Eraffibularox for treatment of primary biliary cholangitis

Abstract

The present invention relates to a pharmaceutical composition comprising a compound selected from the group consisting of Eraffibularor, 2-[2, 6-dimethyl-4-[3-[4-(methylthio) phenyl]-3-oxo-propyl] phenoxy]-2-methyl propionic acid (GFT1007), and a pharmaceutically acceptable salt of Eraffibularor or GFT1007, and a pharmaceutical composition comprising a compound selected from the group consisting of a compound of Eraffibularor, a compound of Eraffibularor, a compound of Eraffibularor, a compound of Eraffibularor, a compound of Eraffibularor, a compound of Eraffibularor, a compound of Eraffibularor The pharmaceutical composition is used in a method of treating primary biliary cholangitis (PBC) in a subject with primary biliary cholangitis (PBC) at baseline plasma alkaline phosphatase (ALP) levels of more than 1.67 * ULN and up to 3 * ULN.

Description

Technical Field

[0001] This invention relates to the field of medicine, and more particularly to the treatment of cholestatic diseases, specifically PBC. Background Technology

[0002] Primary biliary cholangitis (PBC) is a rare, chronic, progressive cholestatic liver disease with an autoimmune etiology, characterized by intrahepatic bile duct damage. In untreated patients, it can progress to liver fibrosis, cirrhosis, decreased liver compensation, and death (unless the patient undergoes a liver transplant). PBC has a disproportionate effect on women and men (approximately 10:1) and is usually diagnosed in patients aged 40 to 60 years. In Europe, North America, Asia, and Australia, the incidence and prevalence of PBC have been reported to range from 0.33 to 5.8 cases per 100,000 inhabitants and 1.91 to 40.2 cases per 100,000 inhabitants, respectively.

[0003] More than 60% of newly diagnosed cases are asymptomatic. Most asymptomatic patients develop symptoms within 10 years. The most common symptoms of PBC are general fatigue (in 70% of cases) and itching (Crosignani A et al., Clinical features and management of primary biliary cirrhosis. World J Gastroenterol. 2008;14(21):3313-3327). The underlying mechanisms of these symptoms are not well elucidated and are not associated with disease stage or clinical outcome.

[0004] Percutaneous coronary syndrome (PBC) represents one of the main indications for liver transplantation. Although rare, PBC remains a significant cause of disease in the Western world. PBC has also been identified as an important risk factor for hepatocellular carcinoma.

[0005] PBC is characterized by cholestasis, caused by progressive damage to the bile ducts and bile flow in the liver, resulting from autoimmune destruction. This leads to an increase in the concentration of hepatotoxic hepatocellular bile acids. This type of hepatocellular damage is associated with a local inflammatory response, causing an abnormally high level of serum alkaline phosphatase (ALP) in the early stages. Therefore, biologically, PBC presents as an ALP level that is more than 1.5 times the upper limit of normal (ULN). ALP levels are generally associated with disease progression. In fact, the risk of liver transplantation or death associated with elevated ALP levels is 2.0 to 2.5 times higher than that associated with normal levels. An international follow-up study showed that ALP >2×ULN was associated with a 2.2 times higher risk of liver transplantation or death within 1 year compared to patients who maintained ALP ≤2×ULN (P<0.0001) (Lammers WJ et al., Gastroenterology, 2014;147(6):1338).

[0006] Abnormally elevated bilirubin levels occurring in the later stages of disease progression are also a strong predictor of outcomes, with the risk of liver transplantation or death being 5.1 to 10.7 times higher than that associated with normal levels.

[0007] As of October 2023, only ursodeoxycholic acid (UDCA) and Ocaliva were approved for the treatment of PBC patients. ® (Obeticholic acid, OCA).

[0008] Ursodeoxycholic acid (UDCA) has been shown to improve ALP and bilirubin levels and delay histological progression, thereby increasing liver transplant-free survival. However, up to 40% of patients treated with UDCA have a suboptimal response (Ali AH et al., Orphandrugs in development for primary biliary cirrhosis: challenges and progress. Orphan Drugs: Research and Reviews. 2015; 5:83-97). ALP has been shown to remain elevated in up to 70% of patients currently receiving treatment or who are intolerant to UDCA (Lammers WJ et al., Levels of alkalinephosphatase and bilirubin are surrogate end points of outcomes of patients with primary biliary cirrhosis: an international follow-up study. Gastroenterology. 2014; 147(6):1338-1349). These patients remain at risk of disease progression and longer-term adverse clinical outcomes. Currently, 44% of patients treated with UDCA develop a liver transplant or die within 15 years.

[0009] Recently, several countries have approved obeticholic acid (OCA) (Ocaliva), a drug proven to lower ALP. ® As a second-line therapy, it is used as monotherapy for PBC in adults who cannot tolerate UDCA, or in combination with UDCA for PBC in adults who have an inadequate response to UDCA. Reduced ALP levels are considered a specific and relevant surrogate marker for PBC treatment and were recently used as the basis for conditional market approval of OCA in this indication.

[0010] Given the efficacy and tolerability issues of currently available treatment options, there is an unmet need for treatment options that can significantly reduce plasma ALP levels in PBC patients.

[0011] Elafibranor (2-(2,6-dimethyl-4-{3-[4-(methylthio)phenyl]-3-oxopropen-1-yl}phenoxy)-2-methylpropionic acid) was evaluated in a phase 3 study of PBC treatment (ELATIVE®). Phase 3 results for PBC showed that the mean relative change (%) in serum ALP from baseline to endpoint was -48.3% in the 80 mg erafibranor treatment group and 3.2% in the placebo group.

[0012] Therefore, compared with placebo, erafibrino treatment resulted in a sustained, statistically significant reduction in plasma ALP levels relative to baseline. Furthermore, erafibrino is safe and well-tolerated by patients. Summary of the Invention

[0013] A phase 3 clinical trial unexpectedly showed that, in participants with PBC whose baseline plasma ALP levels were greater than 1.67 × ULN and up to 3 × ULN, treatment with 2-(2,6-dimethyl-4-{3-[4-(methylthio)phenyl]-3-oxoprop-1-en-1-yl}phenoxy)-2-methylpropionic acid (erafibrano, formerly known as GFT505) (80 mg daily) was more effective than in participants with PBC whose baseline plasma ALP levels were greater than 3 × ULN. The efficacy of erafibrano in subjects with PBC whose baseline plasma ALP levels were greater than 1.67 × ULN and up to 3 × ULN was more than three times greater than in subjects with PBC whose baseline plasma ALP levels were greater than 3 × ULN.

[0014] Therefore, the present invention relates to a pharmaceutical composition comprising a compound selected from the group consisting of erafibrano, 2-[2,6-dimethyl-4-[3-[4-(methylthio)phenyl]-3-oxo-propyl]phenoxy]-2-methylpropionic acid (GFT1007) and pharmaceutically acceptable salts of erafibrano or GFT1007, for the treatment of primary biliary cholangitis (PBC) in subjects with PBC whose baseline plasma alkaline phosphatase (ALP) levels exceed 1.67 × ULN and are at most 3 × ULN.

[0015] The present invention also relates to a pharmaceutical composition comprising a compound selected from the group consisting of erafibrano, GFT1007 and pharmaceutically acceptable salts of erafibrano or GFT1007, in a method for reducing baseline plasma ALP levels in subjects with PBC whose baseline plasma ALP levels exceed 1.67 × ULN and are at most 3 × ULN.

[0016] The present invention also relates to the use of a pharmaceutical composition in the preparation of a medicament comprising a compound selected from the group consisting of erafibrano, 2-[2,6-dimethyl-4-[3-[4-(methylthio)phenyl]-3-oxo-propyl]phenoxy]-2-methylpropionic acid (GFT1007) and pharmaceutically acceptable salts of erafibrano or GFT1007, in a method of treating primary biliary cholangitis (PBC) in subjects with PBC whose baseline plasma alkaline phosphatase (ALP) levels exceed 1.67 × ULN and are at most 3 × ULN.

[0017] The present invention further relates to the use of a pharmaceutical composition comprising a compound selected from the group consisting of erafibrano, GFT1007 and pharmaceutically acceptable salts of erafibrano or GFT1007, the pharmaceutical composition being used in the manufacture of a medicament for use in a method of reducing baseline plasma ALP levels in subjects with PBC who have baseline plasma ALP levels exceeding 1.67 × ULN and at most 3 × ULN.

[0018] The present invention also relates to a method for treating primary biliary cholangitis (PBC) in a subject with PBC whose baseline plasma alkaline phosphatase (ALP) level exceeds 1.67 × ULN and is at most 3 × ULN, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a compound selected from the group consisting of: erafibrano, 2-[2,6-dimethyl-4-[3-[4-(methylthio)phenyl]-3-oxo-propyl]phenoxy]-2-methylpropionic acid (GFT1007), and a pharmaceutically acceptable salt of erafibrano or GFT1007.

[0019] The present invention also relates to a method for reducing baseline plasma ALP levels in subjects with PBC whose baseline plasma ALP levels exceed 1.67 × ULN and are at most 3 × ULN, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a compound selected from the group consisting of erafibrano, GFT1007 and pharmaceutically acceptable salts of erafibrano or GFT1007. Attached Figure Description

[0020] Figure 1 ALP normalization

[0021] Figure 1 The study showed that 15% of participants receiving erafibrinolate and 0% receiving placebo had their alkaline phosphatase levels completely normalized at week 52 (difference, 15%; odds ratio, infinity; 95% CI, 2.8 to infinity; p = 0.0019).

[0022] Figure 2 ALP levels decreased

[0023] Figure 2 The study showed that alkaline phosphatase levels in the Erafibrano group decreased rapidly from baseline to week 4 and remained at levels significantly lower than those in the placebo group until week 52.

[0024] Figure 3This shows the percentage of participants receiving erafibrinolu ...

[0025] Figure 4 This shows the percentage of participants receiving erafibrino who had ALP normalization at week 52, categorized by baseline ALP levels (≤2, 2-≤2.5, 2.5-≤3, 3-≤4, and >4×ULN).

[0026] Figure 5 This shows the average percentage change in ALP from baseline to week 52, categorized by baseline ALP levels (≤2, 2-≤2.5, 2.5-≤3, 3-≤4, and >4×ULN). Invention Details

[0028] This invention relates to a pharmaceutical composition comprising a compound selected from the group consisting of erafibrano, 2-[2,6-dimethyl-4-[3-[4-(methylthio)phenyl]-3-oxo-propyl]phenoxy]-2-methylpropionic acid (GFT1007), and pharmaceutically acceptable salts of erafibrano or GFT1007, in a method of treating primary biliary cholangitis (PBC) in subjects with PBC whose baseline plasma alkaline phosphatase (ALP) levels exceed 1.67 × ULN and are at most 3 × ULN.

[0029] In one particular embodiment, the pharmaceutical composition of the present invention can be used to normalize ALP, albumin and / or bilirubin levels in subjects with PBC whose baseline plasma ALP levels exceed 1.67 × ULN and are at most 3 × ULN.

[0030] In one particular implementation, subjects with PBC have baseline plasma ALP levels exceeding 1.67 × ULN and up to 2.5 × ULN.

[0031] In another specific implementation, subjects with PBC have baseline plasma ALP levels exceeding 1.67 × ULN and up to 2 × ULN.

[0032] 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 compositions of the invention. For example, "baseline ALP plasma level" refers to the ALP plasma level of a subject prior to initiating any treatment with the compositions of the invention.

[0033] In one particular implementation, treatment results in ALP levels below 1.67 × ULN (upper limit of normal) and optionally, total bilirubin within normal limits. The reference range for total bilirubin is 0.2–1.2 mg / dL. The reference range for direct bilirubin is 0.1–0.4 mg / dL.

[0034] In a specific variant of this embodiment, the composition of the invention is administered to the subject to reduce ALP levels by at least 15%, preferably at least 40%.

[0035] In one particular embodiment, the composition of the present invention is administered to a subject to increase bile acid levels, such as chenodeoxycholic acid (CDCA), cholic acid, lithocholic acid, and deoxycholic acid (DCA).

[0036] In another embodiment, the composition of the present invention is administered to a subject to improve Paris I, Paris II, Toronto I, Toronto II, or UK-PBC risk scores.

[0037] In another embodiment, the composition of the present invention is administered to the subject to:

[0038] - Improves AST, γGT, 5'-nucleotidase, total bilirubin, conjugated bilirubin, ALT and albumin levels;

[0039] - Improve lipid parameters

[0040] - Improve C4 and / or FGF19 levels

[0041] - Improve IgM levels; and

[0042] - Improved 5D-Pruritus Scale, PBC 40 QOL, VAS.

[0043] In a particular embodiment of the invention, the subject with PBC has a baseline ALP level of more than 1.67×ULN and at most 3×ULN, a baseline AST level of less than 2×ULN, and a baseline total bilirubin (TB) level of at most 1 mg / dL.

[0044] The term "treatment" or "treating" refers to the medical treatment, prevention, or treatment of cholestatic disease in a subject in need. Treatment involves administering erafibrino, GFT1007, or a pharmaceutically acceptable salt thereof (such as by administering a pharmaceutical composition containing erafibrino) to a subject with a known disease (e.g., a patient) to prevent, cure, delay, reverse, or slow the progression of the disease, thereby improving the patient's condition. Treatment may also be administered to healthy subjects or subjects at risk of developing cholestatic disease.

[0045] The terms “patient,” “subject,” “individual,” or “participant” are interchangeable and refer to mammals, and more specifically, humans, including adults and children. Subjects to be treated according to the invention may be appropriately selected based on several indicators associated with the pathological process of cholestatic disease, such as previous and / or current treatments, related lesions, genotype, exposure to risk factors, and any other relevant biomarkers that can be assessed by any suitable immunological, biochemical, or enzymatic method. Subjects to be treated have PBC characterized as follows:

[0046] At least two of the following three diagnostic factors are present:

[0047] (i) A history of elevated ALP levels for at least 6 months prior to day 0 (random visit).

[0048] (ii) Positive anti-mitochondrial antibody (AMA) titer (>1 / 40 by immunofluorescence assay or M2 positive by enzyme-linked immunosorbent assay (ELISA)) or positive PBC-specific antinuclear antibody (ANA).

[0049] (iii) Liver biopsy consistent with PBC

[0050] - 1.67 x ULN < ALP ≤ 3 x ULN

[0051] Optionally, use UDCA for at least 12 months prior to the screening visit (stable dose for ≥6 months).

[0052] The present invention further relates to a pharmaceutical composition comprising a compound selected from the group consisting of erafibrano, GFT1007 and pharmaceutically acceptable salts of erafibrano or GFT1007, wherein the pharmaceutical composition is used in a method of reducing baseline plasma ALP levels in subjects with PBC whose baseline plasma ALP levels exceed 1.67 × ULN and are at most 3 × ULN.

[0053] In one particular implementation, subjects with PBC have baseline plasma ALP levels exceeding 1.67 × ULN and up to 2.5 × ULN.

[0054] In another specific implementation, subjects with PBC have baseline plasma ALP levels exceeding 1.67 × ULN and up to 2 × ULN.

[0055] In the context of this invention, the term "reduction of baseline plasma ALP levels in a subject" means that after 52 weeks of treatment with the composition of this invention, the subject's baseline plasma ALP level is reduced by at least 15% or the subject's ALP level is reduced to no more than 1.67 × ULN. Reducing baseline plasma ALP levels in subjects with PBC helps improve the subject's condition, particularly indicating a reduction in cholestasis.

[0056] In the context of this invention, ALP results are reported in International Units per Liter (IU / L or U / L). For men older than 18 years, the upper limit of normal (ULN) associated with ALP levels is 129 U / L. For women older than 18 years, the upper limit of normal (ULN) associated with ALP levels is 104 U / L.

[0057] In one particular 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 exceeding 1.67 × ULN and up to 3 × ULN. In another particular embodiment, the selected subjects have baseline plasma ALP levels exceeding 1.67 × ULN and up to 2.5 × ULN, or exceeding 1.67 × ULN and up to 2 × ULN.

[0058] ALP levels are tested using methods generally known in the art. An ALP test requires a blood sample from a vein.

[0059] In the context of this invention, AST results are reported in International Units per Liter (IU / L or U / L). For men older than 18 years, the upper limit of normal (ULN) associated with AST levels is 40 U / L. For women older than 18 years, the upper limit of normal (ULN) associated with AST levels is 32 U / L.

[0060] In some embodiments of the invention, GFT1007, the active metabolite of erafibrino, is used. GFT1007 is 2-[2,6-dimethyl-4-[3-[4-(methylthio)phenyl]-3-oxo-propyl]phenoxy]-2-methylpropionic acid. Its properties and synthesis are described in PCT application WO2007 / 147879, where it is referred to as compound 1.

[0061] According to the present invention, the pharmaceutical compositions of the present invention may include stereoisomers of the following: erafibrano, GFT1007, or pharmaceutically acceptable salts of erafibrano or GFT1007.

[0062] Stereoisomers are isomeric compounds that have the same molecular formula and bonding atomic sequence, but whose atoms have different three-dimensional orientations in space. Stereoisomers include enantiomers, diastereomers, cis-trans and EZ isomers, conformational isomers, and tautomers.

[0063] Erafibrano or GFT1007 can be formulated into pharmaceutically acceptable salts, particularly acid or base salts compatible with pharmaceutical applications. Salts of erafibrano or GFT1007 covered 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 during the final purification step of the compound or by incorporating the salt into a previously purified compound.

[0064] Specifically, "pharmaceutically acceptable salts" include both inorganic and organic acid salts. Counterions can be selected from the following non-exhaustive list: ammonia, L-arginine, phenethylbenzylamine, benzylamine, tert-butylamine, calcium hydroxide, choline hydroxide, tannin, diethanolamine (2,2'-iminobis(ethanol)), diethylamine, pyrrolidine (1-(2-hydroxyethyl)pyrrolidine), 2-(diethylamino)ethanol, ethanolamine (2-aminoethanol), ethylenediamine, glycine, hydrabamine, 1H-imidazole, L-lysine, magnesium hydroxide, meglumine (N-methyl-reductiloxane) Proglucosamine), 4-(2-hydroxyethyl)morpholine, piperazine, potassium hydroxide, sodium hydroxide, triethanolamine (2,2',2''-nitrotri(ethanol)), tromethamine, zinc hydroxide, especially tromethamine, potassium, sodium, phenethylamine, benzathine, L-arginine, ethanolamine, meglumine, glycine, tert-butylamine, L-lysine, pyrroleethanol, choline, preferably tromethamine, potassium, sodium, phenethylamine, benzathine, L-arginine, more preferably tromethamine, potassium, sodium, L-arginine, and more specifically tromethamine.

[0065] In certain embodiments, the present invention covers ammonia, L-arginine, phenethylbenzylamine, benzylamine, tert-butylamine (tert-butylamine), calcium, choline, tannin, diethanolamine (2,2'-iminobis(ethanol)), diethylamine, pyrrolidine (1-(2-hydroxyethyl)pyrrolidine), 2-(diethylamino)ethanol, ethanolamine (2-aminoethanol), ethylenediamine, glycine, hydrabamine, 1H-imidazole, L-lysine, magnesium, meglumine (N-methyl-reduced glucosamine), 4-(2-hydroxyethyl)morpholine, piperazine, potassium, sodium, triethanolamine (2,2',2''-nitrotri(ethanol)), tromethamine, or zinc salts. In a further specific embodiment, the salt of erafibrano or GFT1007 is selected from tromethamine, potassium, sodium, L-arginine, phenethylbenzylamine, benzylamine, ethanolamine, meglumine, glycine, tert-butylamine, L-lysine, choline, pyrrole ethanol, magnesium, or 2-amino-2-methyl-prop-1-ol salts of erafibrano or GFT1007.

[0066] In a preferred embodiment, the pharmaceutical composition of the present invention comprises erafibrano or a pharmaceutically acceptable salt thereof.

[0067] In the preferred embodiment, the pharmaceutical composition of the present invention comprises erafibrino.

[0068] The pharmaceutical compositions used in this invention may contain one or more excipients or mediators acceptable in a pharmaceutical context (e.g., physiological saline solutions, physiological solutions, isotropic solutions, etc., which are compatible with pharmaceutical uses and well known to those skilled in the art). The composition may also contain one or more reagents or mediators selected from dispersants, solubilizers, stabilizers, preservatives, etc. Reagents or mediators suitable for these formulations (liquid and / or injectable and / or solid) are particularly methylcellulose, hydroxymethylcellulose, carboxymethylcellulose, polysorbate 80, mannitol, gelatin, lactose, vegetable oils, gum arabic, liposomes, etc. Erafibrano or GFT1007 may be formulated for enteral or parenteral administration. For example, erafibrano or GFT1007 may be formulated for oral, intravascular (e.g., intravenous or intra-arterial), intramuscular, intraperitoneal, subcutaneous, transdermal, or nasal administration. The pharmaceutical compositions may be in solid or liquid dosage forms. Indicative formulations include (but are not limited to) dosage forms in the form of injectable suspensions, gels, oils, pills, tablets, suppositories, powders, gel caps, capsules, aerosols, ointments, creams, patches, or galenols for long-term and / or slow-release administration.

[0069] In a preferred embodiment, the pharmaceutical composition of the present invention is administered orally. Preferably, the composition is formulated in the form of gels, oils, pills, tablets, powders, gel capsules, capsules, and galen forms or devices to ensure prolonged and / or slow release.

[0070] In a preferred embodiment, the pharmaceutical composition of the present invention is formulated in tablets.

[0071] As used herein, the term "therapeuticly effective amount" refers to the amount of erafibrinolate or GFT1007 used to prevent, eliminate, or reduce PBC and its adverse events, particularly the amount of erafibrinolate or GFT1007 used to prevent, eliminate, or reduce PBC. Specifically, the amount of pharmaceutical salt of erafibrinolate or GFT1007 means the amount of erafibrinolate or GFT1007 in the free form of this pharmaceutical salt.

[0072] The dosage may be adjusted by those skilled in the art. Specifically, the dosage and regimen may be determined by factors such as the stage and severity of the PBC being treated, the weight, age and overall health of the subject being treated, and the physician's judgment.

[0073] In a particular embodiment, erafibrinolide, GFT1007, or a pharmaceutically acceptable salt of erafibrinolide or GFT1007 is administered at a dose of 10 mg to 200 mg, preferably 80 mg to 120 mg per dose. In another particular embodiment, erafibrinolide, GFT1007, or a pharmaceutically acceptable salt of erafibrinolide or GFT1007 is administered at a dose of 80 mg per dose. In yet another particular embodiment, erafibrinolide, GFT1007, or a pharmaceutically acceptable salt of erafibrinolide or GFT1007 is administered at a dose of 120 mg per dose.

[0074] Preferably, the pharmaceutical composition of the present invention is administered once daily, especially orally once daily.

[0075] According to one embodiment, the pharmaceutical composition is in a solid dosage form, such as a tablet. In another specific embodiment, the tablet comprises 10 mg to 200 mg of erafibrinolide, GFT1007, or a pharmaceutically acceptable salt of erafibrinolide or GFT1007, such as 80 mg to 120 mg of erafibrinolide, GFT1007, or a pharmaceutical salt of erafibrinolide or GFT1007. For example, the tablet may contain 80 mg of erafibrinolide or GFT1007, or a pharmaceutical salt of erafibrinolide or GFT1007, or 120 mg of erafibrinolide or GFT1007, or a pharmaceutical salt of erafibrinolide or GFT1007.

[0076] In another embodiment, tablets containing 80 mg of erafibrano or GFT1007 are administered orally once daily.

[0077] In another embodiment, a tablet containing 120 mg of erafibrano or GFT1007 is administered orally once daily.

[0078] As used herein, the terms “patient,” “subject,” or “individual” are used interchangeably and refer to humans, including adults and children. In the context of this invention, the patient suffers from PBC.

[0079] In one implementation, the patient has PBC and responds at least partially to ursodeoxycholic acid (UDCA). In another implementation, the subject with PBC responds poorly to ursodeoxycholic acid (UDCA).

[0080] In a particular embodiment, the present invention relates to the use of a pharmaceutical composition comprising a compound selected from erafibrano, GFT1007, and pharmaceutically acceptable salts of erafibrano or GFT1007, and at least one other therapeutically active agent, in a method of treating a subject with primary biliary cholangitis (PBC) whose baseline alkaline phosphatase (ALP) level exceeds 1.67 × ULN and is at most 3 × ULN and who is inadequately responsive to ursodeoxycholic acid. The other active agent may be particularly selected from other antichostatic agents, such as UDCA or OCA. Therefore, the invention also relates to a combination of the pharmaceutical composition of the invention with UDCA or OCA (preferably UDCA). Specifically, the method comprises administering ursodeoxycholic acid (UDCA) and 80 mg of erafibrano to a subject in need, each dose. More specifically, the method comprises administering ursodeoxycholic acid (UDCA) and erafibrinolate at a dose of 80 mg per administration to a subject with primary biliary cholangitis (PBC) and an inadequate response to ursodeoxycholic acid. Even more specifically, the method comprises administering erafibrinolate at a dose of 80 mg / day and UDCA at a dose of 13-15 mg / kg / day to a subject with PBC and an inadequate response to ursodeoxycholic acid. Example

[0081] NCT04526665 Clinical Trial (ELATIVE®)

[0082] Participants were aged 18 to 75 years and diagnosed with primary biliary cholangitis according to established criteria. Recruitment was conducted at 82 sites in 14 countries. Inclusion criteria were alkaline phosphatase levels ≥1.67 × upper limit of normal (ULN) and total bilirubin levels ≤2 × ULN. Prior to screening, eligible participants had received ursodeoxycholic acid at 13 to 15 mg / kg daily for at least 12 months (at least 3 months at a stable dose) or were intolerant to ursodeoxycholic acid (untreated for at least 3 months).

[0083] In this double-blind, placebo-controlled, phase 3 trial, participants who were inadequately responsive to or intolerant of ursodeoxycholic acid (URC) were randomized 2:1 to receive 80 mg erafibrinolate once daily or placebo. Participants who had been on a stable dose of URC for at least three months prior to enrollment continued their treatment regimen throughout the trial. The total double-blind treatment period consisted of two parts. In Part 1, all randomized participants received double-blind treatment for at least 52 weeks. In Part 2, participants continued double-blind treatment for a variable period after week 52 until all participants completed their week 52 assessment or up to the maximum treatment duration of week 104, whichever came first. The first database lockout occurred after the last participant completed their week 52 visit during their double-blind period. At the end of the double-blind period (lasting 52 to 104 weeks), participants were eligible for an open-label extension, in which they would receive 80 mg erafibrinolate for up to five years.

[0084] The primary endpoint of the NCT04526665 study was the response to treatment in the intention-to-treat population at week 52, defined as ALP < 1.67 × ULN, TB ≤ ULN, and a decrease in ALP ≥ 15% relative to baseline. Primary endpoints were also analyzed based on baseline alkaline phosphatase levels ≤ 3 × ULN and > 3 × ULN.

[0085] From September 2020 to May 2023, 161 participants were randomly assigned to receive 80 mg errafibrano (108 participants) or placebo (53 participants); these participants constituted the intention-to-treat (ITT) and safety population.

[0086] According to the eligibility criteria, all participants had ALP levels ≥1.67×ULN during the screening period. At baseline, 96.3% of participants had ALP levels ≥1.67×ULN (97.2% in the erafibrino 80 mg group and 94.3% in the placebo group), and 39.1% of participants had ALP levels >3×ULN (39.8% in the erafibrino 80 mg group and 37.7% in the placebo group).

[0087] All participants' reactions

[0088] In patients receiving erafibrinolate and placebo, 15% and 0% of patients, respectively, had completely normalized alkaline phosphatase levels at week 52 (difference, 15%; odds ratio, infinity; 95% CI, 2.8 to infinity; p = 0.0019) (see [link to relevant documentation]). Figure 1 ).

[0089] A rapid decrease in alkaline phosphatase levels was observed in the erafibrino group from baseline to week 4, and remained at significantly lower levels than in the placebo group until week 52 (see [link to study]). Figure 2 ).

[0090] Response at week 52 of participants with baseline ALP levels ≤3×ULN or >3×ULN

[0091] Among participants receiving erafibrinolubrano with baseline alkaline phosphatase levels ≤3×ULN (65 participants) and >3×ULN (43 participants), 70.8% and 20.9%, respectively, met the primary endpoint. In contrast, among participants in the placebo group with baseline alkaline phosphatase levels ≤3×ULN (33 patients) or >3×ULN (20 patients), 6.1% and 0%, respectively, met the primary endpoint. Among patients receiving erafibrinolubrano ...

[0092] Table 1: ALP response in subgroups at week 52 (ITT analysis set)

[0093]

[0094] Therefore, participants with higher baseline ALP values ​​(>3×ULN) had a lower rate of cholestasis response (20.9%; no response on placebo) compared to participants with lower baseline ALP values ​​(≤3 ×ULN) (70.8% vs. 6.1%). Erafibrano has been shown to be effective in treating primary biliary cholangitis (PBC) in subjects with baseline plasma alkaline phosphatase (ALP) levels exceeding 1.67 ×ULN and up to 3 ×ULN.

[0095] Response of participants with baseline ALP <3×ULN, AST <2×ULN, and TB ≤1 mg / dL (Paris I)

[0096] Table 2: Percentage of patients who responded to treatment according to the Paris I criteria at week 52 (ITT analysis set)

[0097]

[0098] Using the ITT analysis set, a greater proportion of participants treated with erafibrino showed a response to treatment compared to those receiving placebo, based on ALP <3×ULN, AST <2×ULN, and TB ≤1 mg / dL at week 52 (Paris I). 73 / 106 (68.9%) of participants in the erafibrino group showed a response compared to 25 / 53 (47.2%) in the placebo group, resulting in a 22.0% difference (95% CI: 5.7; 37.4); the response odds ratio (erafibrino vs. placebo) was 2.852 ([95% CI: 1.339; 7.181]; p = 0.0061) (Table 2).

[0099] Participants with baseline ALP levels ≤2, 2-≤2.5, 2.5-≤3, 3-≤4, and >4×ULN responded at week 52.

[0100] Figure 3 This shows the percentage of participants who received erafibrinolate and had a biochemical response at week 52, graded according to baseline ALP levels. A biochemical response (the primary endpoint) was defined as ALP <1.67 × ULN with a reduction of ≥15% from baseline; and normal TB.

[0101] Figure 4 This shows the percentage of participants who received erafibrino and whose ALP levels were normalized at week 52, based on baseline ALP level classification.

[0102] Figure 5 This shows the average percentage change in ALP from baseline to week 52, categorized according to baseline ALP levels.

[0103] Figures 3 to 5 The study showed that participants with lower baseline ALP levels (≤3×ULN) who received erafibrinologne had higher biochemical responses and ALP normalization rates compared to participants with higher baseline ALP levels.

[0104] Specifically:

[0105] - Figure 3 The study showed that over 80% of participants who received erafibrinolubrano had a biochemical response at week 52, with baseline ALP levels between 1.67×ULN and up to 2.5×ULN.

[0106] - Figure 3 It also showed that over 50% of participants receiving erafibrinolu ...

[0107] - Figure 4Participants who received erafibrinologine showed that ALP normalization occurred at least four times more frequently than in other participants with baseline ALP levels between 1.67 × ULN and 2 × ULN.

Claims

1. A pharmaceutical composition comprising a compound selected from the group consisting of erafibrano, 2-[2,6-dimethyl-4-[3-[4-(methylthio)phenyl]-3-oxo-propyl]phenoxy]-2-methylpropionic acid (GFT1007), and pharmaceutically acceptable salts of erafibrano or GFT1007, wherein the pharmaceutical composition is used to treat a subject with primary biliary cholangitis (PBC) whose baseline plasma alkaline phosphatase (ALP) level is greater than 1.67 × ULN and at most 3 × ULN.

2. A pharmaceutical composition comprising a compound selected from the group consisting of erafibrano, GFT1007 and pharmaceutically acceptable salts of erafibrano or GFT1007, the pharmaceutical composition being used in a method of reducing baseline plasma ALP levels in subjects with PBC whose baseline plasma ALP levels exceed 1.67 × ULN and are at most 3 × ULN.

3. The pharmaceutical composition used as described in any one of claims 1 to 2, wherein the composition comprises erafibrano or a pharmaceutically acceptable salt thereof.

4. The pharmaceutical composition used as described in any one of claims 1 to 3, wherein the composition comprises erafibrino.

5. The pharmaceutical composition used as described in any one of claims 1 to 4, wherein the composition is formulated in a form selected from the group consisting of gels, oils, pills, tablets, powders, gel capsules, capsules, and galen forms or devices to ensure long-term and / or slow release.

6. The pharmaceutical composition used as described in any one of claims 1 to 5, wherein the composition is formulated into tablet form.

7. The pharmaceutical composition used as described in any one of claims 1 to 6, wherein the erafibrano is administered once daily.

8. The pharmaceutical composition used as described in any one of claims 1 to 7, wherein the administration is oral.

9. The pharmaceutical composition used as described in any one of claims 1 to 8, wherein the dosage is 80 mg or 120 mg per administration.

10. The pharmaceutical composition used as described in any one of claims 1 to 9, wherein erafibrano is administered at a dose of 80 mg per administration.

11. The pharmaceutical composition used as described in any one of claims 1 to 10, wherein a subject with PBC whose baseline alkaline phosphatase (ALP) level exceeds 1.67 × ULN and is at most 3 × ULN has an inadequate response to ursodeoxycholic acid (UDCA).

12. The pharmaceutical composition used as described in any one of claims 1 to 11, wherein the method comprises further administering to a subject in need another antichostatic agent, preferably ursodeoxycholic acid (UDCA).

13. The pharmaceutical composition used as described in any one of claims 1 to 12, wherein the method comprises administering an 80 mg dose of erafibrano and ursodeoxycholic acid (UDCA) to a subject in need.

14. The pharmaceutical composition used as described in any one of claims 1 to 13, wherein the method comprises administering an 80 mg dose of erafibrano and ursodeoxycholic acid (UDCA) to a subject with primary biliary cholangitis (PBC) whose baseline alkaline phosphatase (ALP) level exceeds 1.67 × ULN and is at most 3 × ULN and who is inadequately responsive to ursodeoxycholic acid.

15. Use of a pharmaceutical composition for manufacturing a medicament comprising a compound selected from the group consisting of erafibrano, GFT1007 and pharmaceutically acceptable salts of erafibrano or GFT1007, for treating a subject with primary biliary cholangitis (PBC) having a baseline plasma ALP level greater than 1.67 × ULN and at most 3 × ULN.

16. Use of a pharmaceutical composition for manufacturing a medicament comprising a compound selected from the group consisting of erafibrano, GFT1007 and pharmaceutically acceptable salts of erafibrano or GFT1007, in a method for reducing baseline plasma ALP levels in subjects with PBC who have baseline plasma ALP levels exceeding 1.67 × ULN and at most 3 × ULN.

17. A method for treating a subject with primary biliary cholangitis (PBC) whose baseline plasma alkaline phosphatase (ALP) level exceeds 1.67 × ULN and is at most 3 × ULN, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a compound selected from the group consisting of erafibrano, GFT1007, and pharmaceutically acceptable salts of erafibrano or GFT1007.

18. A method for reducing baseline plasma ALP levels in a subject with PBC whose baseline plasma ALP levels exceed 1.67 × ULN and are at most 3 × ULN, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a compound selected from the group consisting of erafibrano, GFT1007, and pharmaceutically acceptable salts of erafibrano or GFT1007.

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