Stephen Harrison, MD: Promising Phase 3 Data for Resmetirom in NASH, Fibrosis

In a pivotal stride towards transforming the landscape of nonalcoholic steatohepatitis (NASH) management, new data from the phase 3 MAESTRO-NASH trial of resmetirom in patients with NASH and fibrosis suggest the thyroid hormone receptor-β selective agonist may be poised to become the first approved treatment for the progressive liver disease.¹

Published in The New England Journal of Medicine, results showed a greater proportion of patients in the resmetirom 80 mg and 100 mg treatment arms achieved NASH resolution with no worsening of fibrosis as well as fibrosis improvement by ≥ 1 stage with no worsening of the nonalcoholic fatty liver disease (NAFLD) activity score compared to those receiving placebo.¹

Data for the first 1050 patients from the MAESTRO-NASH trial comes just over a month ahead of the March 14 target PDUFA date assigned to resmetirom by the US Food and Drug Administration (FDA) upon its acceptance of Madrigal Pharmaceuticals’ New Drug Application (NDA) on September 13, 2023.²

“The unmet need for a NASH therapeutic, or MASH therapeutic using the new terminology metabolic associated steatohepatitis is really monumental,” Stephen Harrison, MD, medical director of Pinnacle Clinical Research, emphasized in an interview with HCPLive, citing the growing prevalence of liver disease in the US and current lack of a proven therapy to treat it.

An oral, thyroid hormone receptor (THR)-β selective agonist designed to target key underlying causes of NASH in the liver, resmetirom’s safety and efficacy for adults with NASH has been demonstrated in phase 2 and 3 trials. MAESTRO-NASH, a phase 3, double-blind, randomized, placebo-controlled trial, is 1 of 18 studies in resmetirom’s clinical development program supporting the NDA for its use in adult patients with NASH and fibrosis.^1,2

For inclusion, patients were required to be ≥ 18 years of age, have ≥ 3 metabolic risk factors, and have a controlled attenuation parameter (CAP) ≥ 280 dB per meter as well as a liver-stiffness measurement ≥ 8.5 kPa obtained within 3 months of enrollment by vibration-controlled transient elastography (VCTE). Additionally, histologic evidence of NASH and a NAFLD activity score ≥ 4 with a score ≥ 1 for each component were required for inclusion.¹

A total of 1050 patients were enrolled in the study 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). Among the cohort, the mean age was 56.6 (Standard deviation [SD], 10.9) years and most patients were White (89.3%) with a high incidence of metabolic risk factors, including hypertension (78.1%), dyslipidemia (71.3%), and type 2 diabetes (67.0%).¹

“This population enrolled in this trial, from a demographic perspective, is very similar to the same demographic we would see in the general population that had this degree of underlying fibrosis,” Harrison pointed out in an interview with HCPLive, adding to the generalizability of the study’s findings.

Investigators outlined 2 primary endpoints for the study, both measured at week 52. The first was 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. The second was an improvement in fibrosis by ≥ 1 stage with no worsening of the NAFLD activity score. Additionally, a key secondary endpoint was the percent change from baseline in low-density lipoprotein (LDL) cholesterol at week 24.¹

Results 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). 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).¹

Harrison explained the significance of these findings, especially as they pertain to fibrosis progression: “Fibrosis portends a worse prognosis. The more scar, the worse off these people do, and in this trial, 80% of patients with [a] biopsy [at] week 52 had either fibrosis reversal or no progression of disease.”

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).¹

Adverse events in the resmetirom (91.6% to 91.9%) and placebo (92.8%) groups were mostly mild or moderate in severity. The most frequent adverse events were diarrhea and nausea, both of which were more frequent with resmetirom, as well as COVID-19. Importantly, investigators pointed out 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.¹

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. doi:10.1056/NEJMoa2309000
2. 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 February 6, 2024. https://ir.madrigalpharma.com/news-releases/news-release-details/madrigal-pharmaceuticals-announces-nda-acceptance-and-priority