TOPLINE

Among patients with non-cirrhotic metabolic dysfunction-associated steatohepatitis (MASH) and fibrosis, resmetirom, a selective thyroid hormone receptor-beta agonist, produced similar rates of MASH resolution, fibrosis improvement, and liver fat reduction in those with and without high-risk genotypes for more severe liver disease.

METHODOLOGY

• Although resmetirom is approved for the treatment of MASH with moderate to advanced fibrosis, whether established genetic risk variants linked to MASH progression affect treatment response remains unclear.
• Researchers conducted a secondary analysis of a phase 3 trial involving 738 patients with biopsy-confirmed MASH and fibrosis who consented to genetic testing and whose liver biopsies at baseline and week 52 were complete. The 80 mg and 100 mg resmetirom groups were pooled and compared with placebo.
• They analyzed five genes linked to liver disease risk: PNPLA3, HSD17B13, TM6SF2, MTARC1, and MBOAT7. Patients were then grouped according to their genetic risk levels.
• A genetic risk score, derived by counting the total number of high-risk alleles across the five genes, was also used to evaluate whether a patient's overall inherited risk affected response to resmetirom.
• Treatment response at week 52 was judged by MASH resolution without worsening of fibrosis, fibrosis improvement without worsening of steatohepatitis, and 30% or more relative reduction in liver fat on MRI-proton density fat fraction (MRI-PDFF).

TAKEAWAY

• At week 52, resmetirom outperformed placebo in MASH resolution, fibrosis improvement, and liver fat reduction, with similar response rates noted across genetic risk levels for all five genes.
• Similarly, there was no significant interaction between the combined genetic risk score and treatment response for MASH resolution, fibrosis improvement, and liver fat reduction on MRI-PDFF.
• At baseline, patients with high-risk PNPLA3 genotypes had significantly lower rates of diabetes, dyslipidemia, and hypertension. Those with high-risk HSD17B13 genotypes showed a similar trend, but that was not statistically significant. Researchers suggest that people with higher genetic risk may reach a similar fibrosis stage with fewer traditional metabolic risk factors.
• Reductions in liver enzymes and liver stiffness with resmetirom did not differ meaningfully across genetic risk groups beyond expected variability.

IN PRACTICE

"It is encouraging to see that Rezdiffra [resmetirom] demonstrated consistent effects on liver histology and biomarkers across the genetic risk subgroups evaluated, supporting broad applicability across patients with this serious liver disease," said the lead author in a press release.

SOURCE

The study was led by Naga P. Chalasani, MD, Indiana University School of Medicine, Indianapolis. It was published online on October 5, 2026, in the Journal of Hepatology.

LIMITATIONS

Because this was a secondary analysis with fewer patients in some genetic risk groups, smaller genotype-specific effects and rarer variants could not be excluded. The analysis evaluated only five established MASH-related genotypes. The study did not assess clinical outcomes, and longer follow-up may reveal genetic influences on treatment responses.

DISCLOSURES

This study was supported by Madrigal Pharmaceuticals, Inc., which also provided funding for the phase 3 trial. One author disclosed serving as a paid consultant and receiving research support from the funding source and having equity interests in a contract research organization and a drug discovery start-up. Five authors disclosed being employees and stockholders of the funding source.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.