TREATMENT OF PRIMARY BILIARY CHOLANGITIS WITH ELAFIBRANOR

Abstract

The invention relates to a pharmaceutical composition comprising elafibranor, GFT1007 or a pharmaceutically acceptable salt of elafibranor or of GFT1007, for use to treat primary biliary cholangitis (PBC) without provoking and/or worsening at least one adverse event associated to PBC.

Claims

1. A method of treating primary biliary cholangitis (PBC) without provoking and/or worsening at least one adverse event associated with PBC, the method comprising administering to a subject in need thereof a pharmaceutical composition comprising a compound selected from 2-(2,6-dimethyl-4-{3-[4-(methylsulfanyl)phenyl]-3-oxopropen-1-yl}phenoxy)-2-methylpropanoic acid (elafibranor), 2-[2,6-dimethyl-4-[3-[4-(methylthio)phenyl]-3-oxo-propyl]phenoxy]-2-methylpropanoic acid (GFT1007), a pharmaceutically acceptable salt of elafibranor, and a pharmaceutically acceptable salt of GFT1007.

2. The method according to claim 1, wherein the adverse event is pruritus.

3. A method of treating primary biliary cholangitis (PBC), the method comprising administering to a subject having PBC with pruritus a pharmaceutical composition comprising a compound selected from 2-(2,6-dimethyl-4-{3-[4-(methylsulfanyl)phenyl]-3-oxopropen-1-yl}phenoxy)-2-methylpropanoic acid (elafibranor), 2-[2,6-dimethyl-4-[3-[4-(methylthio)phenyl]-3-oxo-propyl]phenoxy]-2-methylpropanoic acid (GFT1007), a pharmaceutically acceptable salt of elafibranor, and a pharmaceutically acceptable salt of GFT1007.

4. The method according to claim 3, wherein the treatment does not provoke and/or worsen the pruritus.

5. The method according to claim 1, wherein said composition is a tablet, injectable suspension, gel, oil, pill, suppository, powder, gel cap, capsule, aerosol, or a prolonged and/or slow release dosage form.

6. The method according to claim 1, wherein said composition is orally administered once a day.

7. The method according to claim 1, wherein elafibranor, GFT1007, or the pharmaceutically acceptable salt of elafibranor or of GFT1007 is administered at a dose varying between 10 mg and 200 mg per administration.

8. The method according to claim 1, wherein elafibranor, GFT1007, or the pharmaceutically acceptable salt of elafibranor or of GFT1007 is administered at a dose varying between 80 mg and 120 mg per administration.

9. The method according to claim 1, wherein said pharmaceutical composition is a tablet comprising 80 mg of elafibranor or of GFT1007.

10. The method according to claim 1, wherein said pharmaceutical composition is a tablet comprising 120 mg of elafibranor or of GFT1007.

11. The method according to claim 1, wherein the compound is elafibranor or the pharmaceutically acceptable salt thereof.

12. The method according to claim 1, wherein the compound is elafibranor.

13. The method according to claim 3, wherein said composition is a tablet, injectable suspension, gel, oil, pill, suppository, powder, gel cap, capsule, aerosol, or a prolonged and/or slow release dosage form.

14. The method according to claim 3, wherein said composition is orally administered once a day.

15. The method according to claim 3, wherein elafibranor, GFT1007, or the pharmaceutically acceptable salt of elafibranor or of GFT1007 is administered at a dose varying between 10 mg and 200 mg per administration.

16. The method according to claim 3, wherein elafibranor, GFT1007, or the pharmaceutically acceptable salt of elafibranor or of GFT1007 is administered at a dose varying between 80 mg and 120 mg per administration.

17. The method according to claim 3, wherein said pharmaceutical composition is a tablet comprising 80 mg of elafibranor or of GFT1007.

18. The method according to claim 3, wherein said pharmaceutical composition is a tablet comprising 120 mg of elafibranor or of GFT1007.

19. The method according to claim 3, wherein the compound is elafibranor or the pharmaceutically acceptable salt thereof.

20. The method according to claim 3, wherein the compound is elafibranor.

Description

LEGENDS OF THE FIGURES

[0035] FIG. 1: Relative Change from Baseline in Serum Alkaline Phosphatase at Endpoint—

[0036] Primary Efficacy Endpoint—Primary and Supportive Analyses

[0037] ALP=alkaline phosphatase; ANCOVA=analysis of covariance; CI=confidence interval; EOT=end-of-treatment; SD=standard deviation; trt=treatment.

[0038] .sup.aNon-parametric randomization-based ANCOVA with baseline ALP as a covariate. p-values were computed under the null hypothesis (based on re-randomizations of the population) while estimates and CIs were computed under the alternative hypothesis (based on repeated random sampling).

[0039] .sup.bANCOVA with baseline ALP as covariate and without interaction term.

[0040] FIG. 2: Mean Alkaline Phosphatase Values from Baseline through Week 12 by Treatment Group

[0041] FIG. 3: Mean Relative Change from Baseline through Week 12 in Alkaline Phosphatase by Treatment Group

[0042] FIG. 4: Absolute and Relative Change from Baseline in Pruritus Visual Analogue Score

[0043] EOT=end-of-treatment; SD=standard deviation; VAS=visual analogue scale.

[0044] FIG. 5: Median Relative Change from Baseline through Week 12 in Pruritus VAS

[0045] FIG. 6: Absolute and Relative Change from Baseline to Endpoint in Pruritus Domain of the PBC-40 Quality of Life Questionnaire

[0046] EOT=end-of-treatment;

[0047] SD=standard deviation;

[0048] VAS=visual analogue scale.

EXAMPLES

Example 1: Enrollment

[0049] The study was a Phase 2, double-blind, randomized, parallel group, placebo-controlled study, designed to evaluate the efficacy and safety of elafibranor at doses of 80 mg or 120 mg daily vs placebo in an adult PBC population. This study projected to randomize approximately 45 subjects to 3 treatment groups in a 1:1:1 ratio (elafibranor 80 mg, elafibranor 120 mg, or placebo).

[0050] In order to participate in the study, all subjects must have met all of the following criteria: [0051] Was a male or female between 18 to 75 years of age [0052] Had a definite or probable PBC diagnosis demonstrated by the presence of at least 2 of the following 3 diagnostic factors: [0053] History of elevated ALP levels for at least 6 months [0054] Positive antimitochondrial Ab titers (>1/40 on immunofluorescence or antiinflammatory macrophages positive by enzyme-linked immunosorbent assay) or positive PBC-specific antinuclear antibodies [0055] Liver biopsy consistent with PBC [0056] Had an ALP≥1.67×(Upper Limit of Normal—104 U/L for women) [0057] Received UDCA for at least 12 months (stable dose for ≥6 months) before the screening visit.

[0058] Moreover, in order to have been eligible for enrollment in the study, none of the following criteria could have applied to any subject: [0059] Had a history or presence of other concomitant liver diseases including: [0060] Positive hepatitis B surface antigen (HBsAg) at Screening [0061] Positive hepatitis C virus (HCV) RNA [0062] Alcoholic liver disease [0063] Primary sclerosing cholangitis [0064] Definite autoimmune hepatitis (AIH), or “AIH-PBC overlap syndrome” [0065] Biopsy confirmed non-alcoholic steatohepatitis [0066] Known history of alpha-1 antitrypsin deficiency or other metabolic forms of [0067] chronic liver disease [0068] Gilbert's Syndrome

[0069] Subject participation was planned to be a maximum of 20 weeks. The study was comprised of 3 periods: a Screening Period, a Treatment Period, and a Follow-up Period. The Screening Period (Week −4 to Week −1) preceded the 12-week double-blind Treatment Period.

[0070] The mean age at study entry was 59.1 years, with a minimum of 40 and a maximum of 74 years. Gender was disproportionate, with 95.6% females. The majority of subjects were white (97.8%) and not Hispanic or Latino (77.8%). The mean BMI at baseline was 26.9 kg/m2 (minimum 19.1 kg/m2, maximum 39.7 kg/m2). Among female subjects, 11.1% were of child bearing potential; the remaining female subjects were postmenopausal (78.9%) or surgically sterile (21.1%). The 3 treatment groups had similar demographic and baseline characteristics, which were representative of the clinical PBC population.

Example 2: Endpoints

[0071] The tolerability and safety of once-per-day oral administration of elafibranor in 80-mg and 120-mg doses in subjects with PBC was assessed as follows: [0072] Physical examination [0073] Vital signs [0074] Medical history [0075] ECG [0076] Hematological parameters [0077] Liver markers [0078] Other biochemical safety parameters

[0079] A decrease in ALP levels is recognized as a particularly relevant surrogate marker for the treatment of PBC. Consequently the primary endpoint of the study is to evaluate the efficacy of elafibranor 80 mg or 120 mg with respect to relative change from baseline in serum ALP levels compared to placebo.

[0080] Considering that pruritus is a preeminent adverse event in subjects with PBC, assessment of pruritus was also considered. More specifically, the change from baseline in pruritus (through 5D-itch scale (measuring the degree, duration, direction [improvement or worsening], disability [effect on daily activities], and distribution of itching) and visual analogue scale for pruritus (VAS).

[0081] The 5D-itch scale is a reliable, multidimensional measure of itching that has been validated in patients with chronic pruritus to detect changes over time (Elman S, et al., The 5-D itch scale: a new measure of pruritus. Br J Dermatol. 2010; 162(3):587-593.). The VAS is a reliable and validated method of pruritus assessment (Reich A, et al., Visual analogue scale: evaluation of the instrument for the assessment of pruritus. Acta Derm Venereol.2012; 92(5):497-501).

Example 3: Drug Used

[0082] Elafibranor (2-(2,6-dimethyl-4-{3-[4-(methylsulfanyl)phenyl]-3-oxopropen-1-yl}phenoxy)-2-methylpropanoic acid) was supplied as 80 mg or 120 mg white to offwhite round coated tablets with no printed inscription.

[0083] Two placebo tablets (each one of the same size as the corresponding active tablet) to match elafibranor 80 mg or 120 mg were provided as a white to off-white round coated tablet with no printed inscription. The placebo tablets contained the same excipients as the active formulation as well as lactose monohydrate (which was used in place of the active ingredient).

Example 4: Results on ALP Levels

[0084] The mean relative change (%) from baseline to Endpoint in serum ALP was −48.3% for the elafibranor 80 mg treatment group, −40.6% for the elafibranor 120 mg treatment group, and 3.2% for placebo.

[0085] In the primary efficacy analysis conducted using a non-parametric randomization-based ANCOVA with baseline ALP as covariate, each dose demonstrated a statistically significant treatment effect vs placebo (p<0.001). The treatment effect estimate was −52.0% (95% CI [−62.5; −41.5]) for the elafibranor 80 mg treatment group and −43.9% (95% CI [−55.7; −32.1]) for the elafibranor 120 mg treatment group (FIG. 1).

[0086] The primary efficacy supportive analysis conducted using an ANCOVA with baseline ALP as a covariate was consistent with the primary efficacy analysis. The treatment effect estimate was −51.4% (95% CI [−63.3; −39.5]) for the elafibranor 80 mg treatment group and −43.9% (95% CI [−55.8; −31.9]) for the elafibranor 120 mg treatment group (FIG. 1).

[0087] The mean (95% CI) ALP values from baseline through Week 12 are shown in FIG. 2 by treatment group. Both the elafibranor 80 mg and 120 mg treatment groups demonstrated declining mean ALP values over the 12 week study.

[0088] The mean (95% CI) relative changes (%) in ALP values from baseline through Week 12 are shown in FIG. 3 by treatment group. The mean relative changes (%) from baseline shows a decrease in ALP values over time for the elafibranor 80 mg and 120 mg treatment groups beginning at Week 2 and continuing up through Week 12.

[0089] The relative change from baseline in serum ALP was statistically significantly different from placebo at Endpoint for both the elafibranor 80 mg treatment group and the elafibranor 120 mg treatment group.

Example 5: Change in Pruritus (Through 5D-Itch Scale and VAS)

[0090] Pruritus scoring values and absolute changes from baseline are provided for each domain of the 5D-itch scale (duration, degree, direction, disability, and distribution) and for the VAS by subject and by visit; baseline and Endpoint values are flagged in this listing; total scores at each visit are also summarized in this listing.

[0091] Summaries of the pruritus scoring values, absolute changes in pruritus scoring values, and relative changes in pruritus scoring values for the 5D-itch scale (duration, degree, direction, disability, and distribution) and for the VAS were assessed. The median relative change from baseline to Endpoint in the pruritus VAS were −23.7%, −49.5%, and −7.1% for the elafibranor 80 mg, elafibranor 120 mg, and placebo treatment groups, respectively (FIG. 4).

[0092] The median relative changes (%) in the pruritus VAS from baseline through Week 12 are shown in FIG. 5 by treatment group. Both the elafibranor 80 mg and the elafibranor 120 mg treatment groups demonstrated declining median VAS as early as Week 2.

Example 6: Absolute and Relative Change from Baseline in Quality of Life (Using PBC-40 Questionnaire)

[0093] Mean absolute changes from baseline to Endpoint in the pruritus (itching) domain were −0.9, −4.1, and 2.1 for the elafibranor 80 mg, the elafibranor 120 mg, and the placebo treatment groups, respectively. Median absolute changes from baseline to Endpoint in the pruritus/itching domain were −1.0, −1.0, and 0.0 for the elafibranor 80 mg, the elafibranor 120 mg, and the placebo treatment groups, respectively. Median relative changes from baseline to Endpoint in the pruritus/itching domain were −25.0%, −20.8%, and 0% for the elafibranor 80 mg, the elafibranor 120 mg, and the placebo treatment groups, respectively. (FIG. 6).

CONCLUSION

[0094] The percentage of subjects reporting TEAEs (Treatment-Emergent Adverse Events) was 80.0%, 86.7%, and 80.0% for the elafibranor 80 mg, elafibranor 120 mg, and placebo groups, respectively. There was no worsening of pruritus with elafibranor. On the contrary, a higher relative reduction from baseline to Endpoint in the pruritus VAS scoring values was demonstrated for both elafibranor 80 mg (−23.7%) and 120 mg treatment groups (−49.5%) compared to the placebo (−7.1%) treatment group.

[0095] This reduction in the intensity/severity of pruritus was associated with an improvement in terms of quality of life as measured by the median relative change from baseline to Endpoint in the pruritus domain of PBC 40-questionnaire.