No need to genotype before resmetirom: high-risk MASH genes did not blunt response

Design

Prespecified genetic analysis of a phase 3 randomised placebo-controlled trial

Population

738 patients with non-cirrhotic MASH and fibrosis, biopsies at baseline and week 52

Primary outcome

MASH resolution, fibrosis improvement, MRI-PDFF by genotype

Effect

Resmetirom benefit similar across PNPLA3, HSD17B13, TM6SF2, MTARC1 and MBOAT7 risk genotypes

Resmetirom, a thyroid hormone receptor-beta agonist, is approved by the FDA for non-cirrhotic MASH with moderate to advanced fibrosis. Many patients carry gene variants that raise the risk of fat, fibrosis and liver cancer, and it was unclear whether these would limit response.

In a prespecified analysis of 738 patients from the MAESTRO-NASH phase 3 trial with biopsies at baseline and 52 weeks, resmetirom's effects on MASH resolution, fibrosis improvement, MRI liver fat and biomarkers were similar in carriers of high-risk PNPLA3, HSD17B13, TM6SF2, MTARC1 and MBOAT7 variants, alone or as a combined genetic risk score. Carriers of high-risk PNPLA3 or HSD17B13 variants had fewer metabolic risk factors such as diabetes and hypertension at baseline.

The practical conclusion is that genotyping is not needed to decide who receives resmetirom. Selection should rest on fibrosis stage. The study was not powered to detect small genetic effects. The PNPLA3 risk variant is common in South Asians; resmetirom's regulatory status in India is not known.

• Select patients for resmetirom by fibrosis stage, not genotype
• Confirm non-cirrhotic MASH with moderate to advanced fibrosis using non-invasive tests or biopsy
• Remember that lean patients with high-risk genes may have serious liver disease despite few metabolic risk factors
• Continue weight loss, diabetes and lipid management alongside any drug treatment
• Check interacting drugs before starting, including statin dose limits and CYP2C8 inhibitors such as gemfibrozil

Why it matters

Patients with genetic MASH, including many lean South Asians, appear to respond as well as others.

Don't overread it

The analysis could miss small genetic effects, and it does not apply to patients with cirrhosis.

The statistics, in plain English

Interaction analyses test whether the drug's effect differs between gene groups. Finding no significant interaction means no large difference was seen — not that small differences are ruled out.

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