A 52-week, placebo-controlled, randomized, Phase 3 study to evaluate the safety and efficacy of seladelpar in subjects with primary biliary cholangitis (PBC) and an inadequate response to or intolerance to ursodeoxycholic acid (UDCA)

The participants might enter the ongoing open-label safety study (NCT03301506) following this double-blind study.

Primary:

• To evaluate the safety and effect on cholestasis of two seladelpar regimens (5 mg/day titrated to 10 mg/day and 10 mg/day) over 52 weeks of treatment compared to placebo

Key Secondary:

• To evaluate the effect of seladelpar on normalization of alkaline phosphatase (AP) levels
• To evaluate the effect of seladelpar on pruritus

Inclusion Criteria:

1. Must have given written informed consent (signed and dated) and any authorizations required by local law

2. 18 to 75 years old (inclusive)

3. Male or female with a diagnosis of PBC, by at least two of the following criteria:

   • History of AP above ULN for at least six months
   • Positive anti-mitochondrial antibody (AMA) titers (>1/40 on immunofluorescence or M2 positive by enzyme linked immunosorbent assay [ELISA]) or positive PBC-specific antinuclear antibodies
   • Documented liver biopsy result consistent with PBC

4. On a stable and recommended dose of UDCA for the past twelve months OR intolerant to UDCA (last dose of UDCA > 3 months prior to Screening)

5. AP ≥ 1.67 × ULN

6. Females of reproductive potential must use at least one barrier contraceptive and a second effective birth control method during the study and for at least 90 days after the last dose. Male subjects who are sexually active with female partners of reproductive potential must use barrier contraception and their female partners must use a second effective birth control method during the study and for at least 90 days after the last dose

Exclusion Criteria:

1. Previous exposure to seladelpar (MBX-8025)

2. A medical condition, other than PBC, that in the investigator's opinion would preclude full participation in the study or confound its results (e.g., cancer)

3. AST above 3 × ULN

4. ALT above 3 × ULN

5. Total bilirubin above 2.0 × ULN

6. Advanced PBC as defined by the Rotterdam criteria (albumin below LLN AND total bilirubin above 1 × ULN)

7. Creatine kinase (CK) above 1.0 × ULN

8. eGFR below 60 mL/min/1.73 m2 (calculated by MDRD formula)

9. International normalized ratio (INR) above 1.0 × ULN

10. Platelet count below 100 × 103/µL

11. Presence of clinically significant hepatic decompensation, including:

    • History of liver transplantation, current placement on liver transplantation list, or current MELD score ≥ 15
    • Complications of portal hypertension, including known esophageal varices, history of variceal bleeds or related interventions (e.g., transjugular intrahepatic portosystemic shunt placement), relevant ascites, hepatic encephalopathy
    • Cirrhosis with complications, including history or presence of spontaneous bacterial peritonitis

12. Other chronic liver diseases:

    • Current features of auto-immune hepatitis as determined by the investigator based on immunoserology, liver biochemistry and histology
    • Primary sclerosing cholangitis determined by presence of diagnostic cholangiographic findings
    • History or clinical evidence of alcoholic liver disease
    • History or clinical evidence of alpha-1-antitrypsin deficiency
    • Biopsy confirmed nonalcoholic steatohepatitis
    • History or evidence of Gilbert' Syndrome with elevated total bilirubin
    • History or evidence of hemochromatosis
    • Hepatitis B defined as presence of hepatitis B surface antigen (HBsAg)
    • Hepatitis C defined as presence of HCV RNA

13. Known history of HIV

14. Evidence of significant alcohol consumption

15. Evidence of drug abuse

16. Subjects with inadequate response to obeticholic acid (OCA) or intolerance to OCA: OCA must be discontinued 30 days prior to Screening

17. Use of colchicine, methotrexate, azathioprine, or long-term systemic corticosteroids (> 2 weeks) within two months prior to Screening

18. Use of fibrates within 30 days prior to Screening

19. Use of simvastatin within 7 days prior to Screening

20. Use of an experimental or unapproved treatment for PBC within 30 days prior to Screening

21. Use of experimental or unapproved immunosuppressant within 30 days prior to Screening

22. Treatment with any other investigational therapy or device within 30 days or within five half-lives, whatever is longer, prior to Screening

23. For females, pregnancy or breast-feeding

24. Any other condition(s) that would compromise the safety of the subject or compromise the quality of the clinical study, as judged by the investigator