Obeticholic acid reduces progression to cirrhosis in patients with MASH-related fibrosis

Treatment with obeticholic acid (OCA) improves clinical outcome in patients with precirrhotic fibrosis due to metabolic dysfunction-associated steatohepatitis (MASH), with a reduction in histological progression to cirrhosis seen in those receiving the 25-mg dose, as seen in the final results of the REGENERATE study.

Moreover, patients who received OCA 10 mg show fibrosis improvement by ≥1 stage and decreases in the biochemical markers of liver injury and oxidative stress, indicating the suitability of this drug in the treatment of primary biliary cholangitis.

“These data confirm the antifibrotic benefit of OCA observed at month 18 and support OCA-related effects on fibrosis,” said lead author Dr Arun J Sanyal from the Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University, Richmond, Virginia, US, who presented the findings at EASL 2024.

Patients with biopsy-confirmed fibrosis (F2‒F3) were randomized to receive OCA 10 mg (n=825), 25 mg (n=827), or placebo (n=825). The first occurrence of prespecified clinical outcomes, including progression to cirrhosis, was the primary outcome. Measures of histologic improvement and biochemical markers of liver function were secondary.

Sanyal and his team assessed the efficacy of OCA in the intent-to-treat (ITT) population (n=2,187) and its safety in 2,477 patients with a median exposure of >4 years. An independent expert committee then adjudicated the outcomes.

Progression

Patients across treatment groups had similar baseline demographics and clinical characteristics. In the ITT population, clinical outcomes occurred in 18.8 percent of patients in the placebo arm, 15.8 percent in the 10-mg arm, and 14.7 percent in the 25-mg arm. [EASL 2024, abstract LBP-036]

Compared with placebo, OCA 10 mg had a hazard ratio (HR) of 0.814 (95 percent confidence interval [CI], 0.635‒1.043), while that of the 25-mg dose was 0.772 (95 percent CI, 0.600‒0.994). This benefit was due to the fewer OCA-treated patients who progressed to cirrhosis.

More patients in the OCA arms achieved fibrosis improvement by ≥1 stage with no worsening of MASH (p<0.001 for both dose groups) than in the placebo arm.

Such improvement specifically occurred in 27.0 percent, 37.1 percent, and 39.3 percent of those treated with placebo, OCA 10 mg, and OCA 25 mg, respectively. In contrast, worsening of fibrosis by ≥1 stage occurred in 23.5 percent, 19.3 percent, and 18.5 percent, respectively.

Safety profile

Treatment with OCA resulted in greater dose-dependent reductions in mean serum alanine aminotransferase, aspartate aminotransferase, and gamma glutamyl transferase levels when compared with placebo.

Additionally, the three groups had comparable numbers of treatment-emergent adverse events (TEAEs), serious TEAEs, and deaths. Pruritus and gallbladder- and gallstone-related TEAEs more frequently occurred in patients receiving OCA 25 mg than in those treated with OCA 10 mg or placebo.

“The safety results add to the largest safety database in MASH, with a median OCA exposure of 52 months and no new safety concerns with >2 years of additional exposure,” Sanyal said.

OCA, a first-in-class farsenoid X receptor agonist, has been shown to reverse or reduce fibrosis progression in preclinical and clinical studies. [Lancet 2015;385:956-965]

“REGENERATE was discontinued in September 2023 for failure to achieve marketing approval after a consensus reanalysis of the month 18 data,” Sanyal said.