A Multi-part, Double Blind Study to Assess Safety, Tolerability and Efficacy of Tropifexor (LJN452) in PBC Patients

Inclusion criteria

• Age ≥ 18 years
• Diagnosis of PBC as demonstrated by the presence of at least 2 of the following 3 diagnostic criteria:

• History of alkaline phosphatase (ALP) elevated above upper limit of normal (ULN) for at least 6 months
• Positive antimitochondrial antibodies (AMA) titer or if AMA negative or in low titer (<1:80) PBC specific antibodies (anti-GP210 and/or anti-SP100 and/or antibodies against the major M2 components (PDC-E2, 2-oxo-glutaric acid dehydrogenase complex))
• Previous liver biopsy findings consistent with PBC
• At least 1 of the following markers of disease severity:

• ALP ≥ 1.67 × ULN
• Total bilirubin > ULN but < 1.5 × ULN
• In addition, patients must meet the following biochemical criteria at enrollment:

• Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≤ 5 × ULN
• Total bilirubin ≤ 1.5 × ULN
• INR ≤ ULN
• Taking UDCA for at least 12 months, or for at least 6 months and has reached maximal response to UDCA with a plateau in alkaline phosphatase, with no changes in dose for ≥ 3 months prior to Day 1.
• Patients must weigh at least 40 kg to participate in the study, and must have a body mass index (BMI) within the range of 18 - 40 kg/m2. BMI = Body weight (kg) / [Height (m)]2

Exclusion criteria

• Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception for 30 days before randomization, during dosing and for 30 days following the end of treatment.
• Presence of other concomitant liver diseases.

• Cirrhosis with complications, including history or presence of:
• Variceal bleed
• Uncontrolled ascites
• Encephalopathy
• Spontaneous bacterial peritonitis
• Significant hepatic impairment as defined by Child-Pugh classification of B or C, history of liver transplantation, current placement on a liver transplant list or current Model for End Stage Liver Disease (MELD) score ≥15.
• History of conditions that may cause increases in ALP (e.g., Paget's disease).
• Use of investigational drugs, or immunosuppressive drugs at the time of enrollment, or within 5 half-lives, or 30 days of randomization, whichever is longer; or longer if required by local regulations. Use of high dose oral steroids to treat co-morbid conditions (e.g., airways disease) will be allowed but must be properly documented as such in concomitant medications.
• Currently taking obeticholic acid or have taken obeticholic acid within 30 days of randomization
• Previous participation in CLJN452X2201 and received study medication within three months of randomization (or longer if required by local regulations).