NEW SAFETY AND EFFICACY ANALYSES FROM THE REGENERATE TRIAL OF OBETICHOLIC ACID FOR THE TREATMENT OF NONALCOHOLIC STEATOHEPATITIS

Background: Nonalcoholic steatohepatitis (NASH) is a major cause of liver-related morbidity, mortality, and the leading indication for liver transplant in the US. Fibrosis is the best predictor of clinical outcomes in NASH. Obeticholic acid (OCA), a first-in-class farnesoid X receptor agonist, demonstrated efficacy as an antifibrotic agent in the phase 3 REGENERATE trial in NASH. The goal of the new analysis was to confirm the original 18-month biopsy efficacy results and to provide additional safety data from more than 8000 total subject-years, with nearly 1000 subjects receiving OCA for ≥4 years in the REGENERATE study.

Methods: In this multicenter, randomized, double-blind, placebo-controlled phase 3 study, subjects were randomized 1:1:1 to receive once-daily oral placebo, OCA 10 mg, or OCA 25 mg. Safety data were evaluated from 2477 subjects who received ≥1 dose of the study drug. A consensus method using a panel of 3 pathologists for histologic assessment of liver biopsies per NASH Clinical Research Network criteria was employed to confirm the results of the original 18-month interim efficacy analysis performed by individual readers.

Results: Treatment-emergent adverse events (TEAEs), serious TEAEs, and deaths were balanced across treatment groups (N=2477). Pruritus was the most common TEAE in all 3 treatment groups; its incidence was higher in both OCA groups compared to placebo. For adverse events of special interest, incidence of pancreatitis and hepatic disorders was similar between the OCA and placebo groups. The incidence of gallbladder- and gallstone-related TEAEs (including serious events) was higher in both OCA groups compared to placebo, though most were mild to moderate in severity and managed with temporary drug interruption and usual clinical care (Table 1). In the new analysis of the intent-to-treat population (n=931) using a consensus read method, 22.4% of subjects receiving OCA 25 mg experienced ≥1 stage improvement of fibrosis with no worsening of NASH at month 18 vs 9.6% of subjects receiving placebo (primary endpoint), which was consistent with the original analysis performed by individual readers (Figure 1).

Conclusions: In the ongoing REGENERATE trial, subjects receiving OCA 25 mg were twice as likely to experience ≥1 stage improvement in liver fibrosis with no worsening of NASH at month 18 compared to subjects receiving placebo at 18 months using 2 different histologic methodologies. The confirmed antifibrotic effect in liver histology, together with extended exposure within the largest safety database in NASH to date, demonstrates that OCA 25 mg was generally safe and well tolerated, supporting the long-term use of OCA to treat pre-cirrhotic fibrosis due to NASH.