodeoxycholic acid.

18. The drug according to any one of claims 1 to 16, wherein the subject is intolerant or has an insufficient response to ursodeoxycholic acid.

19. The drug according to any one of claims 1 to 18, wherein the subject is intolerant or has an insufficient response to obeticholic acid.

20. The agent according to any one of claims 1 to 19, wherein the subject is intolerant or has an inadequate response to fibrillation.