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 Methods for reducing fatigue in a subject suffering from primary biliary cholangitis (PBC). The pharmaceutical composition of the present invention significantly reduces the PROMIS Fatigue T score (PROMIS profile-Fatigue 7a questionnaire (V1.0)) relative to the baseline in a subject suffering from PBC.

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.

[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 the flow of bile 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. 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. Abnormally high 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.

[0006] Fatigue is one of the most common and exhausting symptoms of primary biliary cholangitis (PBC), affecting more than 50% of PBC patients. One in five PBC patients suffer from severe fatigue, which significantly reduces their quality of life. Fatigue is composed of central and peripheral components, and its pathophysiology remains extremely difficult to understand (EN Lynch et al.; World J Hepatol. 2022 Jan 27; 14(6): 1111-1119). Unlike itching and except in end-stage liver disease, fatigue is not associated with disease progression.

[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] However, fatigue does not respond to UDCA or OCA therapy. In fact, fatigue is defined as one of the most common side effects of OCA treatment. To date, there is no effective treatment for fatigue caused by PBC, and therefore, approaches to fatigue and its management need to be implemented concurrently with the management of the underlying disease.

[0011] Given the efficacy and tolerability issues of currently available treatment options, there is an unmet need for treatment options that can significantly reduce fatigue in PBC patients.

[0012] In PBC treatment (ELATIVE) TM In a phase 3 study, elafibranol (2-(2,6-dimethyl-4-{3-[4-(methylthio)phenyl]-3-oxopropen-1-yl}phenoxy)-2-methylpropionic acid) was evaluated. Phase 3 results from PBC showed that the mean relative change (%) of serum ALP from baseline to endpoint was -48.3% in the 80 mg elafibranol treatment group and 3.2% in the placebo group.

[0013] 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

[0014] An unexpected result from a phase 3 clinical trial showed that participants treated 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) had significantly lower PROMIS fatigue T-scores (PROMIS® Short Form - Fatigue 7a (V1.0)) relative to baseline compared to participants receiving placebo.

[0015] 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 use in a method of relieving fatigue in a subject suffering from primary biliary cholangitis (PBC).

[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 relieving fatigue in a subject suffering from primary biliary cholangitis (PBC).

[0017] The present invention also relates to a method for relieving fatigue in a subject suffering from primary biliary cholangitis (PBC), 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. Attached Figure Description

[0018] Figure 1 and Figure 2 : The average change of PROMIS fatigue T-score relative to baseline over time.

[0019] Figure 1 Compare the mean change from baseline in PROMIS fatigue T score of participants with PBC treated with erafibrino (80 mg daily) to participants in the placebo group from week 4 to week 52.

[0020] Figure 2 The mean change in PROMIS fatigue T score from baseline was compared between week 4 and week 52 in participants with PBC and pruritus treated with erafibrino (80 mg daily) and the placebo group.

[0021] Implementation

[0022] This invention relates to a pharmaceutical composition comprising a compound selected from the group consisting of erafibrano, GFT1007 and pharmaceutically acceptable salts of erafibrano or GFT1007, for use in a method of relieving fatigue in a subject suffering from PBC.

[0023] 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, for use in a method of alleviating PBC-related fatigue in subjects with PBC.

[0024] 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, for use in treating PBC in a subject with PBC and fatigue without causing and / or exacerbating the subject's fatigue.

[0025] 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, GFT1007 and pharmaceutically acceptable salts of erafibrano or GFT1007, in a method for relieving fatigue in a subject suffering from PBC.

[0026] 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, GFT1007 and pharmaceutically acceptable salts of erafibrano or GFT1007, in a method for relieving PBC-related fatigue in subjects suffering from PBC.

[0027] 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, GFT1007 and pharmaceutically acceptable salts of erafibrano or GFT1007, the medicament being used to treat PBC in a subject with PBC accompanied by fatigue, without causing and / or exacerbating the subject's fatigue.

[0028] The present invention also relates to a method for relieving fatigue in a subject suffering from PBC, 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 a pharmaceutically acceptable salt of erafibrano or GFT1007.

[0029] The present invention also relates to a method for relieving PBC-related fatigue in a subject suffering from PBC, 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 a pharmaceutically acceptable salt of erafibrano or GFT1007.

[0030] The present invention also relates to a method for treating PBC in a subject with PBC and fatigue without causing and / or exacerbating the subject's fatigue, 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 a pharmaceutically acceptable salt of erafibrano or GFT1007.

[0031] In the context of this invention, the term "fatigue reduction" can refer to a decrease in feelings of tiredness or fatigue. It can also refer to an increase in energy levels and an increased ability to perform daily activities and fulfill normal family or social roles.

[0032] Patient fatigue can be measured using the PROMIS Short Form-7a Fatigue Questionnaire (V1.0) to assess changes relative to baseline during fatigue treatment. The PROMIS Fatigue Project assesses a range of self-reported symptoms over the past seven days, from mild subjective fatigue to overwhelming, debilitating, and persistent fatigue that may impair the ability to perform daily activities and function normally at home or in a social setting. Fatigue is categorized by the experience of fatigue (frequency, duration, and intensity) and its impact on physical, psychological, and social activities. Item-rating correction is used to score the PROMIS tool. The final score is represented by a T-score, a standardized score with a mean of 50 and a standard deviation (SD) of 10. A 1-point decrease in the PROMIS Fatigue T-score indicates a significant change in fatigue. This improvement corresponds to noticeable changes in alertness and overall health. Similarly, a noticeable deterioration corresponds to a 1-point increase in the PROMIS fatigue T score (Schattenberg et al., “Evaluating Pruritus and Fatigue in Patients with Treatment-Refractory Primary Biliary Cholangitis” EASL 21-24, June 2023).

[0033] The PBC-40 Total Fatigue Score can also be used to measure a patient's fatigue. The PBC-40 consists of 40 questions across six domains: fatigue, mood, social, cognitive function, general symptoms, and itching.

[0034] In a particular embodiment, treatment of PBC patients with the pharmaceutical composition of the present invention can cause a reduction of at least 1 point in the PROMIS fatigue T score relative to baseline. Preferably, treatment of PBC patients with the pharmaceutical composition of the present invention causes a reduction of at least 1.2 points in the PROMIS fatigue T score relative to baseline, more preferably at least 1.4 points.

[0035] In another specific embodiment, treatment of patients with PBC and pruritus using the pharmaceutical composition of the present invention results in a decrease of at least 2 points in the PROMIS fatigue T score relative to baseline. Preferably, treatment of patients with PBC and pruritus using the pharmaceutical composition of the present invention results in a decrease of at least 2.2 points in the PROMIS fatigue T score relative to baseline, more preferably at least 2.3 points.

[0036] Specifically, an improvement in the PROMIS fatigue T-score can be observed after 4 weeks of treatment with the pharmaceutical composition of the present invention. The improvement in the PROMIS fatigue T-score can be even greater after 13 weeks of treatment with the pharmaceutical composition of the present invention. The improvement in the PROMIS fatigue T-score can be even greater after 52 weeks of treatment with the pharmaceutical composition of the present invention.

[0037] The term "treatment" or "treating" refers to the medical treatment, prevention, or treatment of PBC 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, GFT1007, or a pharmaceutically acceptable salt thereof) 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 PBC.

[0038] The terms “patient,” “subject,” or “individual” are used interchangeably and refer to mammals, and more specifically, humans, including adults and children. In the context of this invention, the patient has PBC or PBC with pruritus. Subjects to be treated according to this invention may be appropriately selected based on several indicators associated with the pathological process of cholestasis, 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 who have PBC or PBC with pruritus are characterized as follows:

[0039] At least two of the following three diagnostic factors are present:

[0040] (i) A history of elevated ALP levels for at least 6 months prior to day 0 (random visit).

[0041] (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).

[0042] (iii) Liver biopsy consistent with PBC

[0043] ALP ≥ 1.67 × Upper Limit of Normal (ULN)

[0044] Optionally, use UDCA for at least 12 months prior to the screening visit (stable dose for ≥6 months).

[0045] 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.

[0046] 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.

[0047] 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.

[0048] 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.

[0049] 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.

[0050] 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.

[0051] In a preferred embodiment, the pharmaceutical composition of the present invention comprises erafibrano or a pharmaceutically acceptable salt thereof.

[0052] In the preferred embodiment, the pharmaceutical composition of the present invention comprises erafibrino.

[0053] 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) injectable suspensions for long-term and / or slow-release or oral administration, as well as suspensions, gels, oils, pills, tablets, suppositories, powders, gel caps, capsules, aerosols, ointments, creams, patches, or galenols.

[0054] In a preferred embodiment, the pharmaceutical composition of the present invention is administered orally. Preferably, the composition is formulated in the form of a gel, oil, pill, tablet, powder, gel capsule, capsule, or galen form or device to ensure prolonged and / or slow release.

[0055] In a preferred embodiment, the pharmaceutical composition of the present invention is formulated in tablets.

[0056] As used herein, the term "therapeuticly effective amount" refers to the amount of erafibrinolate or GFT1007 used to prevent, eliminate, or alleviate PBC and its adverse events, particularly the amount of erafibrinolate or GFT1007 used to prevent, eliminate, or alleviate PBC and fatigue. 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.

[0057] The dosage may be adjusted by those skilled in the art. Specifically, the dosage and regimen of administration may be determined by factors such as the stage and severity of the PBC and / or fatigue being treated, the weight, age and overall health of the subject being treated, and the physician's judgment.

[0058] 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.

[0059] Preferably, the pharmaceutical composition of the present invention is administered once daily, especially orally once daily.

[0060] 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.

[0061] In another embodiment, tablets containing 80 mg of erafibrano or GFT1007 are administered orally once daily.

[0062] In another embodiment, a tablet containing 120 mg of erafibrano or GFT1007 is administered orally once daily.

[0063] In one embodiment, the patient has PBC and responds at least partially to ursodeoxycholic acid (UDCA). In another embodiment, the patient with PBC responds poorly to ursodeoxycholic acid (UDCA).

[0064] In a particular embodiment, the present invention relates to the use of a pharmaceutical composition in a method for relieving fatigue in patients with PBC, the 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. 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 UDCA to a subject in need and an 80 mg dose of erafibrano per administration. More specifically, the method comprises administering UDCA to a subject with PBC who has an inadequate response to ursodeoxycholic acid and an 80 mg dose of erafibrano per administration. Even more specifically, the method comprises administering an 80 mg / day dose of erafibrano and a 13-15 mg / kg / day dose of UDCA to a subject with PBC who has an inadequate response to ursodeoxycholic acid. Example

[0065] NCT04526665 Clinical Trial (ELATIVE) TM )

[0066] 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).

[0067] 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 regimen throughout the trial. The total double-blind treatment period consisted of two parts. In Part 1, all randomized patients received double-blind treatment for at least 52 weeks. In Part 2, participants continued double-blind treatment for a variable treatment 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.

[0068] From September 2020 to May 2023, 161 participants were randomly assigned to receive 80 mg erafibrinolate (108 participants) or placebo (53 participants); these participants constituted the intention-to-treat (ITT) and safety cohorts. The pruritus intention-to-treat cohort included 66 participants with moderate to severe pruritus (44 received erafibrinolate and 22 received placebo).

[0069] Since fatigue is a major symptom of PBC, it is important to ensure that the scale accurately captures all symptom experiences of participants during the clinical study and fully reports the impact of each symptom.

[0070] PROMIS Fatigue Summary Questionnaire (SF) 7a

[0071] The Patient Reported Outcomes Measurement Information System (PROMIS®) is the product of extensive efforts since 2004 and is based on modern measurement theory. It addresses the need for accurate and consistent measures of health outcomes, including fatigue, applicable to a wide range of chronic diseases, particularly PBC. The PROMIS Fatigue Short Form 7a (PROMIS Fatigue SF 7a) is a seven-item questionnaire derived from 95 items in the PROMIS Fatigue Project.

[0072] The PROMIS Fatigue Project assesses a range of self-reported symptoms, from mild subjective fatigue to overwhelming, debilitating, and persistent fatigue that may impair the ability to perform daily activities and function normally at home or in a social setting. Fatigue is categorized by the experience of fatigue (frequency, duration, and intensity) and its impact on physical, psychological, and social activities. The fatigue profile is general, not disease-specific. All profiles assess fatigue over the past seven days.

[0073] The PROMIS Fatigue SF 7a (7 items) uses a Likert scale to measure fatigue experience over the past 7 days and the impact of fatigue on daily activities. PROMIS Fatigue SF 7a consists of seven items, answered on a 5-point Likert scale, ranging from 1 = "never" to 5 = "always". One item, "How long does it take you to have enough energy for vigorous exercise?", is a reverse rating, meaning a higher score indicates more severe fatigue.

[0074] The fatigue measurements reported by participants assessed in study NCT04526665 included the PROMIS Fatigue SF 7a questionnaire.

[0075] The analysis was conducted within the ITT (Intention-to-Treat) and pruritus ITT analysis datasets (see Tables 1, 2, and 3). Figure 1 and Figure 2 ).

[0076] In the pruritus ITT analysis ensemble, participants with higher baseline PBC Most Severe Pruritus Numerical Rating Scale (Wi-NRS) scores also had higher baseline PROMIS Fatigue T scores and showed a greater reduction (meaning improvement) relative to baseline at week 52 after administration of 80 mg erafibrinolate compared to placebo, measured by a mean LS difference of -3.77 ([95% CI: -8.01; 0.47]: p = 0.0802) in the PROMIS Fatigue T score relative to placebo. Such reductions were observed as early as week 13, with a mean LS difference of -3.15 ([95% CI: -6.62; 0.33]: p = 0.0752).

[0077] In the ITT analysis cohort, the reduction in baseline observed at week 13 (mean LS difference relative to placebo: -2.11 ([95% CI: 4.21; 0.01]: p = 0.0494)) was greater in participants treated with 80 mg erafibrinolate compared to placebo than at week 52 (mean LS difference relative to placebo: -1.23 ([95% CI: -3.64; 1.18]: p = 0.3161)).

[0078] Table 1: Changes in PROMIS fatigue T-score relative to baseline at week 13 - MMRM

[0079]

[0080] Table 2: Changes in PROMIS fatigue T-score relative to baseline at week 52 - MMRM

[0081]

[0082] The baseline is defined as the last non-missing value at or before the first administration of the randomized study drug.

[0083] Table 3: Changes in PROMIS fatigue T-score relative to baseline over time (week 4 to week 52); see also Figure 1 and Figure 2 .

[0084]

[0085] As measured by the PROMIS Fatigue SF 7a questionnaire, treatment with erafibrino resulted in improved fatigue compared to placebo. This improvement was even greater in patients with moderate to severe pruritus at baseline, demonstrating that erafibrino treatment achieved significant symptom relief in participants with PBC and pruritus.

Claims

1. A pharmaceutical composition comprising a compound selected from 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, for the purpose of relieving fatigue in a subject suffering from primary biliary cholangitis (PBC).

2. The pharmaceutical composition used as described in claim 1, in a method for relieving PBC-related fatigue in a subject suffering from PBC.

3. The pharmaceutical composition used as described in claim 1 or 2, wherein the subject with PBC also suffers from pruritus.

4. The pharmaceutical composition used as described in any one of claims 1 to 3, wherein in subjects with PBC, the PROMIS fatigue T score is reduced by at least 1 point relative to baseline.

5. The pharmaceutical composition used as described in any one of claims 1 to 3, wherein in subjects suffering from PBC and pruritus, the PROMIS fatigue T score is reduced by at least 2 points relative to baseline.

6. The pharmaceutical composition used as described in any one of claims 1 to 5, wherein the composition comprises erafibrano or a pharmaceutically acceptable salt thereof.

7. The pharmaceutical composition used as described in any one of claims 1 to 6, wherein the composition comprises erafibrino.

8. The pharmaceutical composition used as claimed in any one of claims 1 to 7, 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.

9. The pharmaceutical composition used as described in any one of claims 1 to 8, wherein the composition is formulated into tablet form.

10. The pharmaceutical composition used as described in any one of claims 1 to 9, wherein erafibrano is administered once daily.

11. The pharmaceutical composition used as described in any one of claims 1 to 10, wherein the administration is oral.

12. The pharmaceutical composition used according to any one of claims 1 to 11, wherein the dosage is 80 mg or 120 mg per administration.

13. The pharmaceutical composition used as described in any one of claims 1 to 12, wherein erafibrano is administered at a dose of 80 mg per administration.

14. The pharmaceutical composition used as described in any one of claims 1 to 13, wherein the subject with PBC has an inadequate response to ursodeoxycholic acid (UDCA).

15. The pharmaceutical composition used as described in any one of claims 1 to 14, wherein the method comprises further administering to a subject in need another antichostatic agent, preferably ursodeoxycholic acid (UDCA).

16. The pharmaceutical composition used as described in any one of claims 1 to 15, wherein the method comprises administering ursodeoxycholic acid (UDCA) to a subject in need and administering an 80 mg dose of erafibrinolate per dose.

17. The pharmaceutical composition used as described in any one of claims 1 to 16, wherein the method comprises administering ursodeoxycholic acid and 80 mg of errafibrano to a subject suffering from primary biliary cholangitis (PBC) and inadequate response to ursodeoxycholic acid (UDCA).

18. A pharmaceutical composition comprising a compound selected from the group consisting of erafibrano, GFT1007 and pharmaceutically acceptable salts of erafibrano or GFT1007, for use in treating PBC in a subject with PBC and fatigue without causing and / or exacerbating the subject's fatigue.

19. Use of a pharmaceutical composition in the preparation of a medicament comprising a compound selected from the group consisting of erafibrano, GFT1007 and pharmaceutically acceptable salts of erafibrano or GFT1007, in a method of relieving fatigue in a subject suffering from PBC.

20. Use of a pharmaceutical composition in the preparation of a medicament comprising a compound selected from the group consisting of erafibrano, GFT1007 and pharmaceutically acceptable salts of erafibrano or GFT1007, in a method of relieving PBC-related fatigue in a subject suffering from PBC.

21. Use of a pharmaceutical composition in the preparation of a medicament comprising a compound selected from the group consisting of erafibrano, GFT1007 and pharmaceutically acceptable salts of erafibrano or GFT1007, in a method of treating PBC in a subject with PBC and fatigue without causing and / or exacerbating the subject's fatigue.

22. A method for relieving fatigue in a subject suffering from PBC, 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 a pharmaceutically acceptable salt of erafibrano or GFT1007.

23. A method for relieving PBC-related fatigue in a subject suffering from PBC, 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 a pharmaceutically acceptable salt of erafibrano or GFT1007.

24. A method for treating PBC in a subject with PBC and fatigue without causing and / or exacerbating the subject's fatigue, 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 a pharmaceutically acceptable salt of erafibrano or GFT1007.

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