Madrigal publishes Rezdiffra genetic subgroup data in liver journal

Madrigal Pharmaceuticals (NASDAQ: MDGL) announced the publication of a secondary analysis from its Phase 3 MAESTRO-NASH trial in the Journal of Hepatology, examining whether common genetic variants associated with metabolic dysfunction-associated steatohepatitis (MASH) affected patient response to Rezdiffra (resmetirom).

The analysis included 738 patients who consented to genetic testing and completed baseline and Week 52 liver biopsies. Across all major efficacy endpoints, including MASH resolution, fibrosis improvement, MRI-PDFF reduction and multiple biomarkers, the publication reports no meaningful difference in treatment response based on MASH genetic risk variants, including PNPLA3, HSD17B13, TM6SF2, MTARC1 and MBOAT7, or a composite genetic risk score.

In the PNPLA3 subgroup specifically, MASH resolution was achieved in 38.4%, 30.8% and 30.5% of Rezdiffra-treated patients across low, intermediate and high-risk genotypes, compared with 12.9%, 5.1% and 11.7% in the placebo group. Fibrosis improvement rates were 34.2%, 29.5% and 31.4% versus 14.1%, 13.7% and 15.0%, respectively.

The authors noted the analysis was not prospectively powered to detect small genotype-by-treatment interactions, and only select common variants were assessed, meaning smaller genotype-specific effects or rarer variants cannot be excluded.

Naga Chalasani, M.D., lead author and professor at Indiana University School of Medicine, said in the statement that "it will be important to perform similar analyses for other approved and investigational MASH therapies moving forward."

Separately, Madrigal noted it added MGL-0795, a small interfering RNA asset targeting PNPLA3, to its pipeline in May 2026 and plans to consult with the FDA on the design of a Phase 2 combination trial with Rezdiffra.

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