- Design
- Prespecified genetic analysis of a phase 3 RCT (MAESTRO-NASH)
- Population
- 738 patients with non-cirrhotic MASH and fibrosis, biopsy at baseline and week 52
- Primary outcome
- Effect of risk genotypes on resmetirom response
- Effect
- No significant modification of MASH resolution, fibrosis or MRI-PDFF response by genotype
This prespecified analysis of the phase 3 MAESTRO-NASH trial genotyped 738 patients with non-cirrhotic MASH and fibrosis who had liver biopsies at baseline and 52 weeks, and tested whether common risk variants in PNPLA3, HSD17B13, TM6SF2, MTARC1 and MBOAT7 changed the response to resmetirom, a thyroid hormone receptor-beta agonist.
Patients with high-risk PNPLA3 or HSD17B13 genotypes had fewer metabolic risk factors at baseline — their disease was more genetically driven. Despite that, resmetirom's effects on MASH resolution, fibrosis improvement, MRI liver fat and biomarkers were similar across genotypes, singly or combined into a genetic risk score, and independent of sex, ethnicity and metabolic profile.
This matters for South Asian practice, where PNPLA3 risk variants are common and 'lean' MASLD is often genetically driven. The study was not powered for small differences, and there is no reason to genotype before prescribing. The drug's regulatory status in India is not established here.
- Do not genotype patients for PNPLA3 or similar variants before considering resmetirom.
- Expect similar benefit in patients whose MASH appears genetically rather than metabolically driven.
- Keep weight loss and cardiometabolic risk management as the foundation of MASH care.
- Check local licensing and cost before discussing resmetirom with patients.
Why it matters
Patients with genetically driven MASH, common in South Asia, appear to respond like everyone else.
Don't overread it
The analysis was not powered to detect small genotype effects, and it covered only 52 weeks.
The statistics, in plain English
Interaction tests ask whether the drug-versus-placebo difference changes with genotype. Finding no significant interaction means no large difference was seen, not that small differences are excluded.
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