FDA Approves First Treatment for Noncirrhotic Nonalcoholic Steatohepatitis (NASH)

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The FDA has granted accelerated approval to Madrigal Pharmaceuticals’ Rezdiffra (resmetirom) for the treatment of adults with noncirrhotic nonalcoholic steatohepatitis (NASH) with moderate to advanced liver fibrosis that is consistent with stage F2 to F3 fibrosis. The historic regulatory action for the once-daily, oral thyroid hormone receptor-β agonist marks the first treatment approved by the FDA for NASH.¹

“NASH with moderate to advanced liver fibrosis is a serious and progressive liver disease that, until now, has not had an FDA-approved therapy,” Bill Sibold, CEO of Madrigal Pharmaceuticals, said in a 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 Rezdiffra to patients in need.”¹

The approval was based on a series of trials in Rezdiffra’s clinical development program, which was comprised of 12 Phase I trials, two Phase II trials, and four Phase III trials. Continued approval of Rezdiffra for this indication may be contingent on further verification and description of clinical benefit as part of the ongoing confirmatory trials.^1,2

The safety and efficacy of Rezdiffra in adult patients with NASH was shown across Phase II and III trials, including the ongoing, double-blind, randomized, placebo-controlled MAESTRO-NASH Phase III trial, the results of which were published in the New England Journal of Medicine.^2,3

Investigators enrolled 1050 patients in MAESTRO-NASH, of whom 966 had fibrosis stages F1B, F2, or F3 at baseline. Patients were randomly assigned in a 1:1:1 ratio to receive Rezdiffra 80 mg (n = 322), Rezdiffra 100 mg (n = 323), or placebo (n = 321). The trial found that 25.9% of the patients in the 80 mg cohort and 29.9% in the 100 mg cohort achieved NASH resolution with no worsening of fibrosis compared to 9.7% in the placebo cohort (P <.001).

Fibrosis improvement by ≥ 1 stage with no worsening of the NAFLD activity score was 24.2% in the Rezdiffra 80 mg cohort and 25.9% in the 100 mg cohort compared with 14.2% (P <.001) in the placebo cohort. Further, change in low-density lipoprotein cholesterol levels from baseline to week 24 was −13.6% in the 80 mg cohort and −16.3% in the 100 mg cohort vs. 0.1% in the placebo cohort (P <.001).

The ongoing MAESTRO-NASH outcomes trial was developed to produce confirmatory data that contributes to verifying the clinical benefit of Rezdiffra and to potentially support a full FDA approval. An additional ongoing outcomes trial is analyzing progression to liver decompensation events in patients with well-compensated NASH cirrhosis administered Rezdiffra as compared to a placebo.¹

“This is a day of celebration for patients with NASH who have been waiting many years for the first approved therapy,” Wayne Eskridge, co-founder and CEO of the Fatty Liver Foundation, said in the 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. US Food and Drug Administration. FDA Approves First Treatment for Patients with Liver Scarring Due to Fatty Liver Disease. March 14, 2024. Accessed March 15, 2024. https://www.fda.gov/news-events/press-announcements/fda-approves-first-treatment-patients-liver-scarring-due-fatty-liver-disease

2. Madrigal Pharmaceuticals. Madrigal Pharmaceuticals Announces FDA Approval of Rezdiffra™ (resmetirom) for the Treatment of Patients with Noncirrhotic Nonalcoholic Steatohepatitis (NASH) with Moderate to Advanced Liver Fibrosis. March 14, 2024. Accessed March 15, 2024. https://ir.madrigalpharma.com/news-releases/news-release-details/madrigal-pharmaceuticals-announces-fda-approval-rezdiffratm

3. Madrigal Pharmaceuticals. Madrigal Pharmaceuticals Announces NDA Acceptance and Priority Review of the New Drug Application for Resmetirom for the Treatment of NASH with Liver Fibrosis. Press Releases. September 13, 2023. Accessed March 15, 2024.