Intercept aims for another NASH try with new Ocaliva analysis. Will the FDA bite?

Two years after an FDA rejection for its potential nonalcoholic steatohepatitis (NASH) drug, Intercept Pharmaceuticals said it now has the data the agency had asked for. But the new analysis isn’t exactly a home-run win.

Intercept on Thursday trotted out positive data from a new analysis of Ocaliva’s pivotal trial in NASH. The company will meet with the FDA later this month to discuss the resubmission of an application in fibrosis caused by NASH, Intercept CEO Jerry Durso said in a statement.

The positive trial readout means Ocaliva once again has a chance of becoming the first FDA-approved therapy for NASH. But the biotech’s stock fell by about 10% Thursday morning anyway, because, although the new evaluation follows FDA’s direction, it has a few weak points.

Specifically, a new analysis of the phase 3 REGENERATE trial showed that Ocaliva, given once-daily at 25 mg, helped 22.4% of patients with advanced fibrotic NASH achieve at least one stage of liver fibrosis improvement with no worsening of NASH at Month 18. That was significantly higher than the 9.6% recorded in the placebo arm.

The trial has therefore hit one of its primary endpoints agreed upon with the FDA, and it “once again confirmed the anti-fibrotic treatment effect” of Ocaliva at 25 mg, Durso said during an investor call Thursday.

Back in June 2020, the FDA turned down Ocaliva’s petition for an accelerated approval in NASH based on a histopathologic endpoint despite the drug having demonstrated a significant advantage over placebo on that liver fibrosis marker.

The new analysis is different in that it uses a central consensus reading of liver biopsies by three pathologists, whereas the original analysis was based on each individual expert’s own interpretation. In that old readout, the responses were 23.1% versus 11.9% for Ocaliva and placebo, respectively.

But on the issue of whether Ocaliva can actually resolve NASH, the drug once again failed to show a statistically significant benefit at the interim analysis. Only 6.5% of Ocaliva takers enjoyed resolution of NASH with no fibrosis worsening after 18 months, slightly better than 3.5% observed for the placebo group.

Besides, Ocaliva at a lower 10-mg dosing strength didn’t show significant benefits on either endpoint. In its currently FDA-approved primary biliary cholangitis indication, Ocaliva is allowed at 10 mg once daily maximum, and it already carries a black box warning against more frequent dosing.

On the safety side, pruritus remains a tolerability issue as 55% of Ocaliva takers at 25 mg experienced treatment-emergent itchy skin, versus 24% for placebo.

In addition, Intercept also observed several liver toxicity events that are considered “probably or highly likely” related to Ocaliva, Michelle Berrey, M.D., Intercept’s chief medical officer, said during the call.

Compared to the original analysis, the new safety evaluation involved significantly longer drug exposure of a median 42 months versus the previous 15 months, Berrey pointed out. Overall, she labeled Ocaliva’s side effects as “monitorable and manageable.”

NASH has long been a tough nut to crack, with numerous past failures, including a recent midstage flop by Novo Nordisk’s Type 2 diabetes star drug semaglutide. Despite that setback, Novo said its NASH work remains on track.

Besides advanced fibrotic NASH, Intercept is running another phase 3 trial called REVERSE in patients with even more advanced compensated cirrhosis NASH and expects top-line data in the third quarter.