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WO2025215081A1 - Élafibranor pour le traitement à long terme de la cholangite biliaire primitive - Google Patents

Élafibranor pour le traitement à long terme de la cholangite biliaire primitive

Info

Publication number
WO2025215081A1
WO2025215081A1 PCT/EP2025/059717 EP2025059717W WO2025215081A1 WO 2025215081 A1 WO2025215081 A1 WO 2025215081A1 EP 2025059717 W EP2025059717 W EP 2025059717W WO 2025215081 A1 WO2025215081 A1 WO 2025215081A1
Authority
WO
WIPO (PCT)
Prior art keywords
weeks
elafibranor
pharmaceutical composition
pbc
gft1007
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/EP2025/059717
Other languages
English (en)
Inventor
Pascal BIRMAN
Alice Roudot
David MAGREZ
Philippe Motte
Benjamin Miller
Jianfen Shu
Marwan SLEIMAN
Nathan TOUATI
Nuno ANTUNES
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Ipsen Pharma SAS
Genfit SA
Original Assignee
Ipsen Pharma SAS
Genfit SA
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Ipsen Pharma SAS, Genfit SA filed Critical Ipsen Pharma SAS
Publication of WO2025215081A1 publication Critical patent/WO2025215081A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics

Definitions

  • the present invention relates to the field of medicine, in particular the long-term treatment of cholestatic diseases, and more specifically PBC.
  • PBC Primary biliary cholangitis
  • autoimmune etiology characterized by injury of the intrahepatic bile ducts that, in untreated patients, may progress to hepatic fibrosis, cirrhosis, hepatic decompensation, and death unless patients receive a liver transplant.
  • PBC disproportionately affects women vs men (approximately 10:1) and is typically diagnosed in patients between 40 years to 60 years of age. In Europe, North America, Asia, and Australia, the incidence and prevalence rates of PBC are reported as ranging from 0.33 to 5.8 per 100,000 inhabitants and 1.91 to 40.2 per 100,000 inhabitants, respectively.
  • PBC represents one of the leading indications for liver transplantation. Despite its rarity, PBC remains therefore an important cause of morbidity in the Western world. PBC has also been identified as an important risk factor for hepatocellular carcinoma.
  • PBC is characterized by cholestasis caused by autoimmune destruction of biliary ductules with progressive impairment of bile flow in the liver. This results in increased hepatocellular bile acid concentrations which are toxic to the liver. Such hepatocellular injury is associated with a local inflammatory response resulting early on in an abnormal elevation of serum alkaline phosphatase (ALP) levels. Therefore, biologically, PBC is manifested by an elevation of ALP levels of more than 1.5 times the upper limit of normal (ULN).
  • ALP levels are generally associated with disease progression. Indeed, elevations in ALP level are associated with a risk of liver transplantation or death that is 2.0 to 2.5 times higher than the risk associated with normal levels.
  • ALP >2x ULN is associated with a 2.2x greater risk for liver transplant or death at 1 year compared to those who remained ⁇ 2x ULN (P ⁇ 0001) (Lammers WJ et al., Gastroenterology, 2014;147(6):1338).
  • An abnormally elevated bilirubin level, which occurs later in disease progression, is also a strong predictor of outcomes, with a risk of liver transplantation or death that was 5.1 to 10.7 times the risk associated with normal levels.
  • ursodeoxycholic acid LIDCA
  • Ocaliva® obeticholic acid
  • LIDCA Urinodeoxycholic acid
  • ALP has been shown to remain elevated in up to 70% of patients who are currently being treated or are intolerant to UDCA (Lammers WJ, et al. Gastroenterology, 2014; 147(6):1338-1349.). Such patients remain at risk of disease progression and longer term adverse clinical outcomes.
  • 44% of UDCA-treated patients are progressing to liver transplant or death over 15 years.
  • Obeticholic acid (OCA) (Ocaliva ®), which has been shown to reduce ALP, has been recently approved in several countries as second line therapy for the treatment of PBC as monotherapy in adults unable to tolerate UDCA or in combination with UDCA in adults with an inadequate response to UDCA.
  • a decrease in ALP levels is recognized as a particularly relevant surrogate marker for the treatment of PBC, and was recently used as the basis for conditional market approval of OCA in this indication.
  • Elafibranor (2-(2,6-dimethyl-4- ⁇ 3-[4-(methylsulfanyl)phenyl]-3-oxopropen-1-yl ⁇ phenoxy)-2- methylpropanoic acid) was evaluated in a phase 3 study for the treatment of PBC (ELATIVE®).
  • the results of phase 3 on PBC show that the mean relative change (%) from baseline to endpoint in serum ALP was -48.3% for the elafibranor 80 mg treatment group, and 3.2% for placebo.
  • the treatment with elafibranor resulted in a consistent, statistically significant reduction in plasma ALP levels from baseline when compared to placebo.
  • elafibranor is safe and well-tolerated by the patients.
  • a phase 3 clinical study has surprisingly shown that the treatment of participants with 2-(2,6- dimethyl-4- ⁇ 3-[4-(methylsulfanyl)phenyl]-3-oxoprop-1-en-1-yl ⁇ phenoxy)-2-methylpropanoic acid (elafibranor, formerly called GFT505) (80 mg daily) provides a better efficacy after 78 weeks of treatment, than after 52 weeks of treatment: mean change from baseline to Week 78 in ALP plasma level was -135.3 ll/L in participants receiving elafibranor, compared with -117.7 ll/L from baseline to Week 52; mean change from baseline to Week 156 in ALP plasma level was -169.2 U/L in participants receiving elafibranor, compared with -119.6 U/L from baseline to Week 52; mean change from baseline to Week 78 in total bilirubin plasma level was -1 .2 pmol/L in participants receiving elafibranor, compared with
  • the invention further relates to a method for long-term treatment of primary biliary cholangitis (PBC) in a subject having PBC, comprising the administration of a therapeutic effective amount of a pharmaceutical composition comprising a compound selected from the group consisting of elafibranor, 2-[2,6-dimethyl-4-[3-[4-(methylthio)phenyl]-3-oxo-propyl]phenoxy]-2- methylpropanoic acid (GFT1007), and a pharmaceutically acceptable salt of elafibranor or GFT1007, in said subject, for at least 70 weeks, preferably at least 78 weeks, preferably at least 104 weeks, more preferably at least 130 weeks, even more preferably 156 weeks.
  • the administration is a daily administration.
  • the invention further relates to the use of a pharmaceutical composition
  • a pharmaceutical composition comprising a compound selected from the group consisting of elafibranor, 2-[2,6-dimethyl-4-[3-[4- (methylthio)phenyl]-3-oxo-propyl]phenoxy]-2-methylpropanoic acid (GFT1007), and a pharmaceutically acceptable salt of elafibranor or GFT1007, for the manufacture of a medicament for the long-term treatment of primary biliary cholangitis (PBC) in a subject having PBC, for at least 70 weeks, preferably at least 78 weeks, preferably at least 104 weeks, more preferably at least 130 weeks, even more preferably 156 weeks.
  • PBC primary biliary cholangitis
  • the invention further relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound selected from elafibranor, 2-[2,6-dimethyl-4-[3-[4-(methylthio)phenyl]-3-oxo-propyl]phenoxy]-2- methylpropanoic acid (GFT1007), and a pharmaceutically acceptable salt of elafibranor or GFT1007, for use in a method for reducing fatigue during at least 70 weeks in a subject having primary biliary cholangitis (PBC).
  • PBC primary biliary cholangitis
  • the invention further relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound selected from elafibranor, 2-[2,6-dimethyl-4-[3-[4-(methylthio)phenyl]-3-oxo-propyl]phenoxy]-2- methylpropanoic acid (GFT1007), and a pharmaceutically acceptable salt of elafibranor or GFT1007, for use in a method for long-term treatment of pruritus in a subject having primary biliary cholangitis (PBC), wherein said pharmaceutical composition is administered daily for at least 70 weeks.
  • PBC primary biliary cholangitis
  • the invention further relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound selected from elafibranor, 2-[2,6-dimethyl-4-[3-[4-(methylthio)phenyl]-3-oxo-propyl]phenoxy]-2- methylpropanoic acid (GFT1007), and a pharmaceutically acceptable salt of elafibranor or GFT1007, for use in a method for reducing fatigue during at least 78 weeks, preferably at least 104 weeks, more preferably at least 130 weeks, even more preferably at least 156 weeks in a subject having primary biliary cholangitis (PBC).
  • PBC primary biliary cholangitis
  • the invention further relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound selected from elafibranor, 2-[2,6-dimethyl-4-[3-[4-(methylthio)phenyl]-3-oxo-propyl]phenoxy]-2- methylpropanoic acid (GFT1007), and a pharmaceutically acceptable salt of elafibranor or GFT1007, for use in a method for long-term treatment of pruritus in a subject having primary biliary cholangitis (PBC), wherein said pharmaceutical composition is administered daily for at least 78 weeks, preferably at least 104 weeks, more preferably at least 130 weeks, even more preferably at least 156 weeks.
  • PBC primary biliary cholangitis
  • Figure 1 a Mean change from baseline to Week 78 in the cholestasis response.
  • Figure 1 shows the proportion of patients with cholestasis response. A rapid improvement is observed from baseline through Week 4 in the elafibranor group (ELA), at levels significantly higher than the placebo group through Week 78.
  • ELA elafibranor group
  • Figure 1b Mean change from baseline to Week 156 in the cholestasis response.
  • Figure 1b shows the proportion of patients with cholestasis response in the OLE study. This figure shows the improvement from baseline in the elafibranor group (ELA) through Week 156.
  • ELA elafibranor group
  • Figure 2a Mean change from baseline to Week 78 in ALP plasma level.
  • Figure 2 shows rapid reductions in alkaline phosphatase (ALP) levels (U/L) observed from baseline through Week 4 in the elafibranor group (Ela), and sustained at levels significantly lower than the placebo group through Week 78.
  • ALP alkaline phosphatase
  • Figure 2b Mean change from baseline to Week 156 in ALP plasma level.
  • Figure 2a shows reductions in alkaline phosphatase (ALP) levels (U/L) observed from baseline in the OLE study. This figure shows the improvement from baseline in the elafibranor group (ELA) through Week 156.
  • ALP alkaline phosphatase
  • Figure 3a Mean change from baseline to Week 78 in yGT plasma level.
  • Figure 3a shows rapid reductions in yGT (gamma-glutamyl transferase) levels (U/L) observed from baseline through Week 4 in the elafibranor group (Ela), and sustained at levels significantly lower than the placebo group through Week 78.
  • yGT gamma-glutamyl transferase
  • Figure 3b Mean change from baseline to Week 156 in yGT plasma level.
  • Figure 3b shows reductions in yGT (gamma-glutamyl transferase) levels (U/L) observed from baseline in the OLE study. This figure shows the improvement from baseline in the elafibranor group (ELA) through Week 156.
  • ELA elafibranor group
  • Figure 4a Mean change from baseline to Week 78 in total bilirubin plasma level.
  • Figure 4 shows rapid reductions in total bilirubin levels (pmol/L) observed from baseline through Week 4 in the elafibranor group (ELA), and sustained at levels significantly lower than the placebo group through Week 78.
  • Figure 4b Mean change from baseline to Week 156 in total bilirubin plasma level.
  • Figure 4b shows reductions in total bilirubin levels (pmol/L) observed from baseline in the OLE study. This figure shows the improvement from baseline in the elafibranor group (ELA) through Week
  • Figure 5a Mean change from baseline to Week 78 in 5-D itch total score.
  • Figure 5a shows rapid reductions observed from baseline through Week 4 in the elafibranor group (ELA), and sustained at levels significantly lower than the placebo group through Week 78.
  • Figure 5b Mean change from baseline to Week 156 in 5-D itch total score.
  • Figure 5b shows rapid reductions observed from baseline through Week 156 in the elafibranor group (ELA) in the OLE study.
  • ELA elafibranor group
  • Figure 5c Mean change from baseline to Week 156 in WI-NRS (Worst Itch Numeric Rating Scale) score.
  • Figure 5c shows reductions in the elafibranor group (ELA) through Week 156.
  • Figure 5d Mean change from baseline to Week 156 in PBC-40 itch score.
  • Figure 5d shows rapid and constant reduction observed from baseline through Week 156 in the elafibranor group (ELA) in the OLE study.
  • ELA elafibranor group
  • Figure 6 Mean change from baseline to Week 78 in Promis Fatigue T-score.
  • Figure 6 shows rapid reductions observed from baseline through Week 4 in the elafibranor group (ELA), and sustained at levels significantly lower than the placebo group through Week 78.
  • ELA elafibranor group
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound selected from the group consisting of elafibranor, 2-[2,6-dimethyl-4-[3-[4-(methylthio)phenyl]- 3-oxo-propyl]phenoxy]-2-methylpropanoic acid (GFT1007), and a pharmaceutically acceptable salt of elafibranor or GFT1007, for use in a method for long-term treatment of primary biliary cholangitis (PBC) in a subject having PBC, wherein said pharmaceutical composition is administered daily for at least 70 weeks.
  • said pharmaceutical composition is administered daily for at least 78 weeks, preferably at least 104 weeks, more preferably at least 130 weeks, even more preferably at least 156 weeks.
  • treatment refers to therapy, prevention, or prophylaxis of a cholestatic disease in a subject in need thereof.
  • the treatment involves the administration of elafibranor, GFT1007 or a pharmaceutically acceptable salt thereof (such as via the administration of a pharmaceutical composition comprising elafibranor) to a subject (e.g. a patient) having a declared disease to prevent, cure, delay, reverse, or slow down the progression of the disease, improving thereby the condition of patients.
  • a treatment may be also administered to subjects that are either healthy or at risk of developing a cholestatic disease.
  • treatment of PBC or the like is mentioned with reference to the pharmaceutical composition of the invention, there is meant: a) a method for treating PBC, said method comprising administering an effective amount of the pharmaceutical composition of the invention to a subject in need of such treatment; b) the use of a pharmaceutical composition of the invention for the treatment of PBC; c) the use of a pharmaceutical composition of the invention for the manufacture of a medicament for the treatment of PBC; and/or d) a pharmaceutical composition of the invention for use in a method for treating of PBC.
  • treatment of PBC or “treating PBC” includes an improvement or normalization of:
  • AST aspartate aminotransferase
  • 5’-nucleotidase conjugated bilirubin
  • ALT aslanine aminotransferase
  • albumin levels and/or
  • IgM immunoglobulin M
  • long-term treatment refers to a treatment as defined above in which the therapy, prevention, or prophylaxis of the cholestatic disease, in particular PBC, in the subject in need thereof, lasts for at least 70 weeks, preferably at least 78 weeks, preferably at least 104 weeks, more preferably at least 130 weeks, even more preferably at least 156 weeks. This means that the treatment is able to be effective for a period of at least 70 weeks, preferably at least 78 weeks, preferably at least 104 weeks, more preferably at least 130 weeks, even more preferably at least 156 weeks.
  • the long-term treatment is obtained by administering elafibranor, GFT1007 or a pharmaceutically acceptable salt thereof during at least 70 weeks, preferably 78 weeks, preferably at least 78 weeks, preferably at least 104 weeks, more preferably at least 130 weeks, even more preferably at least 156 weeks.
  • the administration is preferably a daily administration (once a day).
  • Cholestasis or cholestatic disease is defined as a decrease in bile flow due to impaired secretion by hepatocytes (hepato-cellular cholestasis) or to obstruction of bile flow through intra- or extrahepatic bile ducts (obstructive cholestasis).
  • cholestasis is any condition in which the flow of bile from the liver is slowed or blocked.
  • cholestatic diseases are Primary Biliary Cholangitis (PBC), Primary Sclerosing Cholangitis (PSC), Intrahepatic Cholestasis of Pregnancy (ICP), Progressive Familial Intrahepatic Cholestasis (PFIC), Biliary atresia, Cholelithiasis, Infectious Cholangitis, Cholangitis associated with Langerhans cell histiocytosis, Alagille syndrome, Nonsyndromic ductal paucity, Drug-induced cholestasis, Total parenteral nutrition (TPN)-associated cholestasis.
  • PBC Primary Biliary Cholangitis
  • PSC Primary Sclerosing Cholangitis
  • ICP Intrahepatic Cholestasis of Pregnancy
  • PFIC Progressive Familial Intrahepatic Cholestasis
  • Biliary atresia Cholelithiasis
  • Infectious Cholangitis Cholangitis associated with Langerhan
  • the subject to be treated has PBC.
  • PBC is characterized by changes in many blood biochemical parameters. Patients’ sera show the enhanced activity of alkaline phosphatase (ALP), y-glutamyltransferase (gamma glutamyltranspeptidase, y-GT), 5’- nucleotidase (5’-NT), and leucineaminopeptidase (LAP), the higher levels of bile acids, cholesterol, phospholipids, copper, y-globulins, and bilirubin, and the lower level of total protein mainly at the expense of albumin fractions.
  • ALP alkaline phosphatase
  • y-glutamyltransferase gamma glutamyltranspeptidase, y-GT
  • 5’-NT nucleotidase
  • LAP leucineaminopeptidase
  • the term “patient”, “subject” or “individual” are interchangeable and refer to a mammal and more particularly a human including adult and child.
  • the patient is suffering from PBC.
  • the subjects to be treated according to the invention can be appropriately selected on the basis of several criteria associated with cholestatic pathological processes such as previous and/or present drug treatments, associated pathologies, genotype, exposure to risk factors, as well as any other relevant biomarker that can be evaluated by means of any suitable immunological, biochemical, or enzymatic method.
  • the subject to be treated is with PBC, typically as characterized as follows:
  • AMA Anti-Mitochondrial Antibodies
  • ELISA enzyme-linked immunosorbent assay
  • ALP > 1.67x upper limit of normal (ULN) - optionally, taking LIDCA for at least 12 months (stable dose for > 6 months) prior to screening visit.
  • the patient has PBC and responds at least partly to LIDCA. In another embodiment, the patient has PBC and does not respond adequately to LIDCA.
  • the pharmaceutical composition of the invention can be used for reducing or normalizing ALP plasma level(s) in a subject having PBC for at least 70 weeks, preferably 78 weeks, preferably at least 78 weeks, preferably at least 104 weeks, more preferably at least 130 weeks, even more preferably at least 156 weeks.
  • the pharmaceutical composition of the invention can be used for reducing or normalizing ALP plasma level(s) in a subject having PBC after at least 70 weeks, preferably 78 weeks, preferably at least 78 weeks, preferably at least 104 weeks, more preferably at least 130 weeks, even more preferably at least 156 weeks of administration, in particular of daily administration.
  • the pharmaceutical composition of the invention can be used for reducing or normalizing ALP, albumin and/or bilirubin level(s) in a subject having PBC for at least 70 weeks, preferably 78 weeks, preferably at least 78 weeks, preferably at least 104 weeks, more preferably at least 130 weeks, even more preferably at least 156 weeks.
  • the pharmaceutical composition of the invention can be used for reducing or normalizing ALP, albumin and/or bilirubin level(s) in a subject having PBC after at least 70 weeks, preferably 78 weeks, preferably at least 78 weeks, preferably at least 104 weeks, more preferably at least 130 weeks, even more preferably at least 156 weeks of administration, in particular of daily administration.
  • the long-term treatment results in a level of ALP lower than 1.67 x ULN (upper limit of normal) for at least 70 weeks, preferably 78 weeks, preferably at least 78 weeks, preferably at least 104 weeks, more preferably at least 130 weeks, even more preferably at least 156 weeks.
  • the long-term treatment results in a level of ALP lower than 1.67 x ULN (upper limit of normal) after at least 70 weeks, preferably 78 weeks, preferably at least 78 weeks, preferably at least 104 weeks, more preferably at least 130 weeks, even more preferably at least 156 weeks of administration, in particular of daily administration.
  • the composition of the invention is administered to the subject once a day during at least 70 weeks, for reducing baseline plasma ALP level by at least 15%, preferably by at least 35 %, more preferably by at least 37 %, even more preferably by at least 45 %.
  • the composition of the invention is administered to the subject once a day during at least 78 weeks, for reducing baseline plasma ALP level by at least 15%, preferably by at least 35 %, more preferably by at least 37 %.
  • composition of the invention is administered to the subject once a day during at least 78 weeks, preferably at least 104 weeks, more preferably at least 130 weeks, even more preferably at least 156 weeks, for reducing baseline plasma ALP level by at least 15%, preferably by at least 35 %, more preferably by at least 37 %, even more preferably by at least 45 %.
  • the pharmaceutical composition of the invention is preferably for use for reducing plasma ALP level in a subject having PBC by at least 15%, preferably by at least 35 %, more preferably by at least 37 %, even more preferably by at least 45 % after at least 70 weeks, in particular after at least 78 weeks, in particular after at least 104 weeks, more particularly after at least 130 weeks, even more particularly after at least 156 weeks of administration.
  • ALP results are reported in international units per liter (I U/L or U/L).
  • I U/L or U/L international units per liter
  • U/L international units per liter
  • UPN upper limit of normal
  • the long-term treatment further results in a level of total bilirubin within normal limit for at least 70 weeks, preferably 78 weeks, preferably at least 78 weeks, preferably at least 104 weeks, more preferably at least 130 weeks, even more preferably at 156 weeks.
  • the reference range of total bilirubin is 0.2-1.2 mg/dL.
  • the reference range of direct bilirubin is 0.1-0.4 mg/dL.
  • the long-term treatment further results in a level of total bilirubin within normal limit after at least 70 weeks, preferably 78 weeks, preferably at least 78 weeks, preferably at least 104 weeks, more preferably at least 130 weeks, even more preferably at 156 weeks of administration, in particular of daily administration.
  • the reference range of total bilirubin is 0.1-1.2 mg/dL (1.71 to 20.5 pmol/L).
  • the composition of the invention is administered to the subject once a day during at least 70 weeks, for reducing baseline total bilirubin level by at least 5%, preferably by at least 6 %, more preferably by at least 7 %, more preferably by at least 8 %, even more preferably by at least 10 %.
  • the composition of the invention is administered to the subject once a day during at least 78 weeks, for reducing baseline plasma total bilirubin level by at least 5%, preferably by at least 6 %, more preferably by at least 7 %.
  • the composition of the invention is administered to the subject once a day during at least 104 weeks, more preferably at least 130 weeks, even more preferably at least 156 weeks, for reducing baseline plasma total bilirubin level by at least 5%, preferably by at least 6 %, more preferably by at least 7 %, more preferably by at least 8 %, even more preferably by at least 10 %.
  • the pharmaceutical composition of the invention is preferably for use for reducing plasma total bilirubin level in a subject having PBC by at least 5 % after at least 70 weeks, preferably after at least 78 weeks, preferably after at least 104 weeks, more preferably after at least 130 weeks, even more preferably after at least 156 weeks of administration.
  • the long-term treatment further results in a level of y-GT within normal limit for at least 70 weeks, preferably 78 weeks, preferably at least 78 weeks, preferably at least 104 weeks, more preferably at least 130 weeks, even more preferably at 156 weeks.
  • the common reference range for adults is 5 to 40 ll/L.
  • the long-term treatment further results in a level of y-GT within normal limit after at least 70 weeks, preferably 78 weeks, preferably at least 78 weeks, preferably at least 104 weeks, more preferably at least 130 weeks, even more preferably at 156 weeks of administration, in particular of daily administration.
  • the composition of the invention is administered to the subject once a day during at least 70 weeks, for reducing baseline y-GT level by at least 20 %, preferably by at least 22%, more preferably by at least 25 %, more preferably by at least 30 %, even more preferably by at least 35 %.
  • the composition of the invention is administered to the subject once a day during at least 78 weeks, for reducing baseline plasma y-GT level by at least 20 %, preferably by at least 22%, more preferably by at least 25 %, more preferably by at least 30 %, even more preferably by at least 35 %.
  • the composition of the invention is administered to the subject once a day during at least 104 weeks, preferably at least 130 weeks, more preferably at least 156 weeks, for reducing baseline plasma y-GT level by at least 20 %, preferably by at least 22%, more preferably by at least 25 %, more preferably by at least 30 %, even more preferably by at least 35 %.
  • the pharmaceutical composition of the invention is preferably for use for reducing plasma y-GT level in a subject having PBC by at least 20 %, preferably by at least 22%, more preferably by at least 25 %, more preferably by at least 30 %, even more preferably by at least 35 %, after at least 70 weeks, preferably after at least 78 weeks, preferably after at least 104 weeks, more preferably after at least 130 weeks, even more preferably after at least 156 weeks, of administration.
  • the long-term treatment further results in improving bile acids level such as chenodeoxycholic acid (CDCA), cholic acid, litocholic acid and deoxycholic acid (DCA) levels, for at least 70 weeks, preferably 78 weeks, preferably at least 78 weeks, preferably after at least 104 weeks, more preferably after at least 130 weeks, even more preferably 156 weeks.
  • bile acids level such as chenodeoxycholic acid (CDCA), cholic acid, litocholic acid and deoxycholic acid (DCA) levels
  • the long-term treatment further results in improving bile acids level such as chenodeoxycholic acid (CDCA), cholic acid, litocholic acid and deoxycholic acid (DCA) levels, after at least 70 weeks, preferably 78 weeks, preferably at least 78 weeks, preferably after at least 104 weeks, more preferably after at least 130 weeks, even more preferably 156 weeks of administration, in particular of daily administration.
  • bile acids level such as chenodeoxycholic acid (CDCA), cholic acid, litocholic acid and deoxycholic acid (DCA) levels
  • the composition of the invention is administered to the subject once a day during at least 70 weeks, preferably 78 weeks, preferably at least 78 weeks, preferably after at least 104 weeks, more preferably after at least 130 weeks, even more preferably 156 weeks for improving bile acids level such as chenodeoxycholic acid (CDCA), cholic acid, litocholic acid and deoxycholic acid (DCA) levels.
  • CDCA chenodeoxycholic acid
  • DCA deoxycholic acid
  • the long-term treatment further results in improving Paris I, Paris II, Toronto I, Toronto II or LIK-PBC risk score, for at least 70 weeks, preferably 78 weeks, preferably at least 78 weeks, preferably after at least 104 weeks, more preferably after at least 130 weeks, even more preferably 156 weeks.
  • the long-term treatment further results in improving Paris I, Paris II, Toronto I, Toronto II or LIK-PBC risk score, after at least 70 weeks, preferably 78 weeks, preferably at least 78 weeks, preferably after at least 104 weeks, more preferably after at least 130 weeks, even more preferably 156 weeks of administration, in particular of daily administration.
  • the composition of the invention is administered to the subject once a day during at least 70 weeks, preferably 78 weeks, preferably at least 78 weeks, preferably after at least 104 weeks, more preferably after at least 130 weeks, even more preferably 156 weeks for improving Paris I, Paris II, Toronto I, Toronto II or LIK-PBC risk score.
  • the long-term treatment further results in improving 5D-itch scale, PBC 40 QOL, VAS, for at least 70 weeks, preferably 78 weeks, preferably at least 78 weeks, preferably after at least 104 weeks, more preferably after at least 130 weeks, even more preferably 156 weeks.
  • the long-term treatment further results in improving 5D-itch scale, PBC 40 QOL, VAS, after at least 70 weeks, preferably 78 weeks, preferably at least 78 weeks, preferably after at least 104 weeks, more preferably after at least 130 weeks, even more preferably 156 weeks of administration, in particular of daily administration.
  • the composition of the invention is administered to the subject once a day during at least 70 weeks, preferably 78 weeks, preferably at least 78 weeks, preferably after at least 104 weeks, more preferably after at least 130 weeks, even more preferably 156 weeks for improving 5D-itch scale, PBC 40 QOL, VAS.
  • the long-term treatment further results in improving Wl NRS score for at least 70 weeks, preferably 78 weeks, preferably at least 78 weeks, preferably after at least 104 weeks, more preferably after at least 130 weeks, even more preferably 156 weeks.
  • the long-term treatment further results in improving Wl NRS score after at least 70 weeks, preferably 78 weeks, preferably at least 78 weeks, preferably after at least 104 weeks, more preferably after at least 130 weeks, even more preferably 156 weeks of administration, in particular of daily administration.
  • the composition of the invention is administered to the subject once a day during at least 70 weeks, preferably 78 weeks, preferably at least 78 weeks, preferably after at least 104 weeks, more preferably after at least 130 weeks, even more preferably 156 weeks for improving Wl NRS score.
  • the long-term treatment further results in improving Promis Fatigue T-score, and/or Epworth Sleepiness Scale (ESS) score, for at least 70 weeks, preferably 78 weeks, preferably at least 78 weeks, preferably after at least 104 weeks, more preferably after at least 130 weeks, even more preferably 156 weeks.
  • the long-term treatment further results in improving Promis Fatigue T-score, and/or Epworth Sleepiness Scale (ESS) score, after at least 70 weeks, preferably 78 weeks, preferably at least 78 weeks, preferably after at least 104 weeks, more preferably after at least 130 weeks, even more preferably 156 weeks of administration, in particular of daily administration.
  • the composition of the invention is administered to the subject once a day during at least 70 weeks, preferably 78 weeks, preferably at least 78 weeks, preferably after at least 104 weeks, more preferably after at least 130 weeks, even more preferably 156 weeks for improving Promis Fatigue T-score, and/or Epworth Sleepiness Scale (ESS) score.
  • ESS Epworth Sleepiness Scale
  • the composition of the invention is administered to the subject once a day during at least 70 weeks, preferably 78 weeks, preferably at least 78 weeks, preferably after at least 104 weeks, more preferably after at least 130 weeks, even more preferably 156 weeks for further: improving AST, yGT, 5’-nucleotidase, total bilirubin, conjugated bilirubin, ALT and albumin levels; and improving lipid parameters; and/or improving C4 and/or FGF19 levels; and/or improving IgM levels; and/or improving 5D-itch scale, PBC 40 QOL, VAS; and/or improving Wl NRS score; and/or improving Promis Fatigue T-score (Fatigue Short Form 7a), and/or Epworth Sleepiness Scale (ESS) score.
  • improving AST, yGT, 5’-nucleotidase total bilirubin, conjugated bilirubin, ALT and albumin levels
  • improving lipid parameters and/or improving C4 and/
  • baseline plasma level refers to the plasma level of a subject before starting any treatment with the composition of the invention.
  • baseline ALP plasma level refer to the ALP plasma level of a subject before starting any treatment with the composition of the invention.
  • the invention further relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound selected from elafibranor, 2-[2,6-dimethyl-4-[3-[4-(methylthio)phenyl]-3-oxo-propyl]phenoxy]-2- methylpropanoic acid (GFT1007), and a pharmaceutically acceptable salt of elafibranor or GFT1007, for use in a method for long-term reduction of fatigue in a subject having primary biliary cholangitis (PBC), wherein said pharmaceutical composition is administered daily for at least 70 weeks.
  • said pharmaceutical composition is administered daily for at least 78 weeks, preferably at least 104 weeks, more preferably at least 130 weeks, even more preferably at least 156 weeks.
  • the present invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound selected from the group consisting of elafibranor, GFT1007, and a pharmaceutically acceptable salt of elafibranor or GFT1007, for use in a method for long-term reduction of fatigue associated to PBC in a subject having PBC, wherein said pharmaceutical composition is administered daily for at least 70 weeks.
  • said pharmaceutical composition is administered daily for at least 78 weeks, preferably at least 104 weeks, more preferably at least 130 weeks, even more preferably at least 156 weeks.
  • reducing fatigue can refer to the decrease in the feeling of tiredness or sense of exhaustion. It can also refer to an increase in the sense of energy and in the ability to execute daily activities and function normally in family or social roles.
  • a method for long-term reduction of fatigue refers to a method for reducing fatigue (as defined above) during at least 70 weeks, preferably during at least 78 weeks, preferably after at least 104 weeks, more preferably after at least 130 weeks, even more preferably during at least 156 weeks.
  • the patient’s fatigue can be measured using the PROMIS Short Form - Fatigue 7a questionnaire (V1 .0) to assess change from baseline in fatigue during treatment.
  • the PROMIS Fatigue item banks assess a range of self-reported symptoms over the past seven days, from mild subjective feelings of tiredness to an overwhelming, debilitating, and sustained sense of exhaustion that likely decreases one’s ability to execute daily activities and function normally in family or social roles. Fatigue is divided into the experience of fatigue (frequency, duration, and intensity) and the impact of fatigue on physical, mental, and social activities.
  • PROMIS instruments are scored using item-level calibrations. The final score is represented by the T- score, a standardized score with a mean of 50 and a standard deviation (SD) of 10.
  • a 1 -point decrease of the PROMIS Fatigue T-score represents a meaningful change in fatigue. This improvement corresponds to changes in alertness and well-being that are easily noticeable. Likewise, a noticeable worsening corresponds to a 1 -point increase of the PROMIS Fatigue T- score (Schattenberg et al.; EASL 21-24 June 2023).
  • the patient’s fatigue can also be measured using the PBC-40 total fatigue score.
  • the PBC- 40 consisting of 40 questions distributed across six domains: fatigue, emotional, social, cognitive function, general symptoms, and itch.
  • Another way to measure patient’s fatigue is to use the Epworth Sleepiness Scale.
  • the Epworth Sleepiness Scale is widely used in the field of sleep medicine as a subjective measure of a patient's sleepiness. The test is a list of eight situations in which the patient rates his tendency to become sleepy on a scale of 0, no chance of dozing, to 3, high chance of dozing. The total score is based on a scale of 0 to 24.
  • reducing pruritus can refer to the reduction in the intensity or severity of pruritus.
  • a method for long-term treatment of pruritus refers to a method for reducing pruritus (as defined above) during at least 70 weeks, preferably during at least 78 weeks, preferably after at least 104 weeks, more preferably after at least 130 weeks, even more preferably during at least 156 weeks.
  • the patient’s pruritus can be measured using the 5D-itch score, the PBC-40 itch score or the Wl NRS score.
  • the 5-D itch scale was developed as a brief but multidimensional questionnaire designed to be useful as an outcome measure in clinical trials. The five dimensions are degree, duration, direction, disability and distribution.
  • the 5D-itch scale is the most comprehensive and provides an accurate snapshot of the impact of pruritus on the patient's daily life, thanks to its score: score ranging from 5 (no impact of pruritus) to 25 (pruritus having a severe impact on the patient). This scale has 5 dimensions (5D). Each of them will be evaluated from 1 to 5.
  • the PBC-40 consisting of 40 questions distributed across six domains: fatigue, emotional, social, cognitive function, general symptoms, and itch.
  • WI-NRS Worst Itch Numeric Rating Scale
  • the invention further relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound selected from elafibranor, 2-[2,6-dimethyl-4-[3-[4-(methylthio)phenyl]-3-oxo-propyl]phenoxy]-2- methylpropanoic acid (GFT1007), and a pharmaceutically acceptable salt of elafibranor or GFT1007, for use in a method for long-term treatment of pruritus in a subject having primary biliary cholangitis (PBC), wherein said pharmaceutical composition is administered daily for at least 70 weeks.
  • said pharmaceutical composition is administered daily for at least 78 weeks, preferably at least 104 weeks, more preferably at least 130 weeks, even more preferably at least 156 weeks.
  • GFT1007 the active metabolite of elafibranor
  • GFT1007 is 2-[2,6-dimethyl-4-[3-[4-(methylthio)phenyl]-3-oxo-propyl]phenoxy]-2- methylpropanoic acid. Its properties and synthesis were described in PCT application W02007/147879, where it is referred to as compound 1.
  • the pharmaceutical composition of the invention may include a stereoisomer of elafibranor, of GFT1007, or of a pharmaceutically acceptable salt of elafibranor or of GFT1007.
  • a stereoisomer is an isomeric compound that has the same molecular formula and sequence of bonded atoms, but differs in the 3D-dimensional orientations of its atoms in space.
  • the stereoisomers include enantiomers, diastereoisomers, cis-trans and E-Z isomers, conformers and tautomers.
  • Elafibranor or GFT1007 can be formulated as pharmaceutically acceptable salt, particularly an acid or base salt compatible with pharmaceutical use.
  • Salts of elafibranor or GFT1007 implemented 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 the previously purified compound.
  • “pharmaceutically acceptable salts” include inorganic as well as organic acids salts.
  • Counter-ions may be selected from the following the non-exhaustive list : ammonia, L- arginine, benethamine, benzathine, tert-butylamine (erbumine), calcium hydroxide, choline hydroxide, deanol, diethanolamine (2,2’-iminobis(ethanol), diethylamine, epolamine (1-(2- hydroxyethyl)pyrrolidine), 2-(diethylamino)-ethanol, ethanolamine (2-aminoethanol), ethylenediamine, glycine, hydrabamine, 1 H-imidazole, L-Lysine, magnesium hydroxide, meglumine (N-methyl-glucamine), 4-(2-hydroxyethyl)-morpholine, piperazine, potassium hydroxide, sodium hydroxide, triethanolamine (2,2',2"-nitrilo-tris(ethanol)
  • the invention implements an ammonia, L-arginine, benethamine, benzathine, tert-butylamine (erbumine), calcium, choline, deanol, diethanolamine (2,2’- iminobis(ethanol), diethylamine, epolamine (1-(2-hydroxyethyl)pyrrolidine), 2-(diethylamino)- ethanol, ethanolamine (2-aminoethanol), ethylenediamine, glycine, hydrabamine, 1 H- imidazole, L-Lysine, magnesium, meglumine (N-methyl-glucamine), 4-(2-hydroxyethyl)- morpholine, piperazine, potassium, sodium, triethanolamine (2,2',2"-nitrilo-tris(ethanol)), tromethamine or zinc salt of elafibranor or GFT1007.
  • the salt of elafibranor or GFT1007 is selected from a tromethamine, potassium, sodium, L-arginine, benethamine, benzathine, ethanolamine, meglumine, glycine, erbumine, L-lysine, choline, epolamine, magnesium or 2-amino-2-methyl-propan-1-ol.
  • the pharmaceutical composition of the invention comprises elafibranor or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition of the invention comprises elafibranor.
  • composition used in the invention can comprise one or several excipients or vehicles, acceptable within a pharmaceutical context (e.g. saline solutions, physiological solutions, isotonic solutions, etc., compatible with pharmaceutical usage and well-known by one of ordinary skill in the art).
  • This composition can also comprise one or several agents or vehicles chosen among dispersants, solubilisers, stabilisers, preservatives, etc.
  • Agents or vehicles useful for these formulations are particularly methylcellulose, hydroxymethylcellulose, carboxymethylcellulose, polysorbate 80, mannitol, gelatin, lactose, vegetable oils, acacia, liposomes, etc.
  • Elafibranor or GFT1007 can be formulated for enteral or parenteral administration.
  • elafibranor or GFT1007 can be formulated for oral, intravascular (e.g. intravenous or intra-arterial), intramuscular, intraperitoneal, subcutaneous, transdermal or nasal administration.
  • the pharmaceutical composition can be a solid or liquid dosage form.
  • Illustrative formulations include, without limitation, an injectable suspension, or suspension for oral ingestion, a gel, an oil, a pill, a tablet, a suppository, a powder, a gel cap, a capsule, an aerosol, an oinment, a cream, a patch, or means of galenic forms for a prolonged and/or slow release.
  • the pharmaceutical composition of the invention is administered orally.
  • the composition is formulated in a form selected from the group consisting of a gel, an oil, a pill, a tablet, a powder, a gel cap, a capsule, and a galenic form or device assuring a prolonged and/or slow release.
  • the pharmaceutical composition of the invention is formulated in a tablet.
  • elafibranor, GFT1007, or a pharmaceutically acceptable salt of elafibranor or of GFT1007 is administered at a dose varying between 10 mg and 200 mg per administration, preferentially between 40 mg and 120 mg per administration, more preferentially between 80 mg and 120 mg per administration.
  • elafibranor, GFT1007, or a pharmaceutically acceptable salt of elafibranor or of GFT1007 is administered at a dose of 80 mg per administration.
  • elafibranor, GFT1007 or a pharmaceutically acceptable salt of elafibranor or of GFT1007 is administered at a dose of 120 mg per administration.
  • a tablet comprising 120 mg of elafibranor or GFT1007 is orally administered once a day for at least 70 weeks, preferably at least 78 weeks, preferably at least 104 weeks, more preferably at least 130 weeks, even more preferably at least 156 weeks.
  • the patient has PBC and responds at least partly to ursodeoxycholic acid (LIDCA).
  • the subject having PBC has an inadequate response to ursodeoxycholic acid (LIDCA).
  • the term “inadequate response to LIDCA” means that a treatment with LIDCA fails to significantly prevent, cure, delay, reverse, or slow down the progression of the disease, and/or fails to significantly improve the condition of the subject having PBC.
  • the treatment with LIDCA fails to provide a significant improvement of:
  • AST aspartate aminotransferase
  • 5’-nucleotidase conjugated bilirubin
  • ALT aslanine aminotransferase
  • albumin levels and/or
  • IgM immunoglobulin M
  • the invention relates to the use of the pharmaceutical composition
  • the pharmaceutical composition comprising a compound selected from elafibranor, GFT1007, and a pharmaceutically acceptable salt of elafibranor or GFT1007, in combination with at least one other therapeutically active agent, in the method for treating primary biliary cholangitis (PBC) in a subject having primary biliary cholangitis (PBC), and an inadequate response to ursodeoxycholic acid.
  • the other active agent may in particular be selected from other anticholestatic agents such as UDCA, OCA or seladelpar (Livdelzi®).
  • the invention thus also relates to the combination of the pharmaceutical composition of the invention with UDCA, OCA or seladelpar, preferably UDCA.
  • the method comprises administering elafibranor at a dose of 80 mg per administration and ursodeoxycholic acid (UDCA), once a day for at least 70 weeks, preferably for at least 78 weeks, preferably at least 104 weeks, more preferably at least 130 weeks, even more preferably for at least 156 weeks to the subject in need thereof.
  • UDCA ursodeoxycholic acid
  • the method comprises administering elafibranor at a dose of 80 mg per administration and ursodeoxycholic acid (UDCA), once a day for at least 70 weeks, preferably for at least 78 weeks, preferably at least 104 weeks, more preferably at least 130 weeks, even more preferably for at least 156 weeks to a subject having primary biliary cholangitis (PBC) and an inadequate response to ursodeoxycholic acid.
  • UDCA ursodeoxycholic acid
  • the method comprises administering elafibranor at a dose of 80 mg per day and LIDCA at a dose of 13-15 mg/kg/day, for at least 70 weeks, preferably for at least 78 weeks, preferably at least 104 weeks, more preferably at least 130 weeks, even more preferably for at least 156 weeks to a subject having PBC and an inadequate response to ursodeoxycholic acid.
  • the present invention also provides a kit for the long-term treatment of PBC comprising the composition of the invention and another anti-cholestatic agent as described above, in particular LIDCA.
  • Inclusion criteria were an alkaline phosphatase level of >1.67 times the upper limit of the normal range (ULN), and a total bilirubin level of ⁇ 2 times the ULN.
  • eligible participants Prior to screening, eligible participants had received 13 to 15 mg/kg ursodeoxycholic acid treatment per day for at least 12 months (stable dose for at least 3 months) or were intolerant to ursodeoxycholic acid (no treatment for at least 3 months).
  • Table 2a and Figures 5a summarize mean changes from baseline 4, 13, 26, 39, 5 and 78, in 5-D itch total score (Prurit) to weeks in participants receiving elafibranor or placebo.
  • Table 2b and Figures 5b, 5c and 5d summarize mean changes from baseline from weeks 4, to week 156, in 5-D itch total score, PBC-40 itch score and Wl NRS score in participants receiving elafibranor comprising the participants including in the OLE period.
  • WI-NRS Wo-NRS (Worst Itch-NRS), PBC-40, 5D-ltch) was observed.
  • PFSF 7a Patient Reported Outcome Measurement Information System
  • PROMIS Patient Reported Outcome Measurement Information System
  • PFSF 7a Patient Reported Outcome Measurement Information System
  • a 5-point Likert scale is used for individual items; scores can range from 7 (no fatigue) to 35 (always fatigue).
  • Raw PROMIS Fatigue Short Form 7a scores are often converted to T-scores, which rescales the raw score into a standardized score with a mean of 50 and a standard deviation of 10. This allows for easier interpretation and comparison across different populations and measures.
  • a T-score of 50 represents the average score for the United States general population. T-scores that are half a standard deviation worse than the mean (approximately 55-60 for negatively-worded concepts like fatigue) are often considered to indicate mild symptoms or impairment.
  • Epworth Sleepiness Scale used to assess daytime sleepiness, in which patients rate their usual chances of dozing off or falling asleep while engaged in eight different activities on a scale from zero to three.
  • the ESS score can range from zero (no daytime sleepiness) to 24 (severe excessive daytime sleepiness).
  • the scores from the ESS can also be categorized into different levels of sleepiness severity, which help in interpreting the results: 0 to 5 (lower normal daytime sleepiness), 6 to 10 (higher normal daytime sleepiness), 11 to 12 (mild excessive daytime sleepiness), 13 to 15 (moderate excessive daytime sleepiness), and 16 to 24 (severe excessive daytime sleepiness).
  • PBC-40 Fatigue one of the six domains of PBC-40, a disease-specific health-related quality of life measure developed for patients with PBC.
  • the fatigue domain consists of 8 items/questions. Each item in the fatigue domain is scored on a 5-point Likert scale from 1 (never) to 5 (always). Patients are asked to reflect on their experiences over the past 4 weeks when answering the fatigue items. Domain scores range from 8 (never fatigued) to 40 (always fatigued).
  • the PBC-40 Fatigue domain does not have specific categories like "normal,” “mild,” “moderate,” or "severe”. Sleep question of PBC-40 Itch: PBC-40 Itch is composed of three questions with one asking participants to rate the statement “itching disturbed my sleep” from 1 (never) to 5 (always), with an additional response option for did not apply/no itch.
  • Table 3a and Figure 6a summarize mean changes from baseline from week 4 through week 78, in Promis Fatigues T-score, in participants receiving elafibranor comprising the participants including in the OLE period.
  • Table 3b summarizes mean changes from baseline to week 104 and week 130 and the percentage of patients with improvement.

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Abstract

La présente invention concerne une composition pharmaceutique comprenant un composé choisi dans le groupe constitué d'élafibranor, d'acide 2-[2,6-diméthyl-4-[3-[4-(méthylthio)phényl]- 3-oxo-propyl]phénoxy]-2-méthylpropanoïque (GFT1007), et d'un sel pharmaceutiquement acceptable d'élafibranor ou de GFT1007, pour utilisation dans une méthode de traitement à long terme de la cholangite biliaire primitive (CBP) chez un sujet atteint de CBP, ladite composition pharmaceutique étant administrée quotidiennement pendant au moins 70 semaines, de préférence 78 semaines, de préférence au moins 104 semaines, de préférence au moins 130 semaines, de préférence encore au moins 156 semaines.
PCT/EP2025/059717 2024-04-09 2025-04-09 Élafibranor pour le traitement à long terme de la cholangite biliaire primitive Pending WO2025215081A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007147879A1 (fr) 2006-06-21 2007-12-27 Genfit Derives de 1,3-diphenylpropane substitues, preparations et utilisations
US20230301951A1 (en) * 2020-08-26 2023-09-28 Genfit Compositions and methods for the treatment of primary biliary cholangitis
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WO2007147879A1 (fr) 2006-06-21 2007-12-27 Genfit Derives de 1,3-diphenylpropane substitues, preparations et utilisations
US20230330048A1 (en) * 2016-03-31 2023-10-19 Genfit Methods of treatment of cholestatic diseases
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KOWDLEY KRIS V. ET AL: "Efficacy and Safety of Elafibranor in Primary Biliary Cholangitis", THE NEW ENGLAND JOURNAL OF MEDICINE, vol. 390, no. 9, 29 February 2024 (2024-02-29), US, pages 795 - 805, XP093210745, ISSN: 0028-4793, DOI: 10.1056/NEJMoa2306185 *
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