New analysis encourages Intercept to refile NASH drug for approval

A drug being tested against a liver disease thought to affect millions of people continues to hold up in a large clinical trial, according to its developer, New Jersey-based Intercept Pharmaceuticals.

The trial has enrolled thousands of patients with nonalcoholic steatohepatitis, or NASH, a disease characterized by a buildup of fat in the liver that progressively scars the organ. NASH is often asymptomatic until later stages, making it more difficult to diagnose. Yet, this “silent” disease has become one of the leading causes for liver transplants in the U.S.

Drug companies large and small have been spent more than a decade trying to develop the first approved treatment for NASH. In that race, Intercept and its candidate, known as obeticholic acid or OCA for short, have held a leading position.

In early 2019, OCA became the first drug to succeed in a Phase 3 study of NASH patients. The trial, named REGENERATE, enrolled participants with moderate to severe liver scarring, and found that a significantly greater percentage of those given a high dose of Intercept’s drug — as opposed to a placebo — had their liver scarring improve without their NASH getting worse.

Specifically, results from 931 participants showed that, after a year and a half of treatment, 23% of those on high-dose OCA experienced no NASH worsening and at least a one-stage improvement in scarring, as measured by a five-tier scale used to gauge liver health. In the placebo group, 12% of participants met that criteria. The study also evaluated OCA’s ability to resolve NASH, but found that, while more patients in both the higher- and lower-dose arms did experience this, the data weren’t statistically significant.

On Thursday, more than three years after that initial readout, Intercept said that a new analysis of the REGENERATE results is also positive.

Intercept explained this analysis “mirrored the original analysis population,” but used a different approach to assess liver tissues — a method that was “in line” with guidance from the Food and Drug Administration. The conclusions, however, were roughly the same, with 22.4% of patients on high-dose OCA and 9.6% on placebo achieving the main scarring goal after 18 months. Again, the goal for NASH resolution was not met.

Researchers also looked at safety data on almost 2,500 participants who received at least one dose of any treatment in the study. Median exposure to therapy in this new analysis was three and a half years, versus 15 months in the prior analysis. Treatment-emergent adverse events, including serious ones, and deaths were “generally balanced” across the OCA and placebo arms, according to Intercept, with the most common event being itching.

Intercept said less than 3% of participants in any group experienced serious gallbladder-related events, while the high-dose OCA group had higher rates of biliary events like gallstones. The company also noted that an independent group of experts identified a “numerically higher number” of liver safety events in the high-dose OCA arm, with the “vast majority” deemed mild. The number of instances of kidney damage or major adverse cardiovascular events was “low and balanced across treatment groups,” Intercept reported.

“We are thrilled that OCA has demonstrated consistent improvement in fibrosis based on a second methodology and we now have two positive, statistically significant results for this primary endpoint from our pivotal REGENERATE trial,” Jerry Durso, Intercept’s CEO, said in a statement.

“The weight of evidence in both safety and efficacy has notably increased and provides a more robust benefit-risk profile of OCA,” Durso added.

Intercept had previously asked the FDA to approve its drug as a NASH treatment, but the agency rejected the application. According to the company, agency staff were not convinced that OCA’s purported benefits outweighed its potential risks, and therefore they wanted to more data to be collected from REGENERATE before undertaking a regulatory review.

With results from the new analysis in hand, Intercept said it intends to refile its application. The company has a pre-submission meeting with the FDA scheduled for later this month.

An approval in NASH would expand the label for OCA, which is already cleared in the U.S. under the brand name Ocaliva to treat a disease that affects bile ducts. Last year, Intercept recorded $363 million in net Ocaliva sales.

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