“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 health care today,” Stephen A. Harrison, MD, FAASLD, medical director for Pinnacle Clinical Research and president of Summit Clinical Research in San Antonio, said in a Madrigal press release. “These unprecedented results from the MAESTRO-NASH clinical trial signal a major turning point for the field.”

In the MAESTRO-NASH phase 3 trial, a 52-week double-blind, placebo-controlled trial, patients with liver biopsy-confirmed NASH were randomized to receive once-daily 80 mg resmetirom (n = 316), 100 mg resmetirom (n = 321) or placebo (n = 318).

Following 52 weeks of treatment, a second liver biopsy would be performed, with the dual primary surrogate endpoints of NASH resolution with at least a 2-point reduction in NAS (NAFLD Activity Score), and either no worsening of fibrosis or a 1-point decrease in fibrosis with no worsening of NAS.

According to topline results, 30% of patients in the 100 mg resmetirom group reached the primary endpoint of NASH resolution with more than a 2-point reduction in NAS and no worsening of fibrosis vs. 26% of patients in 80 mg resmetirom group and 10% of the placebo group at 52 weeks. Additionally, 26% of patients receiving 100 mg resmetirom achieved fibrosis improvement of at least one stage with no worsening of NAS compared with 24% of patients who received the 80 mg dose and 14% of patients on placebo.

Patients who received resmetirom also exhibited potentially clinically meaningful reductions in low-density lipoprotein cholesterol, a key secondary endpoint, among patients who received resmetirom (100 mg: –16%; 80 mg: –12%) vs. placebo (1%).

“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,” Becky Taub, MD, chief medical officer and president of research and development at Madrigal, said in the release. “The topline data also reinforce our confidence in the safety and tolerability profile of resmetirom.”

The researchers reported that resmetirom was safe and well-tolerated at both 100 mg and 80 mg doses, with a similar rate of adverse events across treatment groups: 11.8% for 80 mg, 12.7% for 100 mg and 12.1% for placebo. Treatment discontinuation due to adverse events was similarly low with 2.8% for the 80 mg group, 7.7% for the 100 mg group and 3.7% for the placebo group. Consistent with prior data, the most reported adverse events included an excess of generally mild/transient diarrhea (80 mg: 28%; 100 mg: 34%; placebo: 16%) and generally mild nausea (80 mg: 22%; 100 mg: 19%; placebo: 13%).

“MAESTRO-NASH achieved both primary endpoints proposed by the FDA as reasonably likely to predict clinical benefit and we have established a large safety database, supported by a second phase 3 clinical trial (MAESTRO-NAFLD-1) and MAESTRO-NAFLD-OLE, to inform benefit-risk assessment,” Madrigal CEO Paul Friedman, MD, said in the release.

The company stated that it intends to file a new drug application for accelerated FDA approval of resmetirom early in 2023.

Additionally, in August 2022, Madrigal launched the MAESTRO-NASH-OUTCOMES trial, a randomized double-blind study of patients with early NASH cirrhosis to noninvasively monitor progression to liver decompensation events. A positive outcome on this trial could accelerate the timeline to full FDA approval, as well as support an additional indication for resmetirom in patients with well-compensated NASH cirrhosis.