REGENERATE study: Obeticholic acid shows antifibrotic benefit in NASH

The phase 3 REGENERATE study of the farnesoid X receptor agonist obeticholic acid (OCA), demonstrated significant antifibrotic benefits in participants with non-alcoholic steatohepatitis (NASH).

The multicentre, randomised, double-blind, placebo-controlled REGENERATE study (NCT02548351) included patients with biopsy-confirmed fibrosis (F2–F3), who were randomised 1:1:1 to receive a placebo, OCA 10 mg, or OCA 25 mg [1]. The study aimed to assess clinical outcomes over 48 months, with an interim analysis of histologic improvement at month 18. Despite the initial promising antifibrotic results at month 18, the study was terminated early in September 2023 due to failure to achieve marketing approval after a re-analysis of the data. Dr Arun J Sanyal (Virginia Commonwealth University, VA, USA) presented the final results over 48 months [2]. The primary endpoint was the time to the first occurrence of prespecified clinical outcomes, including progression to cirrhosis. Secondary endpoints focused on histologic improvements.

The intent-to-treat population (n=2,187) was used to assess efficacy. Clinical outcomes occurred in 18.8%, 15.8% (P=0.103 vs placebo), and 14.7% (P=0.044 vs placebo) of the participants treated with placebo, OCA 10 mg, and OCA 25 mg, respectively.

Improvement in fibrosis by ≥1 stage with no worsening of NASH, or NASH resolution with no worsening of fibrosis stage, occurred in 11.8% of the participants receiving placebo, 18.5% of those on OCA 10 mg (P=0.0004), and 20.8% of those on OCA 25 mg (P<0.001) (see Figure). Fewer participants receiving OCA progressed to cirrhosis than those receiving placebo. Treatment-emergent adverse events (TEAEs), serious TEAEs, and deaths were similar across all groups. Pruritus was the most common TEAE and the primary reason for treatment discontinuation, with gallbladder- and gallstone-related TEAEs being more frequent in the OCA 25 mg group.

Figure: Improvement of fibrosis in NASH patients [2]



NASH, non-alcoholic steatohepatitis; OCA, obeticholic acid.

“This end-of-study analysis demonstrates a trend towards benefit in clinical outcomes and reduced histological progression to cirrhosis in participants receiving OCA. The data confirms the antifibrotic benefit of OCA observed at 18 months. Safety results add to the largest longitudinal safety database in NASH, with no new safety concerns observed during more than 2 years of additional exposure,” Dr Sanyal concluded.

1. 
   
   1. Sanyal A, et al. J Hepatol. 2023;79(5):1110-1120.
   2. Sanyal A, et al. Final results from the phase 3 REGENERATE trial evaluating the effects of obeticholic acid in patients with pre-cirrhotic fibrosis due to nonalcoholic steatohepatitis. 1057e, DDW 2024, 18–21 May, Washington DC, USA.

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Posted on 11 July 202426 July 2024