Intercept jumps on NASH phase 3 protocol changes

Intercept was down 12% premarket this morning as it announced an out-of-the-blue update on its late-stage fatty liver disease test, but jumped first thing after changing its endpoints and the definition of NASH improvement for its study.

The update focused on its phase 3 trial, known as “REGENERATE,” of its experimental fatty liver disease (aka NASH) candidate obeticholic acid (OCA), an FXR agonist.

This test is looking at two doses of its med against placebo as a clinical outcomes study which is designed to be used as the main test for the biotech to seek approval in the U.S. and Europe.

After a talk with the FDA, company CEO Mark Pruzanski said in a call with investors this morning: “First, we are amending our co-primary endpoint from fibrosis improvement and NASH resolution to fibrosis improvement or NASH resolution.

“We originally designed REGENERATE to include both primary endpoints based on the FLINT trial results, which showed that OCA treatment resulted in improvement in all key aspects of NASH, notably in fibrosis. While we of course remain confident in demonstrating efficacy on both endpoints, this protocol change effectively gives us two shots on goal.

“We now only need to achieve one endpoint for the trial to be deemed successful. None of our competitors [in NASH, which include Gilead, Shire and Genfit] have trials in NASH supporting efficacy on a dual endpoint. So, assuming we hit both endpoints, we will be able to clearly differentiate OCA from other NASH drugs currently in late-stage development, and create a high hurdle for other competitive products.”

He added that he now thinks the biotech has a “best case scenario” by lowering the hurdle of a successful trial, and he says it will help it get onto a market that could be worth tens of billions of dollars.

The biotech said the second change it has agreed with the FDA is the meaning of “NASH resolution” in its trial (i.e., how it is treating the disease). It had not firmed this up before, Pruzanski said, and this was intentional in its original protocol as, at the time, there was no consensus view on just what this means.

He said that they now have an “objective definition” of what this means, and it “is consistent with that recently endorsed by the Liver Forum.” This comes around a year after rival Genfit and its candidate elafibranor also added a firm NASH resolution into its test.

The number of patients needed for the trial has also been lowered for its interim analysis. In the interim cohort size for the NASH resolution endpoint in FLINT, this test needed a sample size of 1,400 patients; but using its new definition, it only needs a cohort of around 750 patients.

But the CEO added that the interim cohort enrollment had been changed from “within the first half of 2017” to by “mid-2017,” so there has been a delay, given the changes. Data readout should still be ready by 2019.

Pruzanski called these “improvements” and was confident it will be the first NASH drug to market. He said: “One, this will increase even further the success of the trial and two, see us complete enrollment of the interim cohort by mid-2017.”

But analysts at Leerink weren't as positive, saying in a note to clients: "It is discouraging that enrolling the 1,400 patient cohort was unattainable in a timely manner, and we are not convinced that this raises the probability of success in this trial."

When it comes to the endpoint changes, the firm added: "We believe this change is a creative solution to the enrollment challenges, but it leaves open questions about how readily the company will be able to enroll the entire study, and whether such slow enrollment reflects factors which will carry over into the marketplace."

Before the announcement investors feared the worse, with its shares down 12% premarket. During the call at 8:30 ET this morning, however, this jumped as high as high as 25%, before levelling off at around a 4% gain.  

Nonalcoholic steatohepatitis, or NASH, is a form of chronic liver disease caused by a buildup of fat in the liver (progressive fatty liver disease) affecting at least 2% to 5% of Americans. If left untreated, it can cause scarring, or fibrosis in the liver, which could eventually lead to liver failure. It could become the leading cause of liver transplants by the next decade.

Some believe it may become a bigger healthcare problem when it comes to liver disease than alcoholism and hepatitis C, and some analysts have seen the market reaching $35 billion at its peak.