The future could get a bit brighter for patients living with primary biliary cirrhosis (PBC), a rare chronic and gradually progressive liver disease that can lead to hepatic fibrosis, cirrhosis, liver failure and potentially death.

The FDA's Gastrointestinal Drugs Advisory Committee (GIDAC) voted 17-0 Thursday to recommend accelerated approval of Intercept Pharmaceuticals Inc.'s Ocaliva (obeticholic acid) in adults with an inadequate response to, or who are unable to tolerate, ursodeoxycholic acid (UDCA), the only approved therapy for PBC.

While UDCA markedly improves clinical outcomes for many patients, those who don't fully respond or are intolerant to it have a significantly increased risk of needing a liver transplant.

The GIDAC meeting showcased the difficulty in developing a drug for a rare disease in which the pace of progression can vary greatly over many years. Adding to the challenge is that PBC is apt to be accompanied by other autoimmune conditions with similar symptoms, so coming up with a meaningful trial endpoint, especially one that works in all stages of the disease, can be a demanding effort when no relevant biomarkers have been validated.

To get to the point of recommending approval, the committee members, many of whom are hepatology or GI specialists, first had to work through their comfort level with using a reduction in alkaline phosphatase (ALP) as a surrogate endpoint to predict that Ocaliva would have a clinical benefit for patients with PBC.

While a reduction in ALP could reasonably predict an outcome, it's impossible to know for sure if the outcome is a result of the change in ALP or the result of another mechanism, said Marina Silveira, a doctor at the Louis Stokes Cleveland Veterans Administration Medical Center.

Sandeep Khurana, an associate professor and director of hepatology at Georgia Regent University, said, "ALP is all we have, but clearly it's not the best that's available." Most of the other panelists tended to agree with him, pointing out the need for more definition and clarification of the surrogate.

One problem with using a reduction in ALP is determining the cut point. Should any reduction, no matter how small, be considered an outcome? Another issue is the stage of the disease. Most of the patients in Intercept's single phase III trial had early stage PBC. Would ALP be the best biomarker for moderately advanced or advanced stages of the disease?

Susan Ellenberg, a biostatistics professor at the University of Pennsylvania's Perelman School of Medicine, said the focus shouldn't be so squarely on ALP that a trial ignores other levels, like bilirubin, which might be going in the wrong direction.

GRAPPLING WITH BIOMARKETS

The discussion on ALP provided some insight into how the FDA grapples with any new biomarker offered as a "candidate surrogate" to determine if it's reasonably likely to predict a clinical benefit. Only after a surrogate demonstrates that it can predict an outcome will the agency validate it as a biomarker. So far, the agency has qualified only four biomarkers. And several dozen biomarker qualification packages have stalled at the consultation and advice stage, according to a report released last year by the Manhattan Institute for Policy Research. (See BioWorld Today, March 12, 2015.)

At other advisory committee meetings, the FDA has shown wariness in its review of clinical markers as surrogate endpoints. For instance, questions over the use of dystrophin as a biomarker to measure the effectiveness of drugs designed to treat Duchenne muscular dystrophy weighed heavily in the Peripheral and Central Nervous System Drugs Advisory Committee meeting on Biomarin Pharmaceutical Inc.'s Kyndrisa (drisapersen) and a subsequent complete response letter to the company. (See BioWorld Today, Nov. 25, 2015, and Jan. 15, 2016.)

In discussing ALP as an endpoint Thursday, FDA staff said no randomized, controlled trial can support whether an ALP reduction is simply a candidate surrogate or one that's reasonably likely to predict a clinical outcome. The agency is hoping Intercept's ongoing global phase IV outcomes trial will help establish whether ALP works as an endpoint. To ensure the trial, which started in 2014, provides the necessary data, the FDA wants to modify its design.

As currently designed, the phase IV COBALT trial would enroll about 450 patients and would follow patients for up to six years. The trial itself is expected to take eight years. As it is, Intercept has spent 14 years developing the drug for PBC and other indications that were not discussed at the GIDAC meeting.

Ocaliva has been granted orphan drug designation in both the EU and U.S. Its U.S. PDUFA date is May 29.

The positive committee vote sent shares of New York-based Intercept (NASDAQ:ICPT) up $19.17, nearly 12 percent, in afterhours trading to a high of $185 at press time. When the FDA released its favorable briefing documents Tuesday, shares gained $17.76, or 13.3 percent, to close at $151.31. (See BioWorld Today, April 6, 2016.)