Obeticholic Acid Reduces Fibrosis in Nonalcoholic Steatohepatitis

By Will Boggs MD

December 18, 2019

NEW YORK (Reuters Health) - Obeticholic acid reduces fibrosis and disease activity in patients with nonalcoholic steatohepatitis (NASH), according to a planned interim analysis of the ongoing REGENERATE phase-3 trial.

"The improvement in fibrosis is of great significance because it is proof that fibrosis can be reversed with this drug in NASH," Dr. Arun J. Sanyal of Virginia Commonwealth University, in Richmond, told Reuters Health by email. "This is the first NASH drug to do this convincingly."

Obeticholic acid, a farnesoid X receptor (FXR) agonist approved for the treatment of primary biliary cholangitis, has been shown to improve key histological features of NASH, including fibrosis.

The drug received breakthrough designation from the U.S. Food and Drug Administration (FDA) for treating NASH in 2015. Intercept Pharmaceuticals, which funded the trial, filed its new-drug application for the treatment of NASH-related liver fibrosis this November.

Dr. Sanyal and colleagues from 332 centers in 20 countries report the results of a prespecified month-18 interim analysis on the safety and efficacy of obeticholic acid in improving fibrosis and underlying disease activity in 911 patients with NASH.

At baseline, most patients had stage F3 fibrosis (54%-58%) and NAFLD (nonalcoholic fatty-liver disease) activity scores (NAS) scores of 6 or higher (68%-70%), which reflect advanced fibrosis and high disease activity.

The primary endpoint of fibrosis improvement by at least one stage with no worsening of NASH was achieved by 12% of patients in the placebo group, 18% of patients on obeticholic acid 10 mg (P=0.045) and 23% of patients on obeticholic acid 25 mg (P=0.0002), the researchers report in The Lancet.

The second primary endpoint of NASH resolution with no worsening of fibrosis was achieved by more patients in lower-dose (11%) and higher-dose groups (12%) than in the placebo group (8%), but these differences fell short of statistical significance.

Patients in both active-treatment groups experienced significantly greater decreases in key liver enzymes (ALT and AST) than did patients in the placebo group, and obeticholic acid treatment resulted in significantly greater decreases in body weight at month 18.

Treatment-emergent adverse events occurred with similar overall frequency in the three groups. Patients receiving obeticholic acid experienced early increases in LDL-cholesterol, glucose and hemoglobin A1c (all of which subsequently returned towards baseline levels) and persistent dose-dependent decreases in triglycerides.

"These (results) look very encouraging, and it is hoped that in the long term this will translate into decreased progression to cirrhosis," Dr. Sanyal said.

"Obeticholic acid, as with other FXR agonists, increases LDL cholesterol," he said. "In patients with NASH, the target LDL should be monitored and statins used as needed to optimize cardiovascular risk protection. Statins are safe to use in this population."

Dr. Sanyal added, "Cardiovascular disease is a leading cause of morbidity in this population, and all patients with NASH, regardless of whether they are on obeticholic acid, should have cardiovascular risk assessed and optimized in line with local standard of care."

Dr. Mohammed Eslam of Westmead Hospital and the University of Sydney, Australia, who co-authored a linked editorial, told Reuters Health by email, "Obeticholic acid could change management, as it could become first Food and Drug Administration (FDA)-approved medicine for NASH. As liver fibrosis is the main cause of all liver- and non-liver- (such as cardiovascular diseases and diabetes) related complications of NASH, the drug can also improve prognosis of NASH."

"Currently, this clinical trial is still ongoing for at least 4 years, and results of follow-up will help to answer the questions of long-term impact on prognosis," he said.

"Other drugs are expected to be available in the next few years and this will lead to changes in the treatment paradigm," Dr. Eslam added. "However, improved recognition of NAFLD, which is still under-diagnosed, is critical and may identify people who will benefit from these drugs."

Dr. Simone Strasser of Royal Prince Alfred Hospital, The University of Sydney, in Camperdown, Australia, a REGENERATE study investigator but not a co-author of the report, told Reuters Health by email, "If and when obeticholic acid is approved for the treatment of NASH, there will be a major challenge for clinicians to identify which patients may benefit from treatment, who will tolerate treatment, and who is benefitting from treatment. Furthermore, with competing mortality risks of cardiovascular disease and malignancy in patients with NASH and its metabolic risk factors, a long-term clinical benefit must be established."

Intercept Pharmaceuticals had various relationships with several of the authors, including Dr. Sanyal.

SOURCE: https://bit.ly/2LQCULc and https://bit.ly/2tggV9Z The Lancet, online December 5, 2019.

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