Resmetirom for NASH: MASESTRO-NASH Phase 3 Data in NEJM Precede PDUFA Date of 3-14-2024

Treatment with resmetirom in the pivotal phase 3 MAESTRO-NASH clinical trial resulted in resolution of nonalcoholic steatohepatitis (NASH) with no worsening of clinical fibrosis in 25.9% of study participants receiving the 80 mg dose and in 29.9% of those receiving 100 mg. Among those treated with placebo, only 9.7% reached this first of 2 key primary study endpoints.¹

The second primary endpoint, an improvement in fibrosis by at least 1 stage with no decline in nonalcoholic fatty liver disease (NAFLD) activity score was seen in 24.2% of the 80-mg-treated participants and in 25% of those treated with 100 mg, compared with a similar result in 14.2% of those treated with placebo. (P < . 001 for both comparisons).¹

The critical endpoints are proposed by the US Food and Drug Administration (FDA) as “reasonably likely to predict clinical benefit” in NASH, according to an announcement by developer Madrigal Pharmaceuticals.² MAESTRO-NASH is the only phase 3 study in the therapeutic area to meet both endpoints, said Madrigal.

The findings were published in the New England Journal of Medicine¹ in February, just about 6 weeks before the long anticipated FDA PDUFA date for resmetirom set for March 14, 2024.² If granted approval, the thyroid hormone receptor-β selective agonist would become the first approved treatment in a highly competitive research space for the progressive liver disease.²

“MAESTRO-NASH is a landmark study in a disease that has historically been very challenging for drug development. The publication of detailed efficacy and safety data in the New England Journal of Medicine will provide clinicians with valuable information about the medication that may soon become the first approved therapy for patients with NASH,” 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.²

Madrigal announced the first positive topline findings from MAESTRO-NASH in early 2022. In September 2023, the FDA accepted the company’s NDA for resmetirom and granted the investigational drug priority review, setting the current March 2024 PDUFA date at the same time.

An oral, thyroid hormone receptor (THR)-β selective agonist resmetirom 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.²

MAESTRO-NASH

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), resmetirom 100 mg (n = 323), or placebo (n = 321). Participants had a mean age of 56.6 years and were predominantly White (89.3%). Metabolic risk factor prevalence was high, including hypertension (78.1%), dyslipidemia (71.3%), and type 2 diabetes (67.0%).¹

The 2 primary endpoints, assessed at study week 52, were: NASH resolution, defined as achieving a hepatocellular ballooning score of 0, a lobular inflammation score of 0 or 1, and a reduction in the NAFLD activity score by ≥2 points, with no worsening of fibrosis. Fibrosis improvement was defined as improvement by ≥ 1 stage with no worsening of the NAFLD activity score.¹

MAESTRO-NASH investigators also examined multiple secondary endpoints, reporting statistically significant reductions from baseline in liver enzymes, atherogenic lipids and lipoproteins, fibrosis biomarkers, and on liver stiffness measures, compared with placebo. Measured at week 24, the reduction from baseline in low density lipoprotein 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 for both comparisons).¹

Harrison et al reported diarrhea and nausea as the most common adverse events during the study and that they were more frequent with resmetirom. They emphasized that 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.¹

"Despite its serious impact on patients and the health system, there are no approved treatments for the disease. As a liver-directed therapy that has demonstrated efficacy in both reversing fibrosis and resolving NASH in a pivotal Phase 3 clinical trial, we believe resmetirom will change the treatment paradigm for patients with NASH with significant fibrosis if it receives accelerated approval from the FDA,” Becky Taub, MD, chief medical officer and president, research and development at Madrigal said.²

References

1. 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;390:497-509. doi:10.1056/NEJMoa2309000

2. 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