Resmetirom (Rezdiffra) Receives Historic FDA Approval for Noncirrhotic NASH

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In a landmark decision, the FDA has granted accelerated approval to resmetirom (Rezdiffra) for noncirrhotic NASH with moderate to advanced fibrosis.

Credit: US Food and Drug Administration

Credit: US Food and Drug Administration

In a landmark decision for the field of hepatology, the US Food and Drug Administration (FDA) has granted accelerated approval to resmetirom (Rezdiffra) for noncirrhotic nonalcoholic steatohepatitis (NASH) with moderate to advanced fibrosis, making it the first and only treatment to receive approval for the progressive liver disease.1

Announced on March 14, 2024, the decision follows 18 clinical studies in the oral, thyroid hormone receptor (THR)-β selective agonist’s clinical development program: 12 phase 1 studies, a pair of phase 2 studies, and 4 phase 3 studies. The release from Madrigal Pharmaceuticals indicates the continued approval for this indication may be contingent upon verification and description of clinical benefit in ongoing confirmatory trials.1,2

“Previously, patients with NASH who also have notable liver scarring did not have a medication that could directly address their liver damage,” Nikolay Nikolov, MD, acting director of the Office of Immunology and Inflammation in the FDA’s Center for Drug Evaluation and Research, said in a press release.1 “Today’s approval of Rezdiffra will, for the first time, provide a treatment option for these patients, in addition to diet and exercise.”

As described above, resmetirom’s safety and efficacy for adults with NASH has been demonstrated in phase 2 and 3 trials, the latest of which includes MAESTRO-NASH, an ongoing phase 3, double-blind, randomized, placebo-controlled trial, 1 of 4 phase 3 studies in resmetirom’s clinical development program supporting the approval for its use in adult patients with NASH and fibrosis.2,3

A total of 1050 patients were enrolled in MAESTRO-NASH and 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). Results were published in The New England Journal of Medicine and showed NASH resolution with no worsening of fibrosis was achieved in 25.9% of the patients 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 ≥ 1 stage with no worsening of the NAFLD activity score 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). Additionally, the change in LDL cholesterol levels from baseline to week 24 was −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

According to the release, resmetirom's prescribing information does not include a liver biopsy requirement for diagnosis and the recommended dosage is based on actual body weight.2

"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," said MAESTRO lead investigator Stephen Harrison, MD, chairman for both Pinnacle Clinical Research and Summit Clinical Research and Visiting Professor of Hepatology at Oxford University. "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.”

Additionally, to support resmetirom's full approval, the sponsor is required to conduct a postapproval study to verify and describe the treatment's clinical benefit, which will be done by completing the ongoing 54-month, randomized, double-blind placebo-controlled MAESTRO-NASH trial 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.1,2

“Throughout the years, multiple biopsy studies as well as imaging studies have been done, and they have shown nicely that [resmetirom] reversed or improved fat in the liver as well as inflammation as well as fibrosis, either through biopsy, or fibrosis biomarkers and imaging biomarkers,” Mazen Noureddin, MD, MHSc, medical director of the Houston Research Institute and professor of medicine at Houston Methodist Academic Institute, said in an interview with HCPLive.

Noureddin described resmetirom's side effect profile as “favorable” – in MAESTRO-NASH, adverse events in the resmetirom (91.6% to 91.9%) and placebo (92.8%) groups were mostly mild or moderate in severity, and 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.4

Noureddin also expressed curiosity about the cardiovascular effect of resmetirom, citing its impact on LDL and subsequent expected beneficial cardiovascular effect. However, he also noted this will take time to see.

“I think 2024 is a very exciting year for NASH and the NASH field… I think the future is bright. I just hope that we will end up getting rid of liver biopsy in clinical trials in the future, which will expedite the field and facilitate further improvement,” Noureddin concluded.

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 14, 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 14, 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 14, 2024.

4. Brooks, A. Stephen Harrison, MD: Promising Phase 3 Data for Resmetirom in NASH, Fibrosis. HCPLive. February 7, 2024. Accessed March 14, 2024. https://www.hcplive.com/view/stephen-harrison-md-promising-phase-3-data-resmetirom-nash-fibrosis

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