Genetic variation has long offered a plausible excuse for inconsistent drug response, but a pre-specified secondary analysis of the Phase 3 MAESTRO-NASH trial removes that hedge for Rezdiffra. Among the 738 patients who consented to genetic testing and completed baseline and Week 52 liver biopsies, resmetirom produced consistent histologic improvement and reductions in MRI-PDFF regardless of which common MASH-associated genetic risk variants a patient carried. The analysis, published in the Journal of Hepatology, matters commercially because MASH risk is heavily concentrated in patients who carry variants in genes like PNPLA3 and TM6SF2, and a drug that worked only in genetically “average” patients would face real prescribing hesitation in clinical practice.
The trial enrolled 966 patients with biopsy-confirmed MASH and fibrosis stages F1B through F3, split across 80 mg resmetirom, 100 mg resmetirom, and placebo arms. This genetic subanalysis was pre-specified, not a post-hoc dig through the data, which means the findings carry the statistical credibility that comes with a defined hypothesis tested on a defined population. Madrigal’s ability to point to a peer-reviewed, pre-specified result rather than an exploratory analysis will carry weight with hepatologists who treat the highest-risk patients.
Rezdiffra received FDA approval in March 2024 for adults with noncirrhotic MASH with moderate to advanced fibrosis (F2 to F3), used alongside diet and exercise. The genetic subanalysis does not change the approved label, but it does address a practical question that physicians face when a patient’s chart shows a known MASH risk genotype: whether to expect a diminished response. The data published this week say no.
For trial designers and drug developers working on next-generation MASH therapies, the publication sets a real evidentiary standard: pre-specified genetic subgroup analyses are now part of the expected evidence package in this space. The number to watch from Madrigal is how this data shapes prescribing penetration in hepatology practices that routinely genotype high-risk patients, particularly those with a family history of advanced fibrosis.
Jon Napitupulu is Director of Media Relations at The Clinical Trial Vanguard. Jon, a computer data scientist, focuses on the latest clinical trial industry news and trends.
