An industry-first FDA approval for a nonalcoholic steatohepatitis (NASH) therapy may still be a ways off.
After reviewing Intercept Pharmaceuticals’ latest application for obeticholic acid (OCA), the agency appears all but ready to reject the drug in NASH-related pre-cirrhotic liver fibrosis, according to a briefing document released ahead of an expert panel meeting set for Friday.
Citing a long list of safety risks and the practical hurdle for patients to undergo a liver biopsy—coupled with “modest” efficacy—the FDA said it “cannot justify OCA use in NASH subjects with stage 2 or 3 fibrosis.”
The FDA’s negative review could once again thwart Intercept’s bid to win the first NASH approval in the U.S.
If members of the FDA’s Gastrointestinal Drugs Advisory Committee side with the FDA and the agency follows through with its own staff’s analysis, it would mark the second rejection for OCA in NASH.
Intercept’s stock price was down more than 22% Wednesday by publication time.
OCA is already approved under the brand name Ocaliva for the treatment of primary biliary cholangitis and is given up to 10 mg once daily. For NASH, Intercept is proposing a 25-mg strength.
In a modified analysis of more than 1,000 patients, OCA at 25 mg topped placebo when it came to improvement of fibrosis with no worsening of NASH at 18 months, one of the two primary endpoints of the phase 3 REGENERATE trial.
While the marker was acceptable for a review for a potential accelerated approval, the FDA labeled OCA’s 8.6% risk reduction compared with placebo as a “modest” treatment effect.
Giving the FDA even less confidence, OCA 25 mg failed on the other primary endpoint, showing no significant difference on NASH resolution with no worsening of fibrosis. OCA at 10 mg met neither endpoint in the trial.
All in all, the FDA raised uncertainties around “how the magnitude of changes in these surrogate endpoints may translate to meaningful changes in clinical outcomes.”
Then there’s the safety risks. The FDA flagged drug-induced liver injury as a serious problem for OCA 25 mg. The FDA is asking its external advisers to discuss whether periodic liver enzyme monitoring could mitigate the problem in the real world.
In addition, “excess” or “substantial excess” risks were noted for OCA 25 mg in several side effects, including gall bladder inflammation and bile duct stones that can be life-threatening, the onset of diabetes, lipid dysregulation, severe pruritus and acute kidney injury.
OCA’s own risk-benefit profile isn’t all that gave the agency pause for this review. With this application, Intercept is targeting pre-cirrhotic NASH patients with stage 2 to 3 disease. But the FDA noted that a liver biopsy—versus noninvasive tests—is the only way to accurately identify patients who would qualify for the drug.
A liver biopsy itself carries risk, including severe bleeding and a very low chance of death, the FDA pointed out. Besides, the pain involved means patients may be unwilling to undergo the procedure just to know whether they qualify for the drug.
Therefore, OCA’s “modest” efficacy will need to be weighed against the risk not only for those who qualify for the therapy but also from the biopsy standpoint in a general NASH population, the FDA argued.
Besides all the FDA's concerns, there may be one silver lining for Intercept. The agency is asking its advisers whether the drug deserves an accelerated approval based on a surrogate marker while acknowledging that the phase 3 study is still ongoing to collect clinical outcome data.
That means there might still be chance for Intercept to come back to the agency for a third time if those data are positive.
Even before the FDA’s negative review, analysts had already viewed OCA as an underdog in NASH. Madrigal Pharmaceuticals’ resmetirom recently achieved statistically significant improvements on both liver scarring and NASH resolution in its own phase 3 trial.
Calling resmetirom the “clear winner” in its comparison with OCA, SVB Securities analysts have put the Madrigal drug’s peak sales potential at $2.5 billion.
Madrigal has said it plans to submit resmetirom with the FDA by June. The FDA is expected to decide on Intercept’s OCA application by June 22.