Phase 4 Study of Obeticholic Acid Evaluating Clinical Outcomes in Patients With Primary Biliary Cholangitis

Primary Biliary Cholangitis (PBC) is a serious, life-threatening, bile acid related liver disease of unknown cause. Without treatment, it frequently progresses to liver fibrosis and eventual cirrhosis requiring liver transplantation or resulting in death. The investigational drug, Obeticholic Acid (OCA) is a modified bile acid and FXR agonist that is derived from the primary human bile acid chenodeoxycholic acid. The key mechanisms of action of OCA, including its choleretic, anti-inflammatory, and anti-fibrotic properties, underlie its hepatoprotective effects and result in attenuation of injury and improved liver function in a cholestatic liver disease such as PBC. The study will assess the effect of OCA compared to placebo, combined with stable standard care, on clinical outcomes in PBC participants.

This Phase 4, double-blind, randomized, placebo-controlled, multicenter study is being undertaken at up to 170 sites internationally to evaluate the effect of OCA on clinical outcomes in 428 participants with PBC. The study will include a screening period of up to 8 weeks, requiring two clinic visits. Eligible participants will be randomly allocated (1:1) to treatment with either OCA 5 mg or matching placebo tablets, taken orally once daily for the majority of participants; dose and frequency will be modified for participants with cirrhosis and classified as Child-Pugh (CP) B or C. Randomization will be stratified by standard treatment with UDCA (yes/no) and baseline liver function. The treatment period involves clinic visits approximately every 3 months. At the 3 month visit or any study visit thereafter, if study treatment is tolerated, participants' dose should be titrated per protocol in a blinded manner eg for participants who are non-cirrhotic or classified as CP A and randomized to OCA, they should receive the maximum daily dose of 10 mg OCA, those on placebo continue to receive placebo. Subsequently, daily dosage may return to 5 mg if necessary for these participants who are non-cirrhotic or classified as CP A, but should be increased to 10 mg if possible, based on tolerability and clinical judgment. Safety and tolerability will be assessed by monitoring adverse events and vital signs, and blood and urine testing. The study is event driven and total duration will be determined by the time required to accrue approximately 127 primary endpoint events, estimated to be approximately 10 years. Participants are expected to have a minimum follow-up time of approximately 6 years.

Eligibility Criteria:
Key Inclusion Criteria:

1. Definite or probable PBC diagnosis (consistent with American Association for the Study of Liver Diseases \[AASLD\] and the European Association for the Study of the Liver \[EASL\] practice guidelines; Lindor 2009; EASL 2009), as demonstrated by the presence of ≥2 of the following 3 diagnostic factors:

   * History of elevated Alkaline phosphatase levels for at least 6 months
   * Positive antimitochondrial antibody (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 \[PDC-E2, 2-oxo-glutaric acid dehydrogenase complex\])
   * Liver biopsy consistent with PBC
2. A mean total bilirubin \>ULN and ≤5x ULN and/or a mean ALP \>3x ULN
3. Either is not taking UDCA (no UDCA dose in the past 3 months) or has been taking UDCA for at least 12 months with a stable dose for ≥3 months prior to Day 0

Exclusion Criteria:

1. History or presence of other concomitant liver diseases including:

   * Hepatitis C virus infection
   * Active Hepatitis B infection; however, subjects who have seroconverted (hepatitis B surface antigen and hepatitis B e antigen negative) may be included in this study after consultation with the medical monitor
   * Primary sclerosing cholangitis (PSC)
   * Alcoholic liver disease
   * Definite autoimmune liver disease or overlap hepatitis
   * Nonalcoholic steatohepatitis (NASH)
   * Gilbert's Syndrome
2. Presence of clinical complications of PBC or clinically significant hepatic decompensation, including:

   * History of liver transplant, current placement on a liver transplant list, or current Model of End Stage Liver Disease (MELD) score \>12. Subjects who are placed on a transplant list despite a relatively early disease stage (for example per regional guidelines) may be eligible as long as they do not meet any of the other exclusion criteria
   * Cirrhosis with complications, including history (within the past 12 months) or presence of:

     * Variceal bleed
     * Uncontrolled ascites
     * Encephalopathy
     * Spontaneous bacterial peritonitis
   * Known or suspected HCC
   * Prior transjugular intrahepatic portosystemic shunt procedure
   * Hepatorenal syndrome (type I or II) or screening (Visit 1 or 2) serum creatinine \>2 mg/dL (178 μmol/L)
3. Mean total bilirubin \>5x ULN
4. Subjects who have undergone gastric bypass procedures (gastric lap band is acceptable) or ileal resection or plan to undergo either of these procedures
5. Other medical conditions that may diminish life expectancy, including known cancers (except carcinomas in situ or other stable, relatively benign conditions)
6. If female: plans to become pregnant, known pregnancy or a positive urine pregnancy test (confirmed by a positive serum pregnancy test), or lactating
7. Known history of human immunodeficiency virus infection
8. Medical conditions that may cause nonhepatic increases in ALP (eg, Paget's disease or fractures within 3 months)
9. Other clinically significant medical conditions that are not well controlled or for which medication needs are anticipated to change during the study
10. History of alcohol abuse or other substance abuse within 1 year prior to Day 0
11. Participation in another investigational product, biologic, or medical device study within 30 days prior to Screening. Participation in a previous study of OCA is allowed with 3 months washout prior to enrollment in this study
12. Mental instability or incompetence, such that the validity of informed consent or ability to be compliant with the study is uncertain
13. History of known or suspected clinically significant hypersensitivity to OCA or any of its components
14. UDCA naïve (unless contraindicated)