938 Positive Results From REGENERATE: A Phase 3 International, Randomized, Placebo-Controlled Study Evaluating Obeticholic Acid Treatment for NASH

Abstract

INTRODUCTION: Obeticholic acid (OCA), an FXR agonist, improved both fibrosis and histologic features of nonalcoholic steatohepatitis (NASH) in the Ph2 FLINT study. This Month 18 pre-specified interim analysis of the Ph3 REGENERATE study evaluated the effect of OCA on liver histology in patients (pts) with biopsy-confirmed NASH1. METHODS: Pts with NASH and fibrosis stages F2-3 (ITT), and an exploratory group of F1 pts with metabolic syndrome, were randomized to placebo (PBO), OCA 10 mg, or OCA 25 mg QD. Primary endpoints were fibrosis improvement (≥1 stage) with no worsening of NASH, or NASH resolution with no worsening of liver fibrosis per liver biopsy. The safety population included all randomized and dosed pts (F1-3, N = 1968). Clinical outcomes will be evaluated at the end-of-study. RESULTS: The ITT population included 931 pts (PBO [n = 311], OCA 10mg [n = 312] or OCA 25mg [n = 308]), comprised of 44% F2 and 56% F3. Baseline characteristics were well-balanced across groups. Results in Table 1. The primary fibrosis endpoint was met by 11.9% PBO, 17.6% OCA 10 mg (P = 0.0446 vs PBO), and 23.1% OCA 25 mg (P = 0.0002 vs PBO) pts (ITT). The primary NASH endpoint was not statistically significant (ITT); however significantly more pts on OCA 25 mg showed improvements in hepatocellular ballooning (P = 0.0011 vs PBO) and lobular inflammation (P = 0.0322 vs PBO). Dose-dependent reductions in ALT, AST and GGT were observed. Pruritus was the most common AE (19% PBO, 28% OCA 10mg, 51% OCA 25 mg) and was predominantly mild to moderate in severity (severe pruritus: < 1% PBO, < 1% OCA 10mg, 5% OCA 25 mg). SAEs occurred in 11% PBO, 11% OCA 10 mg and 14% OCA 25 mg pts. Increases in LDLc with OCA were observed by Week 4, but approached baseline by Month 18 (OCA 25mg: LS mean change Wk4 +22.6 mg/dL, M18 + 4.0 mg/dL). Three deaths occurred; none were considered treatment-related (PBO n = 2; OCA 25 mg n = 1). CONCLUSION: Treatment with OCA 25mg improved liver fibrosis, key histologic features of steatohepatitis and liver biochemistry, demonstrating consistent efficacy with an overall AE profile similar to previous studies. 1 Interim analysis results at 18 months are based on surrogate endpoints and impact on clinical outcomes has not been confirmed. The REGENERATE study is ongoing to confirm the clinical benefit of OCA.