- Design
- Prespecified genetic analysis of a phase 3 placebo-controlled trial
- Population
- 738 genotyped patients with non-cirrhotic MASH and fibrosis, MAESTRO-NASH
- Primary outcome
- Interaction of risk genotypes with resmetirom effect on histology, MRI-PDFF and biomarkers at week 52
- Effect
- Similar resmetirom benefit across PNPLA3, HSD17B13, TM6SF2, MTARC1 and MBOAT7 genotypes
Variants in PNPLA3, HSD17B13, TM6SF2, MTARC1, MBOAT7 and SERPINA1 change susceptibility to steatotic liver disease, steatohepatitis, fibrosis and liver cancer. This prespecified analysis of the phase 3 MAESTRO-NASH trial asked whether they also change the response to resmetirom, a thyroid hormone receptor beta agonist. It included 738 patients with non-cirrhotic MASH and fibrosis who were genotyped and had biopsies at baseline and week 52.
Patients with high-risk PNPLA3 or HSD17B13 genotypes had fewer metabolic risk factors such as diabetes and hypertension at baseline, consistent with genetically driven disease. But resmetirom's effects on MASH resolution, fibrosis improvement on biopsy, MRI-PDFF and biomarkers were similar regardless of genotype, individually or as a combined genetic risk score, and independent of sex, ethnicity and metabolic factors.
The practical consequence is that genotyping is not needed to decide who gets resmetirom, and patients with genetically driven disease, who may have fewer metabolic levers to pull, can expect a similar response. The analysis was not powered to detect small interactions. Resmetirom is approved in the United States for non-cirrhotic MASH with moderate to advanced fibrosis; its status elsewhere, including India, is not established here.
- Do not order MASH risk genotyping to decide whether to prescribe resmetirom.
- Patients with high-risk genotypes, who had fewer metabolic risk factors, responded similarly.
- Resmetirom data cover non-cirrhotic MASH with fibrosis; do not extrapolate to compensated cirrhosis.
- Continue lifestyle and metabolic treatment alongside any MASH-directed drug.
- Reassess fibrosis non-invasively during treatment to judge response.
Why it matters
Genetic risk does not appear to put patients beyond reach of this drug.
Don't overread it
The analysis was not powered to detect small genotype effects, and 52-week histology is not a clinical outcome.
The statistics, in plain English
No significant interaction means the trial found no evidence that genotype changes the drug's effect, but with 738 patients a small difference could have been missed. Biopsy endpoints at 52 weeks are surrogates for clinical outcomes.
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