Results from a new efficacy and safety analysis of the REGENERATE trial of obeticholic acid for treatment of pre-cirrhotic fibrosis due to nonalcoholic steatohepatitis

Abstract

Background & aims: Obeticholic acid (OCA) is a first-in-class farnesoid X receptor agonist and antifibrotic agent in development for treating pre-cirrhotic liver fibrosis due to nonalcoholic steatohepatitis (NASH). We aimed to validate the original 18-month liver biopsy analysis from the phase 3 REGENERATE trial of OCA for treatment of NASH with a consensus panel analysis, provide additional histology data in a larger population, and evaluate safety from >8000 total patient-years' exposure with nearly 1000 subjects receiving study drug for >4 years.

Methods: Digitized whole-slide images were evaluated independently by panels of 3 pathologists using the NASH Clinical Research Network scoring system. Primary endpoints were (1) improvement in fibrosis ≥1 stage with no worsening of NASH or (2) NASH resolution with no worsening of fibrosis. Safety was assessed by laboratory values and adverse events.

Results: Prespecified efficacy analyses included 931 subjects. The proportion of subjects achieving improvement ≥1 stage fibrosis with no worsening of NASH was 22.4% for OCA 25 mg vs 9.6% for placebo (p<0.0001). More subjects receiving OCA 25 mg (6.5%) achieved NASH resolution with no worsening of fibrosis vs placebo (3.5%; p=0.093). Histology data in a larger population of 1607 subjects supported these results. Safety data included 2477 subjects. Incidence of treatment-emergent adverse events (TEAEs), serious TEAEs, and deaths was not substantively different across treatment groups. Pruritus was the most common TEAE. Rates of adjudicated hepatic, renal, and cardiovascular events were low and similar across treatment groups.

Conclusions: These results confirm the antifibrotic effect of OCA 25 mg. OCA was generally well tolerated over long-term dosing. The data support a positive benefit:risk profile in patients with pre-cirrhotic liver fibrosis due to NASH.

Impact and implications: Patients with nonalcoholic steatohepatitis (NASH) often have liver scarring (fibrosis), which causes an increased risk of liver-related illness and death. Preventing progression of fibrosis to cirrhosis or reversing fibrosis are the main goals of drug development for treating NASH. In this clinical trial of obeticholic acid (OCA) in patients with NASH (REGENERATE), we reaffirmed our previous results demonstrating that OCA was superior to placebo in improving fibrosis using a more rigorous consensus panel analysis of liver biopsies taken at month 18. We also showed that OCA treatment resulted in dose-dependent reductions of serum liver biochemistries and liver stiffness measurements compared with placebo, even in subjects in whom histologic fibrosis did not change at 18 months, providing evidence that the benefit with OCA extends beyond what is captured by the ordinal NASH CRN scoring system. OCA was well tolerated with a favorable safety profile supporting a positive benefit:risk in patients with pre-cirrhotic liver fibrosis due to NASH.