Resmetirom worked similarly regardless of common MASH risk genotypes

Design

Prespecified genetic analysis of a phase 3 randomised trial

Population

738 MAESTRO-NASH participants with non-cirrhotic MASH and paired biopsies

Primary outcome

MASH resolution and fibrosis improvement at week 52 by genotype

Effect

Resmetirom effects similar across PNPLA3, HSD17B13, TM6SF2, MTARC1 and MBOAT7 genotypes

A prespecified genetic analysis of 738 participants in the phase 3 MAESTRO-NASH trial of resmetirom, a thyroid hormone receptor beta agonist, examined whether risk variants in PNPLA3, HSD17B13, TM6SF2, MTARC1, MBOAT7 and SERPINA1 changed response at 52 weeks.

Patients with high-risk PNPLA3 or HSD17B13 genotypes had fewer metabolic risk factors such as diabetes and hypertension at baseline. Resmetirom's effects on MASH resolution, fibrosis improvement on biopsy, MRI liver fat and biomarkers were similar across genotypes, alone or combined. The study was not powered to detect small differences.

The PNPLA3 risk variant is common in South Asian populations, so the finding has particular relevance in India, where the regulatory status of resmetirom is not established.

• Genotyping is not needed to predict resmetirom response, on this analysis
• Patients with genetic MASLD risk may have fewer metabolic risk factors; do not rule out MASH because a patient is lean or non-diabetic
• The PNPLA3 risk variant is common in South Asian populations
• Resmetirom's availability in India is not established

Why it matters

Genetically driven MASLD, common in lean South Asians, appeared to respond as well as metabolic MASLD.

Don't overread it

The analysis was not powered to detect small genotype effects.

The statistics, in plain English

A finding of no significant interaction in 738 patients means large genotype effects are unlikely, but small differences could have been missed.

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