Phase 2 Study on Effects of Obeticholic Acid (OCA) on Lipoprotein Metabolism in Participants With Primary Biliary Cirrhosis

A Phase 2 Clinical Trial Investigating the Effects of Obeticholic Acid on Lipoprotein Metabolism in Subjects With Primary Biliary Cirrhosis

The purpose of this study was to determine if OCA had an effect on cholesterol levels in the blood in participants with primary biliary cirrhosis (PBC).

This was a phase 2, open-label, multicenter study evaluating the effects of OCA on lipoprotein metabolism in participants with PBC; in particular, OCA's effects on high-density lipoprotein cholesterol. Nuclear magnetic resonance spectroscopy was utilized to quantify the changes in lipoprotein particle sizes and concentrations. Components of reverse cholesterol transport were also assessed.

Key Inclusion Criteria:

1. Definite or probable PBC diagnosis as demonstrated by the presence of ≥ 2 of the following 3 diagnostic factors:

   • History of elevated alkaline phosphatase levels for at least 6 months
   • A positive anti-microbial antibody (AMA) titer or, if AMA negative or in low titer (<1:80), PBC-specific antibodies
   • Liver biopsy consistent with PBC

2. Taking UDCA for at least 12 months (stable dose for ≥ 3 months) prior to Day 0 or unable to tolerate UDCA (no UDCA for ≥ 3 months prior to Day 0).

3. Contraception: Female participants must have been postmenopausal, surgically sterile, or if premenopausal, were prepared to use ≥ 1 effective (≤ 1% failure rate) method of contraception during the trial and until at least 30 days after the last dose of Investigational Product.

4. Must have provided written informed consent and agreed to comply with the trial protocol.

Key Exclusion Criteria:

1. Participants with decompensated PBC (as determined by the Investigator).

2. Severe pruritus or systemic treatment for pruritus (for example, treatment with bile acid sequestrants or rifampicin) within 2 months of Day 0.

3. History or presence of other significant liver diseases including:

   • Active or chronic Hepatitis B or C virus infection
   • Primary sclerosing cholangitis
   • Alcoholic liver disease
   • Definite autoimmune liver disease or overlap hepatitis
   • Nonalcoholic steatohepatitis

   Note: Participants with Gilbert's disease or those with a history of hepatitis B who were currently antigen negative and seroconverted were not considered exclusionary.

4. Uncontrolled diabetes or other uncontrolled or unstable medical condition that may have interfered with trial results.

5. Administration of any of the following medications as specified below:

   • Prohibited 28 days prior to Day 0: bile acid sequestrants including cholestyramine, colesevelam, colestipol or omega-3 fatty acid containing dietary supplements
   • Prohibited 3 months prior to Day 0 and throughout trial participation: serum-lipid modifying agents including 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors, fenofibrate or other fibrates, nicotinic acid and derivatives, ezetimibe, Vitamin E (other than as standard dietary supplement)
   • Prohibited 6 months prior to Day 0 and throughout the trial participation: azathioprine, colchicine, cyclosporine, methotrexate, mycophenolate mofetil, pentoxifylline; budesonide and other systemic corticosteroids; potentially hepatotoxic drugs (including α-methyl-dopa, sodium valproic acid, isoniazide, or nitrofurantoin)
   • Prohibited 12 months prior to Day 0 and throughout the trial participation: antibodies or immunotherapy directed against interleukins or other cytokines or chemokines

6. Planned change in diet or exercise habits during participation in the trial.

7. Presence or history of clinically significant cardiac arrhythmias that may have prohibited the participant from participating in the trial.

8. If female: known pregnancy, or had a positive urine pregnancy test (confirmed by a positive serum pregnancy test), or lactating.

9. Recent (3 months prior to day 0) participation in another trial involving OCA or participation in another investigational trial (30 days prior to Day 0) and during the trial.