Madrigal's Resmetirom Wins Historic FDA Approval for Noncirrhotic NASH

Resmetirom is the first-ever drug to be approved anywhere for management of the progressive liver disease.

Madrigal Pharmaceuticals today made medical and pharmaceutical history with the US Food and Drug Administration’s landmark approval of resmetirom (Rezdiffra) for noncirrhotic nonalcoholic steatohepatitis (NASH) with moderate to advanced fibrosis. Resmetirom becomes the first treatment approved for management of the progressive liver disease for which the prognosis can be dire.1

The accelerated approval was based on the company’s most recent phase 3 data from the MAESTRO-NASH trial, 1 of 4 phase 3 studies2 in resmetirom’s clinical development program. MAESTRO-NASH continues as an outcomes study designed to generate confirmatory data that may be used to verify the drug’s clinical benefit and to support full approval, according to the Madrigal announcement.1

Resmetirom is an oral, thyroid hormone receptor (THR)-β selective agonist that increases hepatic fat metabolism and reduces lipotoxicity. The agent’s safety and efficacy for adults with NASH has been demonstrated in phase 2 and 3 trials. MAESTRO-NASH is 1 of 18 studies in Madrigal’s clinical development program supporting the 2023 NDA.3

“The approval of the first medication for NASH is a true game-changer for healthcare providers, the research community and, most importantly, patients living with this serious liver condition. Based on the robust efficacy and safety data generated in two large Phase 3 MAESTRO studies, I believe Rezdiffra will become the foundational therapy for patients with NASH with moderate to advanced liver fibrosis,” said Stephen Harrison, MD, chairman, Pinnacle Clinical Research and Summit Clinical Research, San Antonio, Texas, visiting professor of hepatology, Oxford University, and lead principal investigator of the MAESTRO studies said in the company statement.1

Harrison and colleagues enrolled 1050 participants in MAESTRO-NASH; 966 with fibrosis stages F1B, F2, or F3 at baseline were randomly assigned in a 1:1:1 ratio to receive resmetirom 80 mg (n = 322 patients), resmetirom 100 mg (n = 323), or placebo (n = 321).4 Results were published in The New England Journal of Medicine and showed NASH resolution with no worsening of fibrosis in 25.9% of the participants in the resmetirom 80 mg group and 29.9% of those in the resmetirom 100 mg group, compared to 9.7% of those in the placebo group (P < .001).4

Fibrosis improvement by one stage or more with no worsening of the NAFLD activity score, the second of the study's 2 primary endpoints, was also superior in the resmetirom 80 mg (24.2%) and resmetirom 100 mg (25.9%) groups versus the placebo group (14.2%; P < .001).4 Fibrosis improvement and NASH resolution were consistent regardless of age, gender, type 2 diabetes status, or fibrosis stage.4

Harrison et al also reported improvement in LDL cholesterol levels from baseline to week 24 of −13.6% in the resmetirom 80 mg group and −16.3% in the resmetirom 100 mg group, as compared with 0.1% in the placebo group (P < .001).4

The safety evaluation for resmetirom returned a favorable profile, with diarrhea and nausea reported as the most common adverse events during the study, and more frequent with resmetirom but noted as mostly mild or moderate. The incidence of serious adverse events was similar across trial groups: 10.9% in the resmetirom 80 mg group, 12.7% in the resmetirom 100 mg group, and 11.5% in the placebo group.

According to the Madrigal announcement, resmetirom's prescribing information does not include a liver biopsy requirement for diagnosis and the recommended dosage is based on actual body weight.1

In its ongoing phase, the 54-month MAESTRO-NASH trial is measuring the extent of liver inflammation and scarring. A second ongoing outcomes trial is evaluating progression to liver decompensation events in patients with well-compensated NASH cirrhosis treated with resmetirom versus placebo.1

“This is a day of celebration for patients with NASH who have been waiting many years for the first approved therapy. I believe this approval milestone will bring new energy and momentum to the NASH community, accelerating our efforts to improve disease education, build care pathways, and expand investment in NASH research,” Wayne Eskridge, cofounder and chief executive officer of the Fatty Liver Foundation, stated in the announcement.1

The FDA granted resmetirom Breakthrough Therapy, Fast Track and Priority Review designations for this indication.

References
1. Madrigal Pharmaceuticals announces FDA approval of Rezdiffra (resmetirom) for the treatment of patients with noncirrhotic nonalcoholic steatohepatitis (NASH) wiht moderate to advanced fibrosis. News release. Madrigal Pharmaceuticals. March 14, 2024. Accessed March 14, 2024. https://ir.madrigalpharma.com/news-releases/news-release-details/madrigal-pharmaceuticals-announces-fda-approval-rezdiffratm
2. Harrison SA, Ratziu V, Anstee QM, et al. Design of the phase 3 MAESTRO clinical program to evaluate resmetirom for the treatment of nonalcoholic steatohepatitis. Aliment Pharmacol Ther. 2024;59(1):51-63. doi:10.1111/apt.17734
3. Madrigal Pharmaceuticals announces publication of the phase 3 MAESTRO-NASH trail of resmetirom in the New England Journal of Medicine. News release. Madrigal Pharmaceuticals. February 8, 2024. Accessed March 4, 2024. https://ir.madrigalpharma.com/news-releases/news-release-details/madrigal-pharmaceuticals-announces-publication-phase-3-maestro
4. Harrison SA, Bedossa P, Guy CD, et al. A phase 3, randomized, controle trial of remetirom in NASH with liver fibrosis. N Engl J Med. 2024;390:497-509. doi:10.1056/NEJMoa2309000