Treatment of primary biliary cholangitis

Abstract

The present invention relates to Elafibranor for use in the treatment of primary biliary cholangitis (PBC) in a subject suffering from PBC, said subject having a baseline plasma alkaline phosphatase (ALP) level greater than 1 x ULN (upper limit of normal) and strictly less than 1.67 x ULN prior to receiving Elafibranor.

Description

Technical Field

[0001] This invention relates to the medical field, particularly to the treatment of primary biliary cholangitis. Background Technology

[0002] This invention is dedicated to PBC (primary biliary cholangitis, formerly known as primary biliary cirrhosis), a cholestatic disease.

[0003] Cells in the liver produce bile, which travels through ducts within the liver to the gallbladder. Bile is a digestive fluid produced by the liver. It travels through the bile ducts to the gallbladder and small intestine, where it helps digest fats and fat-soluble vitamins.

[0004] Petechiae baumannii (PBC) is a chronic inflammatory (or long-term) liver disease that slowly destroys the small to medium-sized bile ducts (tubular structures that carry bile) within the liver. In PBC patients, the bile ducts are damaged by inflammation. This causes bile to remain in the liver, gradually damaging and destroying hepatocytes and leading to cirrhosis or liver scarring.

[0005] Percutaneous cholangitis (PBC) is a rare, chronic, progressive autoimmune cholestatic liver disease characterized by lymphocytic cholangitis and associated with increased mortality. In untreated patients or those who do not respond adequately to ursodeoxycholic acid (UDCA), PBC typically progresses to fibrosis, cirrhosis, liver failure, and death unless a liver transplant is performed.

[0006] The estimated prevalence of polycystic purpura (PBC) in North America, Europe, and the Asia-Pacific region is 1.91 to 40.2 per 100,000 people, with an incidence rate of 0.23 to 5.31 per 100,000 people. The incidence rate in North America and Europe has been increasing over time. PBC primarily affects women, with a female-to-male ratio of approximately 9:1. PBC is typically diagnosed between the ages of 40 and 60, and global estimates suggest that approximately 1 in 1,000 women over the age of 40 have PBC.

[0007] Approximately 60% of patients with PBC are asymptomatic at diagnosis and are usually referred to a hepatologist for abnormal liver enzyme tests (most commonly, elevated alkaline phosphatase (ALP) or gamma-glutamyl transferase (GGT) found during routine health assessments). Most patients develop symptoms within 10 years of diagnosis. Initial presentations in symptomatic patients may include fatigue, itching, weight loss, right upper quadrant pain, and sometimes jaundice.

[0008] According to practice guidelines, the diagnosis of PBC is based on the presence of at least two of the following three diagnostic criteria: elevated serum ALP levels (>1.5 times the upper limit of normal [ULN]), histological evidence of chronic non-suppurative bile duct destruction (flower duct lesions), and the presence of antimitochondrial antibodies (AMA) in the blood at a titer of 1:40 or higher. Diagnosis usually does not require liver biopsy, but it may be useful in cases where no definitive diagnosis is available, such as in patients with negative AMA, or in situations requiring differential diagnosis of potentially clinically similar conditions, such as autoimmune hepatitis and nonalcoholic steatohepatitis (NASH).

[0009] In early-stage PBC, patients are often asymptomatic despite underlying inflammatory damage to small bile ducts and mild abnormalities in serum liver biochemistry tests; this stage can last for decades. This is followed by mid-stage PBC, where biochemical and clinical symptoms of cholestasis develop, and underlying lesions progress to patent ductus arteriosus and liver fibrosis; this stage can last up to 10 years or longer. In late-stage PBC, patients may develop progressive jaundice, portal hypertension, and liver failure, sometimes worsening within 2 to 4 years and progressing to liver-related death without liver transplantation. Hepatocellular carcinoma can also develop in late-stage PBC.

[0010] Almost all patients with PBC will experience symptoms during the course of the disease. Itching and fatigue are the most common symptoms. Other common symptoms include Sjögren's syndrome, abdominal pain, joint pain, leg hyperactivity, insomnia, depression, and cognitive impairment.

[0011] Itching affects 70% of patients with primary liver cancer (PBC) and can contribute significantly to morbidity. Because itching follows a diurnal rhythm and is typically more severe at night, PBC patients may also experience decreased sleep quality, leading to increased fatigue and negative impacts on quality of life (QoL). Itching can occur early in the disease and may persist even after UDCA treatment, when biochemical responses occur or ALP normalizes. Fatigue affects up to 80% of PBC patients and also negatively impacts QoL. Fatigue frequently interferes with patients' ability to perform daily activities and is associated with decreased mental and physical capacity. While itching may improve with liver transplantation, fatigue often persists even after liver transplantation.

[0012] In adult patients with persistent biochemical cholestasis (e.g., elevated alkaline phosphatase (ALP) in blood tests), PBC can be diagnosed based on elevated ALP and the presence of antimitochondrial antibodies (AMA). Current guidelines do not recommend liver biopsy for the diagnosis of PBC unless PBC-specific antibodies are lacking, or there is reason to suspect overlap with autoimmune hepatitis or coexistence with other liver diseases.

[0013] The rate of disease progression varies from patient to patient, but generally, patients who do not respond well to existing therapies or who do not receive drug therapy progress faster.

[0014] The definition of an inadequate response is traditionally based on published definitions, which center on reducing ALP levels below a specific threshold. This is supported by existing knowledge that elevated ALP levels, as well as elevated bilirubin levels, have been shown to be highly predictive of adverse long-term clinical outcomes, including the need for liver transplantation and death.

[0015] Ursodeoxycholic acid (UDCA) was the first PBC treatment approved by regulatory authorities. UDCA improves blood ALP and bilirubin levels, slows histological progression of the disease, and improves liver transplant-free survival. UDCA is recommended as a first-line therapy for PBC patients. However, up to 40% of PBC patients do not respond adequately to UDCA therapy. Furthermore, up to 5% of PBC patients are intolerant to UDCA.

[0016] In recent years, obeticholic acid (a semi-synthetic analog of the primary bile acid chenodeoxycholic acid) has been approved by regulatory agencies as a second-line therapy under accelerated approval regulations. However, only a subset of PBC patients who did not respond optimally to UDCA treatment showed adequate response to the addition of obeticholic acid, and a significant proportion experienced clinically significant pruritus. Importantly, improvements in survival or disease-related symptoms have not been definitively established. Furthermore, following reports of patients with advanced cirrhosis developing liver failure after treatment with obeticholic acid, regulatory agencies restricted its use in patients with advanced PBC and advanced cirrhosis in 2021.

[0017] Data from the global PBC study group showed that any ALP elevation above 1 × upper limit of normal (ULN) was associated with an increased risk of adverse outcomes in PBC patients, and this risk was similar in patients with ALP elevations > 1 × ULN to < 1.67 × ULN compared to those with elevations ≥ 1.67 × ULN. Furthermore, any sustained elevation of ALP after UDCA treatment indicated association with ongoing disease activity in PBC. Patients with ALP levels ≤ ULN had higher survival rates compared to those with ALP > ULN, particularly in patients < 62 years of age with advanced fibrosis and a liver stiffness measurement (LSM) ≥ 10 kPa. These observations support the additional survival benefit of achieving serum ALP normalization.

[0018] Although a portion of PBC patients respond adequately to available treatments, the vast majority of PBC patients do not respond optimally or are intolerant to available treatments, and therefore remain at risk of disease progression and long-term adverse clinical outcomes.

[0019] Elafibranor (GFT505, IPN60190) is an orally administered dual PPARα,δ agonist developed by Ipsen for use in combination with UDCA in adults with PBC who have an inadequate response to UDCA, or as a monotherapy in adults who cannot tolerate UDCA.

[0020] Recently, the double-blind (phase III, double-blind, randomized, placebo-controlled study of ELATIVE, designed to evaluate the efficacy and safety of erafibrino in PBC patients with inadequate response or intolerance to UDCA treatment) (GFT505B-319-1(NCT04526665)) was completed, demonstrating that erafibrino treatment better improved cholestasis compared to placebo. This was assessed based on the primary endpoint, which was a combination of decreases in ALP and total bilirubin (TB). Furthermore, erafibrino was safe and well-tolerated by patients.

[0021] Given the efficacy and tolerability issues of existing treatment options, the need for second-line therapy clearly remains unmet, especially in PBC patients who have an inadequate response or intolerance to UDCA. Notably, patients with PBC and baseline plasma ALP > 1 × ULN but < 1.67 × ULN traditionally represent an unstudied subset: they were excluded from ELATIVE and other phase 3 studies using obeticholic acid and seladelpar. Therefore, there is a neglected unmet need in these PBC patients. Summary of the Invention

[0022] A clinical study has surprisingly shown that treatment with erafibrino reduced the correlation of biochemical markers in plasma, suggesting that the compound is beneficial for the treatment of PBC.

[0023] Surprisingly, the compound was shown to be beneficial in subjects with PBC who, prior to receiving erafibrino, had baseline plasma alkaline phosphatase (ALP) levels greater than 1 x ULN (upper limit of normal) and at most 1.67 x ULN, particularly strictly less than 1.67 x ULN.

[0024] This invention relates to erafibrano for the treatment of subjects with primary biliary cholangitis (PBC) who, prior to receiving erafibrano, have a baseline plasma alkaline phosphatase (ALP) level greater than 1 x ULN (upper limit of normal) and at most 1.67 x ULN, particularly strictly less than 1.67 x ULN.

[0025] Another object of the present invention is erafibrano for normalizing plasma ALP levels in subjects with PBC, whose baseline plasma alkaline phosphatase (ALP) levels prior to receiving erafibrano are greater than 1 x ULN (upper limit of normal) and at most 1.67 x ULN, particularly strictly less than 1.67 x ULN.

[0026] Another object of the present invention is erafibrano for reducing plasma ALP levels in subjects with PBC, whose baseline plasma alkaline phosphatase (ALP) levels prior to receiving erafibrano are greater than 1 x ULN (upper limit of normal) and at most 1.67 x ULN, particularly strictly less than 1.67 x ULN.

[0027] Another object of the present invention is a method for treating PBC in subjects who, prior to receiving erafibrino, have a baseline plasma alkaline phosphatase (ALP) level greater than 1 x ULN (upper limit of normal) and at most 1.67 x ULN, particularly strictly less than 1.67 x ULN, the method comprising administering an effective dose of erafibrino to the subject in need.

[0028] Another object of the present invention is a method for treating PBC, comprising administering an effective dose of erafibrino to a subject suffering from PBC, the subject having a baseline plasma alkaline phosphatase (ALP) level greater than 1 x ULN (upper limit of normal) and at most 1.67 x ULN, particularly strictly less than 1.67 x ULN, prior to receiving erafibrino.

[0029] In one specific embodiment of the invention, subjects to be treated are identified by testing the ALP levels of potential subjects and then selecting subjects who have a baseline plasma ALP level greater than 1 x ULN (upper limit of normal) and at most 1.67 x ULN, particularly strictly less than 1.67 x ULN, prior to receiving erafibrino.

[0030] In one specific embodiment of the invention, the dosage of erafibrino is 0.01 mg to 1 g per administration, preferably 1 mg to 150 mg per administration, more preferably 70 mg to 130 mg, and even more preferably 80 mg.

[0031] In one specific implementation plan, Erafibrano is administered once daily.

[0032] In another specific implementation, subjects with PBC who have an inadequate response to UDCA are given an 80 mg dose of erafibrinolate once daily, preferably in combination with UDCA.

[0033] The present invention also provides the use of erafibrano in the preparation of pharmaceutical compositions, preferably oral pharmaceutical compositions, for the treatment of PBC in subjects who, prior to receiving erafibrano, have a baseline plasma alkaline phosphatase (ALP) level greater than 1 x ULN (upper limit of normal) and at most 1.67 x ULN, particularly strictly less than 1.67 x ULN.

[0034] According to the present invention, the pharmaceutical composition may be formulated as an injectable suspension, gel, oil, pill, tablet, suppository, powder, gel capsule, capsule, aerosol, or in the form or device of a galen that ensures prolonged and / or slow release.

[0035] According to the present invention, the disclosed methods, compounds, uses, compositions or kits relate to treating PBC in subjects who, prior to receiving erafibrino, have a baseline plasma alkaline phosphatase (ALP) level greater than 1 x ULN (upper limit of normal) and at most 1.67 x ULN, particularly strictly less than 1.67 x ULN.

[0036] Abbreviations and Definitions In the context of this invention, the following abbreviations and empirical formulas are used in the figures, tables and text: ALP alkaline phosphatase ALT (alanine aminotransferase) AMA antimitochondrial antibody ASBTi apical sodium-dependent bile acid transporter inhibitor AST aspartate aminotransferase C4 Serum 7α-hydroxy-4-cholesterol-3-one CDCA (Chemolytic acid) CPK (creatine phosphokinase) DCA (deoxycholic acid) ECG (electrocardiogram) eGFR is used to estimate glomerular filtration rate. FGF19 fibroblast growth factor 19 FXR Farnesol X receptor GGT γ-glutamyltransferase HBV (Hepatitis B Virus) HDL-C (High-density lipoprotein cholesterol) HIV (Human Immunodeficiency Virus) IgM Immunoglobulin M IL-20 Interleukin-20 LDL-C (low-density lipoprotein cholesterol) MELD End-Stage Liver Disease Model MRI (Magnetic Resonance Imaging) NASH (Non-Alcoholic Steatohepatitis) NOX NADPH oxidase OCA (Obicholic Acid) Primary biliary cholangitis (PBC) PK Pharmacokinetics PPAR peroxisome proliferator-activated receptor PT-INR (Prothrombin Time - International Normalized Ratio) QOL (Quality of Life) TB total bilirubin TG triglycerides TGF (Transforming Growth Factor) UDCA (ursodeoxycholic acid) ULN Normal Upper Limit VAS Visual Analog Scoring Other features, properties and advantages of the present invention will become more apparent from the following description and examples. Detailed Implementation

[0037] As described above, one object of the present invention is erafibrano for treating PBC in subjects who, prior to receiving erafibrano, have a baseline plasma alkaline phosphatase (ALP) level greater than 1 x ULN (upper limit of normal) and at most 1.67 x ULN, particularly strictly less than 1.67 x ULN.

[0038] In the context of this invention, the term "before receiving erafibrino" means before the first administration of erafibrino to the subject. In other words, subjects with PBC who had a baseline plasma alkaline phosphatase (ALP) level greater than 1 x ULN (upper limit of normal) and at most 1.67 x ULN, particularly strictly less than 1.67 x ULN, prior to receiving erafibrino, had never received erafibrino treatment.

[0039] Another object of the present invention is erafibrano for reducing plasma ALP levels in subjects with PBC, whose baseline plasma alkaline phosphatase (ALP) levels prior to receiving erafibrano are greater than 1 x ULN (upper limit of normal) and at most 1.67 x ULN, particularly strictly less than 1.67 x ULN.

[0040] In one specific implementation, erafibrano can be used to normalize the ALP, albumin, and / or TB levels in subjects with PBC who, prior to receiving erafibrano, have a baseline plasma alkaline phosphatase (ALP) level greater than 1 x ULN (upper limit of normal) and at most 1.67 x ULN, particularly strictly less than 1.67 x ULN.

[0041] In the context of this invention, the term "baseline plasma level" refers to the plasma level of a subject prior to initiating any treatment with the composition of the invention containing erafibrino. For example, "baseline ALP plasma level" refers to the ALP plasma level of a subject prior to initiating any treatment with the composition of the invention containing erafibrino.

[0042] In one specific implementation, the subject has PBC and responds at least partially to UDCA.

[0043] In another implementation, the subject had PBC and was inadequately responsive to UDCA.

[0044] In the context of this invention, the term "inadequate response to UDCA" or "insufficient response to UDCA" means that, despite treatment with UDCA, the plasma ALP level in a subject with an inadequate response to UDCA remains higher than that of ULN.

[0045] In another implementation, the subject had PBC and was intolerant to UDCA.

[0046] In one specific implementation, erafibrino is administered, preferably orally, to subjects with PBC and those who have an inadequate response to UDCA, at a dose of 80 mg or 120 mg.

[0047] The term "effective amount" or "therapeutic effective amount" refers to the amount of a compound sufficient to produce the desired therapeutic effect, and erafibrino is administered in an amount sufficient to demonstrate the desired effect.

[0048] In one specific aspect, the effect is an improvement in alkaline phosphatase and / or GGT levels, signifying a reduction in cholestasis. Therefore, the invention also relates to erafibrano for improving ALP and / or GGT levels in subjects with PBC, whose baseline plasma alkaline phosphatase (ALP) levels prior to receiving erafibrano are greater than 1 x ULN (upper limit of normal) and at most 1.67 x ULN, particularly strictly less than 1.67 x ULN.

[0049] In one specific implementation, erafibrano is administered to subjects with PBC whose baseline plasma alkaline phosphatase (ALP) levels prior to receiving erafibrano are greater than 1 x ULN (upper limit of normal) and at most 1.67 x ULN (particularly strictly less than 1.67 x ULN) to normalize plasma ALP, albumin, and / or bilirubin levels.

[0050] In one specific implementation, the subject has PBC and, prior to receiving erafibrino, has a baseline plasma alkaline phosphatase (ALP) level greater than 1 x ULN (upper limit of normal) and at most 1.67 x ULN, particularly strictly less than 1.67 x ULN, and the treatment results in an ALP level equal to or less than 1 x ULN, and preferably less than 0.5 x ULN.

[0051] In a particular variant of this implementation, erafibrano is administered to reduce ALP levels by at least 15%.

[0052] In a particular variant of this implementation, erafibrano is administered to reduce ALP levels by at least 40%.

[0053] In one specific implementation, the subject had PBC whose baseline plasma alkaline phosphatase (ALP) level prior to receiving erafibrinolu ...

[0054] In one specific implementation, the subject has PBC and, prior to receiving erafibrino, has a baseline plasma alkaline phosphatase (ALP) level greater than 1 x ULN (upper limit of normal) and at most 1.67 x ULN, particularly strictly less than 1.67 x ULN, and the treatment results in an ALP level equal to or less than 1 x ULN, preferably less than 0.5 x ULN, and total bilirubin (TB) less than 0.7 x ULN.

[0055] In one specific implementation, the subject has PBC and, prior to receiving erafibrino, has a baseline plasma alkaline phosphatase (ALP) level greater than 1 x ULN (upper limit of normal) and at most 1.67 x ULN, particularly strictly less than 1.67 x ULN, and the treatment results in normalization of plasma ALP levels to equal or less than 0.5 x ULN, a reduction in ALP levels of at least 40%, and total bilirubin (TB) less than 0.7 x ULN.

[0056] In one specific implementation, erafibrano is administered to subjects with PBC whose baseline plasma alkaline phosphatase (ALP) levels prior to receiving erafibrano are greater than 1 x ULN (upper limit of normal) and at most 1.67 x ULN, particularly strictly less than 1.67 x ULN), to increase bile acid levels, such as CDCA, cholic acid, lithocholic acid, and deoxycholic acid (DCA).

[0057] In another implementation, errafibrano is applied to improve Paris I, Paris II, Toronto I, Toronto II, or UK-PBC risk scores.

[0058] In another implementation, erafibrano is administered to subjects with PBC whose baseline plasma alkaline phosphatase (ALP) levels prior to receiving erafibrano are greater than 1 x ULN (upper limit of normal) and at most 1.67 x ULN, particularly strictly less than 1.67 x ULN, for the following purposes: -Improves AST, GGT, 5'-nucleotidase, total bilirubin, conjugated bilirubin, ALT and albumin levels; - Improve lipid parameters; -Improve C4 and / or FGF19 levels; - Improve IgM levels; and / or -Improved 5D-Itch Scale, PGI-S score, PGI-C score, PBC 40 QOL, and VAS.

[0059] The term “treatment” refers to the treatment, prevention or avoidance of PBC in subjects who, prior to receiving erafibrino, have a baseline plasma alkaline phosphatase (ALP) level greater than 1 x ULN (upper limit of normal) and at most 1.67 x ULN, particularly strictly less than 1.67 x ULN.

[0060] The treatment comprises administering erafibrino (e.g., by administration of a pharmaceutical composition containing erafibrino) to subjects with PBC (e.g., patients) whose baseline plasma alkaline phosphatase (ALP) level prior to receiving erafibrino is greater than 1 x ULN (upper limit of normal) and at most 1.67 x ULN, particularly strictly less than 1.67 x ULN, to prevent, cure, delay, reverse, or slow the progression of the disease, thereby improving the patient's condition. Treatment may also be given to healthy subjects or those at risk of developing cholestatic disease.

[0061] The terms “patient,” “subject,” or “individual” are interchangeable and refer to mammals, more specifically humans, including adults and children. Subjects treated according to the present invention may be appropriately selected based on several criteria associated with PBC, such as previous and / or current drug treatments, relevant pathology, genotype, exposure to risk factors, and any other relevant biomarkers that can be evaluated by any suitable immunological, biochemical, or enzymatic method.

[0062] The subjects awaiting treatment had PBC, characterized as follows: - At least two of the following three diagnostic factors are present: (i) A history of elevated ALP levels for at least 6 months prior to day 0 (random visit). (ii) Positive antimitochondrial antibody (AMA) titer (> 1 / 40, positive M2 on immunofluorescence or enzyme-linked immunosorbent assay (ELISA)) or positive PBC-specific antinuclear antibody (iii) Liver biopsy consistent with PBC -1 x ULN < ALP ≤ 1.67 x ULN, especially 1 x ULN < ALP < 1.67 x ULN -Optionally, take UDCA for at least 12 months (stable dose ≥ 6 months) prior to screening visit.

[0063] The present invention also relates to erafibrino in a method for reducing plasma ALP levels in subjects with PBC, wherein the subjects, prior to receiving erafibrino, have baseline plasma ALP levels greater than 1 x ULN and at most 1.67 x ULN, particularly strictly less than 1.67 x ULN.

[0064] In the context of this invention, the term "reduction of plasma ALP levels in a subject" means that, after 52 weeks of treatment with erafibrinolu ...

[0065] In the context of this invention, the term "normalizing the ALP level of a subject" means achieving a sustained normal ALP level (i.e., below ULN) after initial normalization. Normalizing the plasma ALP level of a subject with PBC helps improve the condition of said subject, particularly indicating a reduction in cholestasis.

[0066] In the context of this invention, ALP results are reported in International Units per Liter (IU / L or U / L). For men aged 18 years and older, the upper limit of normal (ULN) for ALP levels is 129 U / L. For women aged 18 years and older, the upper limit of normal (ULN) for ALP levels is 104 U / L.

[0067] In one specific embodiment of the invention, subjects to be treated are identified by testing the ALP levels of potential subjects and then selecting subjects with baseline plasma ALP levels greater than 1 x ULN and at most 1.67 x ULN, particularly strictly less than 1.67 x ULN, prior to receiving erafibrinolu ...

[0068] In the context of this invention, AST results are reported in International Units per Liter (IU / L or U / L). For men aged 18 years and older, the upper limit of normal (ULN) for AST levels is 40 U / L. For women aged 18 years and older, the upper limit of normal (ULN) for AST levels is 32 U / L.

[0069] According to one specific implementation scheme, the subject has a Child-Pugh score of A.

[0070] According to one specific implementation, the subject does not have a Child-Pugh score of B or C.

[0071] Cirrhosis is defined as compensated or decompensated and further classified using the Child-Pugh system well known to those skilled in the art. Patients with cirrhosis are classified according to certain clinical parameters. Children classified as Child-Pugh A are compensated and may present with very few obvious symptoms. Patients classified as Child-Pugh B or Child-Pugh C are decompensated and may present with external symptoms such as ascites.

[0072] The Child-Pugh score consists of five clinical features: ascites, hepatic encephalopathy, albumin, total bilirubin, and PT-INR, and is used to assess the prognosis of chronic liver disease and cirrhosis. Each indicator has a score from 1 to 3, which are added together to obtain a total score from 5 to 15. The higher the score, the worse the prognosis. Patients with a total score of 5-6 are classified as Child-Pugh A. Patients with a total score of 7-9 are classified as Child-Pugh B. Patients with a total score of 10-15 have the most severe condition and are classified as Child-Pugh C.

[0073] The Child-Pugh score was first proposed in 1973 to predict surgical outcomes in patients with esophageal variceal bleeding. Several studies have shown that the Child-Pugh score is an independent prognostic indicator for a variety of diseases, including primary biliary cholangitis (PBC). The Child-Pugh score can be easily calculated at the bedside.

[0074] The table below lists the components of the scoring system and the score allocation. The predicted 1-year survival rate based on the Child-Pugh score is shown in the table below: Erafibrano can have different stable isomers.

[0075] The synthesis of erafibrano can be carried out, for example, as described in compound 29 of WO2004 / 005233.

[0076] Erafibrano can be formulated into pharmaceutically acceptable salts, particularly acid salts or base salts compatible with pharmaceutical use. The erafibrano salts described herein include pharmaceutically acceptable acid addition salts, pharmaceutically acceptable base addition salts, pharmaceutically acceptable metal salts, ammonium salts, and alkylated ammonium salts. These salts can be obtained in the final purification step of the compound, or by incorporating the salt into a previously purified compound.

[0077] Specifically, "pharmaceutically acceptable salts" include both inorganic and organic acid salts. The anti-charge ion can be selected from the following non-exhaustive list: ammonia, L-arginine, benzylamine, benzathine, tert-butylamine, calcium hydroxide, choline hydroxide, deanol, diethanolamine (2,2'-iminobis(ethanol), diethylamine, epoisen (1-(2-hydroxyethyl)pyrrolidine), 2-(diethylamino)-ethanol, ethanolamine (2-aminoethanol), ethylenediamine, glycine, hydrabamine, 1H-imidazole, L-lysine, hydroxide Magnesium hydroxide, meglumine (N-methyl-glucosamine), 4-(2-hydroxyethyl)-morpholine, piperazine, potassium hydroxide, sodium hydroxide, triethanolamine (2,2',2"-nitro-tri(ethanol)), tromethamine, zinc hydroxide, especially tromethamine, potassium, sodium, phenethylbenzylamine, benzathine, L-arginine, ethanolamine, meglumine, glycine, tert-butylamine, L-lysine, epoisen, choline, preferably tromethamine, potassium, sodium, phenethylbenzylamine, benzathine, L-arginine, more preferably tromethamine, potassium, sodium, L-arginine, and even more particularly tromethamine.

[0078] In specific embodiments, the present invention incorporates the following components: ammonia, L-arginine, phenethylbenzylamine, benzylamine, tert-butylamine, calcium, choline, dimethylaminoethanol, diethanolamine (2,2'-iminodi(ethanol), diethylamine), epollamine (1-(2-hydroxyethyl)pyrrolidine), 2-(diethylamino)-ethanol, ethanolamine (2-aminoethanol), ethylenediamine, glycine, hydrabamine, 1H-imidazole, L-lysine, magnesium, and glucose. Methylamine (N-methylglucosamine), 4-(2-hydroxyethyl)-morpholine, piperazine, potassium, sodium, triethanolamine (2,2',2"-nitro-tri(ethanol)), tromethamine, or zinc salt. In another specific embodiment, the salt of erafibrano is selected from tromethamine, potassium, sodium, L-arginine, phenethylbenzylamine, benzathine, ethanolamine, meglumine, glycine, diethylamine, L-lysine, choline, epoisen, magnesium, or 2-amino-2-methyl-prop-1-ol salt.

[0079] Pharmaceutical compositions containing erafibrino for the treatment of PBC in subjects with PBC may contain one or more pharmaceutically acceptable excipients or mediators (e.g., saline solutions, physiological solutions, isotonic solutions, etc., compatible with the intended use and well known to those skilled in the art), wherein the subject has a baseline plasma alkaline phosphatase (ALP) level greater than 1 x ULN (upper limit of normal) and at most 1.67 x ULN, particularly strictly less than 1.67 x ULN, prior to receiving erafibrino. These compositions may contain one or more agents or mediators selected from dispersants, solubilizers, stabilizers, preservatives, etc.

[0080] Reagents or mediators that can be used in these formulations (liquid and / or injectable and / or solid) are particularly methylcellulose, hydroxymethylcellulose, carboxymethylcellulose, polysorbate 80, mannitol, gelatin, lactose, vegetable oil, gum arabic, liposomes, etc.

[0081] These compositions can be formulated into injectable suspensions, gels, oils, pills, suppositories, powders, gel capsules, capsules, aerosols, etc., ultimately ensuring prolonged and / or slow release via a galenal or device. For such formulations, reagents such as cellulose, carbonates, or starch can be advantageously used.

[0082] Erafibrano can be administered in an effective amount using a pharmaceutical composition as defined above.

[0083] Erafibrano can be administered in different ways and in different forms, thus allowing the compound to be administered in therapeutically effective amounts.

[0084] Therefore, for example, it can be administered in a systemic manner: orally, parenterally, by inhalation or injection, such as intravenously, intramuscularly, subcutaneously, percutaneously, or intra-arterially.

[0085] Oral administration is the preferred route of administration for the treatment of PBC of a pharmaceutical composition containing erafibrino, wherein the subject has a baseline plasma alkaline phosphatase (ALP) level greater than 1 x ULN (upper limit of normal) and at most 1.67 x ULN, particularly strictly less than 1.67 x ULN, prior to receiving erafibrino.

[0086] Suitable formulations, particularly tablet formulations, are described in PCT / EP2024 / 055754.

[0087] Those skilled in the art can adjust the frequency and / or dosage associated with administration based on the patient's function, pathology, form of administration, etc. Typically, erafibrano can be administered at doses of 0.01 mg to 1 g per administration, preferably 1 mg to 150 mg per administration, more preferably 70 mg to 130 mg per administration, for the treatment of PBC in subjects with PBC who, prior to receiving erafibrano, have a baseline plasma alkaline phosphatase (ALP) level greater than 1 x ULN (upper limit of normal) and at most 1.67 x ULN, particularly strictly less than 1.67 x ULN.

[0088] If necessary, it can be applied daily, or even several times a day.

[0089] In one specific implementation plan, Erafibrano is administered once daily.

[0090] In another specific implementation, erafibrano is administered once daily at a dose of 80 mg or 120 mg, preferably 80 mg.

[0091] In one specific implementation, erafibrino is administered to the patient throughout their life.

[0092] In one specific implementation, erafibrino is not administered as the sole therapeutic active agent.

[0093] Therefore, in one specific embodiment, the present invention also relates to the use of erafibrano in combination with at least one other therapeutically active agent for the treatment of PBC in patients with PBC, wherein the subject, prior to receiving erafibrano, has a baseline plasma alkaline phosphatase (ALP) level greater than 1 x ULN (upper limit of normal) and at most 1.67 x ULN, particularly strictly less than 1.67 x ULN.

[0094] Other active agents may be specifically selected from other antichostatic agents, such as UDCA or OCA.

[0095] Therefore, the present invention also relates to a combination of errafibrano with UDCA or OCA, preferably with UDCA.

[0096] This invention also relates to combinations of erafibrino and anticholestasis agents.

[0097] Other anticholestasis agents include, but are not limited to: - Top sodium-dependent bile acid transporter inhibitor (ASBTi); - Bile acids; -Cetase inhibitors; -CCR antagonists; -CD40 inhibitors; -CD80 inhibitor; - Dual NOX (NADPH oxidase) 1 & 4 inhibitors; - Farnesol X receptor (FXR) agonists; -Reconstructed fibroblast growth factor (FGF) 19; -Fractalkine ligand inhibitor; -Inhibitor of sodium cotransporter of ileal bile acids; - Monoclonal antibodies; -PPARα agonists; -PPARγ agonists; -PPARδ agonists; -PPARα / γ agonists; -PPARα / δ agonists; -PPARγ / δ agonists; and -PPARα / γ / δ agonists or PPARpan agonists.

[0098] Illustrative apical sodium-dependent bile acid transporter inhibitors include, but are not limited to, odevixibat; volixibat; maralixibat (formerly SHP-625); linerixibat; elobixibat; and CJ-14199.

[0099] Illustrative bile acids include, but are not limited to, obeticholic acid and ursodeoxycholic acid (UDCA).

[0100] Illustrative cathepsin inhibitors include, but are not limited to, VBY-376; VBY-825; VBY-036; VBY-129; VBY-285; Org-219517; LY3000328; RG-7236 and BF / PC-18.

[0101] Illustrative CCR antagonists include, but are not limited to, cenicriviroc (a CCR2 / 5 antagonist); PG-092; RAP-310; INCB-10820; RAP-103; PF-04634817; and CCX-872.

[0102] Illustrative CD40 inhibitors include, but are not limited to, FFP-104; xl-050; DOM-0800; XmAb-5485; KGYY-15; FFP-106; TDI-0028 and ABI-793.

[0103] Illustrative CD80 inhibitors include, but are not limited to, RhuDex; FPT-155; ToleriMab; galiximab; SCH-212394; IGM-001; ASP-2408 and SCH-204698.

[0104] Illustrative dual NOX (NADPH oxidase) 1 & 4 inhibitors include, but are not limited to, GKT-831 (formerly GKT137831) and GKT-901.

[0105] Illustrative farnesoid X receptor (FXR) agonists include, but are not limited to, obeticholic acid; GS-9674; LJN-452; EDP-305; AKN-083; INT-767; GNF-5120; LY2562175; INV-33; NTX-023-1; EP-024297; Px-103 and SR-45023.

[0106] Illustrative remodeling fibroblast growth factor 19 (FGF-19) includes, but is not limited to, NGM-282.

[0107] Illustrative Fractalkine ligand inhibitors include, but are not limited to, E-601 1 and KAN-0440567. Illustrative ileal bile acid sodium cotransporter inhibitors include, but are not limited to, odecibart; GSK-2330672; vocibart; CJ-14199 and elocibart.

[0108] Illustrative monoclonal antibodies include, but are not limited to, bertilimumab; NGM-313; IL-20-targeting mAb; fresolimumab (anti-TGF3), formerly known as GC1008; temorumab, also known as BTT-1023; namacizumab; omalizumab; ranibizumab; bevacizumab; lebrikizumab; epratuzumab; felvizumab; matuzumab; monalizumab; reslizumab; and inebilizumab.

[0109] Illustrative PPARα agonists include, but are not limited to, fenofibrate, ciprofibrate, pemafibrate, gemfibrozil, clofibrate, binifibrate, clinofibrate, clofibrate, nicofibrate, pirifibrate, plafibride, ronifibrate, theofibrate, tocofibrate, and SR10171.

[0110] Illustrative PPARγ agonists include, but are not limited to, pioglitazone, deuterated pioglitazone, rosiglitazone, efatutazone, ATx08-001, OMS-405, CHS-131, THR-0921, SER-150-DN, KDT-501, GED-0507-34-Levo, CLC-3001, and ALL-4.

[0111] Illustrative PPARδ agonists include, but are not limited to, GW501516 (Endurabol or ({4-[(4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazolyl-5-yl)methyl)thio]-2-methylphenoxy}acetic acid) or MBX8025 (Seladelpar or {2-methyl-4-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[l,2,3]triazol-4-ylmethylaromatic]-phenoxy}-acetic acid) or GW0742 ([4-[[[2-[3-fluoro-4-(trifluoromethyl)phenyl]-4-methyl-5-thiazolyl]methyl]thio]-2-methylphenoxy]acetic acid) or L165041 or HPP-593 or NCP-1046.

[0112] Illustrative PPARα / γ agonists (also known as glitazar) include, but are not limited to, saroglitazar, alglitazar, muraglitazar, tesaglitazar, and DSP-8658.

[0113] In addition to erafibrano, illustrative PPARα / δ agonists include, but are not limited to, T913659.

[0114] Illustrative PPARγ / δ agonists include, but are not limited to, linoleic acid (CLA) and T3D-959.

[0115] Illustrative PPARα / γ / δ agonists (or “PPARpan agonists”) include, but are not limited to, IVA337, TTA (tetradecyl thioacetic acid), bavachinin, GW4148, GW9135, bezafibrate, lobeglitazone, and CS038.

[0116] In another embodiment, the present invention provides a method for treating a subject with PBC, comprising administering erafibrino, particularly in the form of a pharmaceutical composition containing the compound, preferably an oral pharmaceutical composition containing the compound, wherein the subject, prior to receiving erafibrino, has a baseline plasma alkaline phosphatase (ALP) level greater than 1 x ULN (upper limit of normal) and at most 1.67 x ULN, particularly strictly less than 1.67 x ULN.

[0117] In another embodiment, the present invention provides a method for treating a subject with PBC, comprising administering erafibrino, particularly in the form of a pharmaceutical composition containing the compound, preferably an oral pharmaceutical composition containing the compound, wherein the subject, prior to receiving erafibrino, has a baseline plasma alkaline phosphatase (ALP) level greater than 1 x ULN (upper limit of normal) and at most 1.67 x ULN, particularly strictly less than 1.67 x ULN.

[0118] In another embodiment, the present invention also provides a kit for treating subjects with PBC, comprising erafibrano, optionally in combination with another antichostatic agent as described above, wherein the subject, prior to receiving erafibrano, has a baseline plasma alkaline phosphatase (ALP) level greater than 1 x ULN (upper limit of normal) and at most 1.67 x ULN, particularly strictly less than 1.67 x ULN.

[0119] In another embodiment, the present invention also provides a kit for treating subjects with PBC, comprising erafibrano, optionally in combination with another antichostatic agent as described above, wherein the subject, prior to receiving erafibrano, has a baseline plasma alkaline phosphatase (ALP) level greater than 1 x ULN (upper limit of normal) and at most 1.67 x ULN, particularly strictly less than 1.67 x ULN.

[0120] As previously stated, the present invention also provides the use of erafibrano in the preparation of pharmaceutical compositions, preferably oral pharmaceutical compositions, for the treatment of PBC in subjects who, prior to receiving erafibrano, have a baseline plasma alkaline phosphatase (ALP) level greater than 1 x ULN (upper limit of normal) and at most 1.67 x ULN, particularly strictly less than 1.67 x ULN.

[0121] In another embodiment, the present invention also discloses the use of erafibrano in the preparation of a medicament for treating PBC in a subject who, prior to receiving erafibrano, has a baseline plasma alkaline phosphatase (ALP) level greater than 1 x ULN (upper limit of normal) and at most 1.67 x ULN, particularly strictly less than 1.67 x ULN.

[0122] In another embodiment, the present invention also discloses the use of erafibrano in the preparation of a medicament for the prevention of hepatic decompensation in subjects with PBC, the subjects having a baseline plasma alkaline phosphatase (ALP) level greater than 1 x ULN (upper limit of normal) and at most 1.67 x ULN, particularly strictly less than 1.67 x ULN, prior to receiving erafibrano.

[0123] The present invention also relates to a method of treating PBC in subjects with PBC, comprising administering a therapeutically effective amount of erafibrino, wherein the subject, prior to receiving erafibrino, has a baseline plasma alkaline phosphatase (ALP) level greater than 1 x ULN (upper limit of normal) and at most 1.67 x ULN, particularly strictly less than 1.67 x ULN.

[0124] In another embodiment of the invention, the invention also discloses a kit for treating PBC in subjects with PBC, the kit comprising erafibrino, the subjects having a baseline plasma alkaline phosphatase (ALP) level greater than 1 x ULN (upper limit of normal) and at most 1.67 x ULN, particularly strictly less than 1.67 x ULN, prior to receiving erafibrino.

[0125] The invention is further described with reference to the following non-limiting embodiments.

[0126] The invention will be better understood by referring to the following embodiments, which are for illustrative purposes only and should not be construed as limiting the invention in any way.

[0127] Example Example 1: Clinical Trial of PBC A phase IIIb randomized, parallel-group, double-blind, placebo-controlled, two-arm study was conducted in patients with PBC and those who had an inadequate or intolerable response to ursodeoxycholic acid to evaluate the efficacy of once-daily 80 mg erafibrano in normalizing ALP levels in participants with PBC and those who had an inadequate or intolerable response to UDCA and whose baseline ALP levels were >1 × ULN and <1.67 × ULN, compared to placebo.

[0128] Main purpose The primary objective was to evaluate the efficacy of daily oral administration of 80 mg erafibrino in normalizing ALP in adult subjects with PBC compared to placebo.

[0129] Secondary objective The secondary objective is: • Evaluate the efficacy of biochemical markers of response to daily oral administration of 80 mg erafibrino in adult subjects with PBC compared to placebo.

[0130] • Evaluate the efficacy of daily oral administration of 80 mg erafibrino in patient-reported outcomes in adult subjects with PBC compared to placebo.

[0131] • Evaluate the safety and tolerability of daily oral administration of 80 mg erafibrino in adult subjects with PBC compared to placebo.

[0132] Exploratory The purpose of exploration is: • Evaluate the effects of daily 80 mg erafibrino on biomarkers compared to placebo: liver tests, noninvasive biomarkers of fibrosis, biomarkers of pruritus, lipid parameters, PBC prognostic score, biomarkers of inflammation and immune response, biomarkers of bile acid synthesis, and bone mineral density.

[0133] • Evaluate the efficacy of daily oral administration of 80 mg erafibrino for target clinical outcome events in adult subjects with PBC compared to placebo.

[0134] • The pharmacokinetic (PK) of erafibrano and its metabolite GFT1007 in the subject population was evaluated using a population-based PK method.

[0135] • Assess the relationship between PK and PD (efficacy and safety, if applicable) endpoints.

[0136] • If applicable, evaluate the association between the biomarker and clinical data for the selected efficacy and safety endpoints.

[0137] Inclusion criteria 1. Male or female participants must be ≥18 years old when signing the informed consent form.

[0138] 2. Participants with a confirmed or probable diagnosis of PBC, who exhibit ≥2 of the following three historical diagnostic criteria: i. A history of elevated ALP levels ≥6 months prior to SV1.

[0139] ii. Positive AMA titer (≥1 / 40, positive M2 assay by immunofluorescence or enzyme-linked immunosorbent assay) or positive PBC-specific antinuclear antibody.

[0140] iii. Liver biopsy consistent with PBC.

[0141] 3. Based on two values ​​obtained during the screening period, ALP > 1 × ULN and < 1.67 × ULN. The interval between the two measurements should be at least 2 weeks.

[0142] 4. Subjects taking UDCA should have taken the drug for at least 6 months prior to SV1, with a stable dose for ≥ 3 months. Subjects who have not taken UDCA or are intolerant to UDCA may participate in the trial and should have taken their last dose of UDCA for ≥ 3 months prior to SV1.

[0143] 5. Prior to screening, participants who were taking medications to treat itching (such as cholestyramine, rifampin, naltrexone, sertraline, or colchicine) must have been on a stable dose for ≥ 3 months.

[0144] 6. The use of contraceptives by men or women should comply with local regulations regarding contraceptive methods used by clinical researchers: (a) Male participants must consent to use effective contraception if their partner is at risk of pregnancy. Participants must consent to use contraception throughout the study and for 30 days after the last dose of the study intervention.

[0145] (b) Female participants are eligible to participate if they are not pregnant or breastfeeding and meet one of the following criteria: -Women who are infertile (WONCBP) or - Women of childbearing potential (WOCBP) should use highly effective contraceptive methods (annual failure rate <1%) during the study intervention and for at least 30 days after the last dose of the study intervention, preferably methods with low user dependence. Researchers should evaluate the likelihood of contraceptive method failure associated with the first dose of the study intervention (e.g., recent non-adherence).

[0146] WOCBP must be negative for a highly sensitive pregnancy test (urine or serum, as required by local regulations) within 24 hours prior to receiving the first dose of the study intervention.

[0147] - If the urine test cannot confirm a negative result (e.g., the result is unclear), a serum pregnancy test is required. In this case, if the serum pregnancy result is positive, the participant must be excluded.

[0148] 7. Able to sign informed consent forms, including complying with informed consent forms (ICF) and the requirements and limitations listed in this program.

[0149] Exclusion criteria: 1. Other history or presence of liver disease, including: i. Primary sclerosing cholangitis.

[0150] ii. Autoimmune hepatitis (AIH) that cannot be explained solely by inadequate response to UDCA according to the simplified diagnostic criteria of the International Autoimmune Hepatitis Group ≥ 6, or if treated for overlap between PBC and AIH, or if there is clinical suspicion and evidence of overlapping AIH features.

[0151] iii. Positive for Hepatitis B surface antigen (HBsAg). Participants who are negative for hepatitis B virus deoxyribonucleic acid (HBV DNA), negative for HBsAg, and positive for hepatitis B core antibody (HBcAb) are eligible.

[0152] iv. Hepatitis C virus (HCV) infection defined by positive anti-HCV antibody and positive HCV ribonucleic acid (RNA) (Note: If confirmed HCV RNA cannot be detected and there is a persistent record of viral response, participants who are positive for anti-HCV antibody and have a history of previously treated HCV infection may be recruited).

[0153] v. Alcohol-related liver disease vi. Nonalcoholic steatohepatitis [NASH, also known as MASH (metabolic steatohepatitis-associated steatohepatitis)] 2. Participants with known cirrhosis and a Child-Pugh B or C score. Participants with cirrhosis and a Child-Pugh A score are also eligible.

[0154] 3. History of liver transplantation.

[0155] 4. A history of clinically significant liver decompensation or the presence of clinically significant liver decompensation, including: i. Current position on the liver transplant list, current model of end-stage liver disease due to liver injury (MELD)-Na score ≥ 12 (only when MELD > 11, the end-stage liver disease model including serum sodium (MELD-Na) is calculated).

[0156] ii. Evidence of complications of cirrhosis, including ascites requiring treatment; a history of variceal bleeding or related interventions (e.g., variceal ligation or sclerotherapy, or transjugular intrahepatic portosystemic shunt (TIPS) placement); the presence of grade 2 or higher hepatic encephalopathy according to the West-Haven criteria; or a history of spontaneous bacterial peritonitis. Note: Participants with grade I esophageal varices may be eligible to enroll.

[0157] iii. Hepatorenal syndrome (type 1 or type II).

[0158] 5. Known history of human immunodeficiency virus (HIV) infection.

[0159] 6. Medical conditions that may cause non-hepatic elevation of ALP (e.g., Paget's disease).

[0160] 7. Evidence of any other unstable or untreated clinically significant immunological, endocrine, hematological, gastrointestinal, neurological or psychiatric disease assessed by the investigator; other clinically significant conditions that are not well controlled.

[0161] 8. Cancer or non-hepatic conditions with a life expectancy of less than 2 years.

[0162] 9. Known malignant tumor or history of malignant tumor within the past 2 years, with the exception of successfully treated localized basal cell carcinoma or cutaneous squamous cell carcinoma; or carcinoma in situ of the cervix.

[0163] 10. History of hepatocellular carcinoma.

[0164] 11. Alpha-fetoprotein (AFP) > 20 ng / mL, and a 4-phase hepatic computed tomography (CT) or magnetic resonance imaging (MRI) scan indicates the presence of liver cancer.

[0165] 12. According to the schedule specified below, the administration of the following drugs during the study and before the study is prohibited: i. Systemic (oral or parenteral) use within 3 months prior to SV1: fibrates, seladelpar, glitazones, obeticholic acid, azathioprine, cyclosporine, methotrexate, mycophenolate mofetil or long-term systemic corticosteroids (only chronic parenteral and oral administration); potentially hepatotoxic drugs (including α-methyldopa, valproic acid, isoniazid or nitrofurantoin) 13. Participants with prior exposure to elafibranor.

[0166] 14. Participants who are participating, planning to participate, or have participated in an investigational drug study or a medical device study containing active substances within 30 days or 5 half-lives (whichever is longer) prior to SV1. If the previous study was an experimental therapy investigating potential benefits for PBC, and it has been proven that the potential therapeutic agent has no beneficial effect in PBC and there are no safety issues, the participant may be enrolled after 30 days or 5 half-lives (whichever is longer). For therapeutic agents investigating potential benefits for PBC where the potential benefit is not yet clear, participants may be enrolled 6 months thereafter.

[0167] 15. Total bilirubin (TB) > 2 × ULN. If the direct bilirubin is < 30% of TB, participants with Gilbert's syndrome are eligible with TB higher than 2 × ULN.

[0168] 16. For SV1, screen for ALT and / or AST > 5 × ULN, or based on variability > 40% between two consecutive measurements. The interval between the two measurements should be at least 2 weeks.

[0169] 17. CPK > 2 × ULN.

[0170] 18. Platelet count < 75,000 / µL.

[0171] 19. In the absence of anticoagulation therapy, the international normalized ratio is > 1.3.

[0172] 20. Estimated glomerular filtration rate (eGFR) at SV1 according to the formula of the Dietary Modulation for Kidney Disease (MDRD)-6 study: <45 mL / min / 1.73 m 2 .

[0173] Note: In cases of decreased eGFR, if the researcher believes that the value may not represent the actual eGFR of the potential subjects, a retest is permitted after adequate hydration.

[0174] 21. Major kidney disease, including nephrotic syndrome and chronic kidney disease (defined as participants with significant impairment of kidney function or evidence of potential kidney damage).

[0175] Other exclusions: 22. For female participants: known pregnancy, or a positive serum pregnancy test, or breastfeeding.

[0176] 23. Regularly drinking alcohol exceeding the recommended limit of 2 standard drinks per day for men or 1 standard drink per day for women, where one standard drink corresponds to 10 g of alcohol.

[0177] 24. SV1 has a history of alcohol abuse or other substance abuse within the year prior to the diagnosis.

[0178] 25. Known hypersensitivity to the study product or any excipients of erafibrano.

[0179] 26. Due to mental instability or lack of capacity, the validity of the informed consent or the ability to comply with the study is uncertain.

[0180] 27. Any other situation that the researcher believes would interfere with participation in or completion of the study, or would put participants at risk, including potential participants assessed as being at high risk of non-compliance with the study.

[0181] Randomization Patients meeting all eligibility criteria will be randomized in a 2:1 ratio to one of the following groups: -Erafibrano 80 mg / day; or - Placebo.

[0182] Randomization rates were stratified based on ALP at the start of the study (ALP > 1 × ULN to ≤ 1.33 × ULN vs. ALP > 1.33 × ULN to < 1.67 × ULN). Participants will continue to receive a stable maintenance dose of UDCA throughout the study, if applicable.

[0183] This study consists of three time periods: • A screening period of up to 8 weeks; • A 52-week treatment period; • A 4-week follow-up period following the last dose of the study intervention.

[0184] Primary endpoint The primary endpoint is: • Percentage of participants whose alkaline phosphatase was normalized (i.e., alkaline phosphatase ≤ 1.0 × ULN) at week 52.

[0185] Secondary endpoint The secondary endpoint is: • Assess at weeks 4, 12, 24, and 36: -Percentage of participants who have normalized ALP.

[0186] • Assess at weeks 4, 12, 24, 36, and 52: - Absolute and percentage changes in ALP relative to baseline; - The number and percentage of participants whose ALP has normalized and decreased by ≥ 15% relative to baseline; - The number and percentage of participants with ALP and a decrease of ≥ 40% relative to baseline; - Number and percentage of participants with ALP < 0.5 × ULN; - Absolute and percentage changes in TB relative to the baseline; - Number and percentage of participants with TB < 0.7 × ULN; - The number and percentage of participants with normalized ALP and TB < 0.7 × ULN; - The number and percentage of participants with normalized TB and ALP were defined as TB ≤ ULN and ALP ≤ ULN; - The number and percentage of participants with a complete biochemical response, defined as normal levels of TB, ALP, transaminases, albumin, and INR.

[0187] • Passed the week 52 assessment: - The number and percentage of participants with moderate to severe pruritus at baseline (i.e., a score ≥4) and a clinically meaningful response in the PBC's most severe pruritus NRS, defined as a reduction of ≥1.8 points relative to baseline.

[0188] • Assess at weeks 4, 24, and 52: -5-D pruritus score change relative to baseline; -Change in PGI-S score relative to baseline; -PGI-C score; - Change in PBC-40 QoL score relative to baseline; - Changes in PROMIS Fatigue Summary 7a score relative to baseline.

[0189] • Regarding the duration of participation in the research: - The number and percentage of participants who experienced TEAE, treatment-related TEAE, SAE, and AESI; - The number and percentage of participants who developed clinically significant changes in PCSA and / or physical examination results, vital signs and ECG relative to baseline; - The number and percentage of participants who developed PCSA relative to baseline and whose hematology, coagulation, chemistry, liver function, kidney function (including urinalysis), and other laboratory tests and procedures changed.

[0190] Exploratory endpoint • Assess at weeks 4, 12, 24, 36, and 52: - Changes in liver function relative to baseline, measured by AST, ALT, GGT, conjugated bilirubin, albumin, and INR.

[0191] • Week 52 assessment: - Use Fibroscan® to assess the change of LSM relative to baseline via VCTE. - Non-invasive measurements of liver fibrosis (such as changes from baseline via the ELF test).

[0192] • Assess at weeks 12, 24, 36, and 52: - Changes in pruritus cycle markers (such as IL-31, LPA, and autocrine motor factor) relative to baseline.

[0193] • Assess at weeks 4, 12, 24, 36, and 52: - Changes in lipid parameters relative to baseline, measured by TC, LDL-C, HDL-C, calculated VLDL-C, and TG.

[0194] • Week 52 assessment: - Changes in PBC risk scores relative to baseline: UK PBC score and GLOBE score.

[0195] • Assessments were conducted at weeks 24 and 52: - Changes in IgG and IgM relative to baseline.

[0196] - Changes in inflammatory circulating markers (such as high-sensitivity C-reactive protein, fibrinogen, haptoglobin, and tumor necrosis factor α) relative to baseline.

[0197] • Assessments were conducted at weeks 24 and 52: -C4 and FGF-19 changes relative to baseline • Week 52 assessment: - Changes in bone mineral density relative to baseline.

[0198] - The number and percentage of participants who experienced any of the following relevant clinical events (and timing): -All-cause mortality rate; - Liver-related mortality; -Liver transplantation; - Participants with a baseline MELD or MELD-Na score < 12 and a MELD-Na score ≥ 15.

[0199] -Liver decompensation.

[0200] - Plasma concentrations and individual PK parameters after a single administration and at steady state.

[0201] - Group PK parameters.

[0202] - If applicable, estimate the (PK / PD) population and individual model parameters.

[0203] - Biomarkers and clinical data analysis through modeling.

[0204] In subjects with PBC and baseline plasma alkaline phosphatase (ALP) levels greater than 1 x ULN and at most 1.67 x ULN, particularly strictly less than 1.67 x ULN, erafibrino is expected to be superior to placebo in preventing clinical outcome events that show disease progression, including disease progression leading to liver transplantation or death.

Claims

1. Erafibrano for the treatment of primary biliary cholangitis (PBC), wherein the subject to be treated is a subject with PBC whose baseline plasma alkaline phosphatase (ALP) level is greater than 1 x ULN (upper limit of normal) and strictly less than 1.67 x ULN prior to receiving erafibrano.

2. Erafibrano for normalizing plasma ALP levels in subjects with PBC, wherein the subjects to be treated are subjects with PBC whose baseline plasma alkaline phosphatase (ALP) levels prior to receiving erafibrano are greater than 1 x ULN (upper limit of normal) and strictly less than 1.67 x ULN.

3. The erafibrino used according to any one of claims 1 or 2, wherein subjects to be treated are identified by testing the ALP levels of potential subjects and then selecting subjects with baseline plasma ALP levels greater than 1 x ULN (upper limit of normal) and strictly less than 1.67 x ULN prior to receiving erafibrino.

4. Erafibrano used according to any one of claims 1 to 3, wherein the subject responds at least partially to UDCA.

5. Erafibrano used according to any one of claims 1 to 4, wherein the subject has an inadequate response to UDCA.

6. Erafibrano used according to any one of claims 1 to 5, wherein the subject is intolerant to UDCA.

7. Erafibrano used according to any one of claims 1 to 6, for administration at a dose of 70 mg to 130 mg, preferably at a dose of 80 mg.

8. The erafibrano used according to any one of claims 1 to 7, in the form of a pharmaceutical composition, preferably an oral pharmaceutical composition.

9. The Erafibrano of claim 8, wherein the composition is formulated as an injectable suspension, gel, oil, pill, suppository, powder, gel capsule, capsule, aerosol, or in a galenal form or device that ensures prolonged and / or slow release.

10. Erafibrano as used according to any one of claims 1 to 9, for once-daily application.

11. Erafibrano as used according to any one of claims 1 to 10, for oral administration once daily at a dose of 80 mg.

12. Erafibrano used according to any one of claims 1 to 11, in combination with another anticholestasis agent, preferably in combination with UDCA.

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