Intercept charts new path to NASH approval for obeticholic acid, as long as safety holds

A year after the FDA handed Intercept Pharmaceuticals a disappointing ruling for its potential nonalcoholic steatohepatitis (NASH) medicine, the company thinks it's found a detour—as long as its safety holds up. 

After months of deliberations with the FDA over the first half of the year, Intercept now has enough feedback to begin re-reviewing obeticholic acid's late-stage clinical trial and sort through additional safety data for the drug's long-sought NASH approval, CEO Jerome Durso told analysts on a call Thursday. 

Those discussions came after Intercept's stinging FDA rejection for an accelerated approval last June. Intercept's drug, already approved for primary biliary cholangitis (PBC) as Ocaliva, looked poised to become the first approved in the hotly contested NASH arena with a specific nod in patients with liver fibrosis, or scarring. 

NASH is a progressive fatty liver disease that largely stems from obesity, rather than alcohol misuse. The fat buildup can cause inflammation and scarring and, in some cases, may lead to cirrhosis, liver failure and cancer. 

RELATED: NASH front-runner Intercept, already delayed twice, faces another FDA setback

There are no approved drugs in the NASH field, although it has sent many pharma players tumbling trying. Analysts believe the disease could generate as much as $35 billion in annual sales. 

Notable failures in NASH include Pfizer, which has recently canned three prospects, alongside companies like Genfit and NGM Biopharmaceuticals. Many hopefuls have been plagued by side effects that have caused trial patients to drop out, such as itchiness. 

After multiple pandemic delays last year, the FDA told Intercept in a letter last June that obeticholic acid’s “predicted benefit … remains uncertain” and doesn’t warrant the safety risks.

At the time, the New York-based company said the agency wanted longer-term data from its phase 3 trial to back one of its endpoints, a reduction in liver fibrosis. The drug has been hit with even more safety concerns since then. In May, the FDA restricted the Ocaliva's approval in PBC, saying it could lead to liver failure in some patients with advanced cirrhosis. 

Now, Intercept is looking to get back on track, and it’s leaning on its new chief medical officer, M. Michelle Berrey, M.D., to lead the way. The company’s goal is to have a presubmission meeting with the FDA by the first half of 2022, Durso said.

“As they become available, we’ll be evaluating safety and efficacy findings internally to inform our decision-making about a potential resubmission,” Durso told analysts. 

RELATED: Intercept cuts 25% of workforce after NASH rejection from FDA

To get there, Intercept will increase the number of independent pathologists to evaluate each clinical trial biopsy from one to three after the FDA raised questions about using a single pathologist, Berrey said.

This method is intended to eliminate potential bias and guarantee consensus among the experts, who will compare the biopsies at baseline and after 18 months on the treatment. If two of the pathologists are split on their reading, the third will break the tie. 

Because this change will affect the trial's conclusions, Intercept will have the panel of pathologists re-review all of the biopsies from its late-stage effort, known as Regenerate. This includes 500 biopsies that weren't part of the interim analysis, Berrey said.

Intercept has also racked up new obeticholic acid safety data since that interim analysis in late 2019, with patients reporting more than double the amount of time on the drug, Berrey said.

The re-review process, which will be used in another phase 3 trial called Reverse studying patients with cirrhosis, will take until the first half of 2022. Until then, the company will be “evaluating internally and making data-driven decisions” on its potential NASH bid.

To RBC Capital Markets, Intercept’s data boost and new trial design will “have much more power" to determine a benefit for obeticholic acid patients, according to a note sent on Thursday. However, it “still remains unclear” exactly how well the treatment has to perform to satisfy regulators, particularly when considering safety, RBC analyst Brian Abrahams wrote.

Editor's note: This article has been updated to reflect Intercept's NASH medicine goes by obeticholic acid. Ocaliva is the brand name for the drug's use in PBC.