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WASHINGTON -- A daily oral dose of obeticholic acid (Ocaliva) led to improvement in liver fibrosis without disease worsening for patients with non-alcoholic steatohepatitis (NASH), and with a good safety profile, according to a new interim analysis of the phase III trial that relied on a consensus panel of pathologists.

For the primary analysis of patients with stage F2-F3 fibrosis, the group on the 25-mg dose of obeticholic acid were significantly more likely to meet the endpoint response of at least one stage of fibrosis improvement without any worsening of NASH (22.4% vs 9.6% with placebo at 18 months; P<0.0001), reported Arun Sanyal, MD, of the Virginia Commonwealth University in Richmond.

A higher response rate with the farnesoid X receptor antagonist versus placebo, respectively, was seen in patients with stage F3 fibrosis:

• F2 fibrosis: 18.7% vs 9.9% (P=0.0396)
• F3 fibrosis: 25.4% vs 9.5% (P=0.0001)

Overall improvement in fibrosis stage occurred in nearly twice as many patients on the 25-mg dose at 18 months (37.3% vs 19.8% with placebo), while worsening of fibrosis stage was less frequent with the 25-mg dose (17.6% vs 23.8% with placebo), according to findings presented at a late-breaking presentation at the annual Liver Meeting sponsored by the American Association for the Study of Liver Diseases (AASLD).

A third arm of the trial studied a 10-mg dose of obeticholic acid, but both the primary outcome and other key endpoints were not significantly improved over placebo at this dose level.

The new interim analysis of the ongoing trial is consistent with prior results that relied on a single pathology reader per biopsy. Following FDA's of the drug for NASH, and discussions with the agency, developer Intercept increased the number of readers in an effort to eliminate potential bias. In the new analysis, two pathologists had to independently agree on response criteria, with a third reader acting as a tiebreaker.

Another sticking point with obeticholic acid has been its safety. The FDA last year restricted the use of the drug in primary biliary cholangitis -- where the drug was initially approved in 2016 -- due to the risk of serious liver injury in patients with advanced cirrhosis.

According to Sanyal, the drug showed a favorable safety in NASH, with data available on 2,477 total patients, about 1,000 of whom have safety data out to year 4.

Deaths occurred in a similar proportion of patients on the 25-mg obeticholic acid dose (1.2%), 10-mg dose (1.1%), and on placebo (1.0%). The most common treatment-emergent adverse event (TEAE) with obeticholic acid was pruritus (55% vs 33% vs 24%, respectively).

"This is the largest safety database in NASH to date," Sanyal explained.

Obeticholic acid led to an early and modest spike in low-density lipoprotein (LDL) levels, which eventually returned to around baseline levels at 12 months. Serious TEAEs were seen in a similar proportion of treatment groups: 26.1% of patients on the 25-mg obeticholic acid dose, 24.7% of those on the 10-mg dose, and 21.9% of placebo patients.

"The confirmed antifibrotic effect, together with extended exposure, supports a positive benefit-risk in patients with advanced fibrosis due to NASH," Sanyal noted in his presentation.

However, the updated analysis arrives a little more than a month since Intercept announced the negative findings of the phase III trial involving obeticholic acid in NASH patients with compensated cirrhosis. Undeterred, the company said it to resubmit an application for approval by the end of the year based on the REGENERATE data.

The double-blind, multicenter REGENERATE trial enrolled NASH patients with stages F1-F3 fibrosis from 2015 to 2018. Participants were randomized 1:1:1 to receive once-daily oral doses of obeticholic acid, at the 25-mg or 10-mg dose level, or placebo. The primary analysis included 931 patients with F2 (40%) or F3 (60%) fibrosis. Mean patient age was 54-55 and 58-60% were women. Nearly all were white, and mean body mass index of 34.

To date, no drug has been approved for NASH, and the disease remains a major cause of liver transplantation, as well as morbidity and mortality. In the U.S., approximately 20% of NASH patients have advanced fibrosis, a "principal predictor" of liver-related deaths.

"Development of effective pharmacotherapy for NASH has been challenging," said Na Li, MD, PhD, of the Ohio State University Wexner Medical Center in Columbus, who is also a sub-investigator for the REGENERATE trial.

"Obeticholic acid by far is the first agent from phase III trials that showed significant improvement in fibrosis," said Li. "This is definitely exciting news for our patients with NASH."

"However, potential side effects, particularly pruritus, and the necessity of long-term therapy remain clinical concerns for tolerability," Li explained.

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