FDA Grants Accelerated Approval of Resmetirom for Noncirrhotic Nonalcoholic Steatohepatitis With Moderate to Advanced Liver Fibrosis

The FDA has granted accelerated approval of resmetirom (Rezdiffra; Madrigal Pharmaceuticals) in conjunction with diet and exercise for the treatment of adults with nonalcoholic steatohepatitis (NASH) with moderate to advanced liver fibrosis (consistent with stages F2 to F3 fibrosis). However, the continued approval resmetirom—a once-daily, oral thyroid hormone receptor-β agonist—for this indication may require further verification and description of clinical benefit in ongoing confirmatory trials, according to a press release.¹

NASH is a more advanced form of nonalcoholic fatty liver disease and is a progressive disease with no approved treatment. Patients with NASH, and especially those with more advanced metabolic risk factors (hypertension and concomitant type 2 diabetes [T2D]), are at increased risk for adverse cardiovascular events and increased morbidity and mortality.^1,2

“NASH with moderate to advanced liver fibrosis is a serious and progressive liver disease that, until now, has not had an FDA-approved therapy,” said Bill Sibold, chief executive officer of Madrigal, in the press release. “This is a historic moment for the NASH field and represents the best of what our industry is capable of. We’re excited to deliver [resmetirom] to patients in need.”¹

The accelerated approval of resmetirom was based on results from the phase 3, ongoing pivotal, multicenter, randomized, double-blind, placebo-controlled MAESTRO-NASH trial (NCT03900429), which were published in the New England Journal of Medicine. The MAESTRO-NASH enrolled 1759 patients with biopsy-confirmed NASH. Following 52 weeks of treatment on doses of 100 mg and 80 mg, resmetirom showed statistically significant improvement compared to placebo on 2 primary endpoints: NASH resolution (including a reduction in the nonalcoholic fatty liver disease [NAFLD] activity score by ≥2 points) with no worsening of fibrosis, and an improvement in fibrosis by at least one stage with no worsening of the NAFLD activity score. Of note, the improvements observed in fibrosis and the resolution of NASH were consistent regardless of age, gender, T2D status, or fibrosis stage.^1,2

The MAESTRO-NASH trial is ongoing outcomes trial that is designed to generate confirmatory data that will help to verify clinical benefit of resmetirom and may support full approval. Additionally, a second ongoing outcomes trial is evaluating progression to liver decompensation events in patients with well-compensated NASH cirrhosis treated with resmetirom compared with placebo.¹

The prescribing information for resmetirom does not include a liver biopsy requirement for diagnosis, according to the press release. The recommended dosage of resmetirom is based on actual body weight, with patients weighing less than 100 kg (220 lbs) recommended to receive 80 mg orally once daily, and patients weighing less than 100 kg (220 lbs) recommended to receive 100 mg orally once daily.¹

“This is a day of celebration for patients with NASH who have been waiting many years for the first approved therapy,” said Wayne Eskridge, co-founder and chief executive officer of the Fatty Liver Foundation, in the press release. “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.”¹

REFERENCES

1. Madrigal Pharmaceuticals Announces FDA Approval of Rezdiffra™ (resmetirom) for the Treatment of Patients with Noncirrhotic Nonalcoholic Steatohepatitis (NASH) with Moderate to Advanced Liver Fibrosis. News Release. 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, Bedossa P, Guy CD, et al. A Phase 3, Randomized, Controlled Trial of Resmetirom in NASH with Liver Fibrosis. N Engl J Med. 2024;390(6):497-509. doi:10.1056/NEJMoa2309000