Madrigal's stock enters orbit after 2nd phase 3 NASH success sets up FDA filing

Madrigal Pharmaceuticals plans to file a request for accelerated approval with the FDA in non-cirrhotic NASH with liver fibrosis in the first half of next year. (Stock photo/Getty Images)

The tricky indication of nonalcoholic steatohepatitis (NASH) has confounded many a biotech, but Madrigal Pharmaceuticals and its investors think the company is finally onto a winner with its second positive phase 3 readout.

In a phase 3 study of more than 950 patients, liver biopsies at 52 weeks showed that both 80-mg and 100-mg daily doses of resmetirom hit both liver histological improvement endpoints that the FDA had proposed as reasonably likely to predict clinical benefit, Madrigal reported.

Specifically, 26% of patients on the 80-mg dose and 30% on 100 mg, respectively, achieved the primary endpoint of a reduction in the NASH activity score—which includes ballooning and inflammation—of two or more points as well as no worsening of fibrosis. When it came to the other primary endpoint of at least a one-stage improvement in fibrosis, the figures were 24% and 26% for the two dose groups. In contrast, the placebo cohorts saw improvements of 10% and 14% for the two primary endpoints.

The selective thyroid hormone receptor agonist was also shown to hit a key secondary endpoint of lowering the level of low-density lipoprotein cholesterol, with 12% and 16% reductions at 24 weeks for the two doses compared to a 1% increase for the placebo group. 

The biotech described the drug as safe and well tolerated, with the roughly 12% frequency of serious adverse events across the two dose groups broadly matching the placebo cohort. The most common adverse events reported by patients taking resmetirom were an excess of generally mild and transient diarrhea and generally mild nausea.

The trial is one of four phase 3 MAESTRO studies Madrigal is conducting for resmetirom in NASH. The latest announcement sent the Pennsylvania-based biotech’s shares skyrocketing over 200% in early-hours trading to $199 apiece from a closing price Friday of $63.80.

Combined with data from another phase 3 trial called MAESTRO-NAFLD-1, Madrigal plans to file a request for accelerated approval with the FDA in non-cirrhotic NASH with liver fibrosis in the first half of next year.

“These pivotal phase 3 results demonstrate the potential for resmetirom to help patients achieve improvement in both the underlying steatohepatitis that drives this disease and the resulting fibrosis that is associated with progression to cirrhosis and its complications,” Chief Medical Officer Becky Taub, M.D., said in a premarket release Monday. “The topline data also reinforce our confidence in the safety and tolerability profile of resmetirom.”

“NASH with liver fibrosis puts patients at risk of progressing to liver failure, liver cancer, need for liver transplant and premature mortality; with no approved treatment, this disease represents one of the most urgent unmet needs in healthcare today,” said the study’s principal investigator Stephen Harrison, M.D.

“These unprecedented results from the MAESTRO-NASH clinical trial signal a major turning point for the field,” added Harrison, who is also chairman of both Pinnacle Clinical Research and Summit Clinical Research.