Safety, pharmacokinetics and pharmacodynamics of obeticholic acid in subjects with fibrosis or cirrhosis from NASH

Abstract Background & Aims Fibrosis stage is a strong predictor of nonalcoholic steatohepatitis (NASH) outcomes. Two blinded studies evaluated the pharmacokinetics, pharmacodynamics and safety of obeticholic acid (OCA) in subjects with staged NASH fibrosis or cirrhosis. Methods Study 747‐117 randomized 51 subjects with NASH (fibrosis stages F1–F4) to daily placebo, OCA 10 or OCA 25 mg (1:2:2) for 85 days. Study 747‐118 randomized 24 subjects with NASH cirrhosis (F4; Child‐Pugh [CP]‐A) and normal liver control subjects matched for similar body weight to daily OCA 10 or OCA 25 mg (1:1) for 28 days. Individual and combined study data were analysed. Results No severe or serious adverse events (AEs) or AEs leading to discontinuation or death occurred. Pruritus was the most frequent AE. Plasma OCA exposure (dose‐normalized area under the curve) increased with fibrosis stage but was a relatively poor predictor of hepatic OCA exposure (primary site of action), which remained constant across fibrosis stages F1–F3 and increased 1.8‐fold compared with F1 in subjects with cirrhosis due to NASH. Both cohorts showed robust changes in farnesoid X receptor activation markers with OCA treatment and marked decreases in alanine transaminase, aspartate transaminase and gamma‐glutamyltransferase. Conclusions Despite higher drug exposures in subjects with NASH cirrhosis, short‐term daily treatment with OCA 10 or 25 mg was generally safe and well tolerated in subjects with NASH fibrosis or NASH CP‐A cirrhosis. Both cohorts experienced improvements in nonhistologic pharmacodynamic markers consistent with previously conducted OCA phase 2 and phase 3 studies in NASH fibrosis.