Journal of hepatology · 2026
Effects of MASH risk genotypes on resmetirom efficacy in patients with MASH and fibrosis.
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Chalasani Naga P, Taub Rebecca, Mogg Robin, Labriola Dominic, Camacho Raul C, Zhang Hang, Anstee Quentin M
Аннотация
BACKGROUND & AIMS: Resmetirom, a thyroid hormone receptor beta agonist, improves metabolic dysfunction-associated steatohepatitis (MASH) and liver fibrosis in patients with non-cirrhotic MASH. Risk genotypes of PNPLA3, HSD17B13, TM6SF2, MTARC1, MBOAT7, and SERPINA1 have been associated with altered susceptibility to metabolic dysfunction-associated steatotic liver disease (MASLD), MASH, fibrosis, cirrhosis, and/or hepatocellular carcinoma. We evaluated the impact of MASLD risk genotypes on baseline characteristics and the response to resmetirom vs. placebo with respect to MASH, fibrosis, MRI-proton density fat fraction (MRI-PDFF), and other biomarkers.
METHODS: Testing the effects of MASLD risk genotypes or combinations of high-risk alleles on liver biopsy, MRI-PDFF, and biomarker responses to resmetirom was a pre-specified analysis in 738 patients enrolled in the MAESTRO-NASH phase III trial who consented to DNA collection, were genotyped for all genes, and had liver biopsies at baseline and Week 52.
RESULTS: At baseline, patients with high-risk genotypes of PNPLA3 or HSD17B13 had a lower frequency of metabolic risk factors, including type 2 diabetes mellitus and hypertension, than patients with low-risk genotypes. Interaction analyses and efficacy assessments indicated that resmetirom had similar positive effects on MASH resolution, fibrosis improvement on liver biopsy, MRI-PDFF response, and biomarkers at Week 52 in MAESTRO-NASH patients with high-risk genotypes of PNPLA3, HSD17B13, TM6SF2, MTARC1, and MBOAT7, either individually or as part of a composite genetic risk score. These effects were independent of sex, Hispanic ethnicity, and metabolic risk factors. Due to the limited sample size, the study was not powered to detect small effects of risk genotypes on resmetirom efficacy.
CONCLUSIONS: Resmetirom's effects on MASH, liver fibrosis, MRI-PDFF, and MASH biomarkers in the MAESTRO-NASH trial were not significantly impacted by the presence of common MASH risk genotypes, suggesting that resmetirom's mechanism of action may help mitigate the deleterious effects of MASH risk variants.
CLINICAL TRIAL: Number: NCT03900429 IMPACT AND IMPLICATIONS: Resmetirom has recently been approved for the treatment of metabolic dysfunction-associated steatohepatitis (MASH). It leads to MASH resolution and improvement of fibrosis in patients with non-cirrhotic MASH. Patients with MASH have higher prevalence of certain genetic variants which can be associated with more severe disease. In this study we evaluated the relationship between the presence of select MASH risk genotypes (e.g. PNPLA3, TM6SF2, or HSD17B13) or the combined total of MASH genetic risk alleles on the response to resmetirom and placebo in 738 patients with non-cirrhotic MASH with serial liver biopsies at baseline and week 52. Within the limitation of study sample size, resmetirom's benefits on MASH resolution, fibrosis improvement and hepatic steatosis were independent of the presence of MASH genetic risk genotypes either alone or in combination.
METHODS: Testing the effects of MASLD risk genotypes or combinations of high-risk alleles on liver biopsy, MRI-PDFF, and biomarker responses to resmetirom was a pre-specified analysis in 738 patients enrolled in the MAESTRO-NASH phase III trial who consented to DNA collection, were genotyped for all genes, and had liver biopsies at baseline and Week 52.
RESULTS: At baseline, patients with high-risk genotypes of PNPLA3 or HSD17B13 had a lower frequency of metabolic risk factors, including type 2 diabetes mellitus and hypertension, than patients with low-risk genotypes. Interaction analyses and efficacy assessments indicated that resmetirom had similar positive effects on MASH resolution, fibrosis improvement on liver biopsy, MRI-PDFF response, and biomarkers at Week 52 in MAESTRO-NASH patients with high-risk genotypes of PNPLA3, HSD17B13, TM6SF2, MTARC1, and MBOAT7, either individually or as part of a composite genetic risk score. These effects were independent of sex, Hispanic ethnicity, and metabolic risk factors. Due to the limited sample size, the study was not powered to detect small effects of risk genotypes on resmetirom efficacy.
CONCLUSIONS: Resmetirom's effects on MASH, liver fibrosis, MRI-PDFF, and MASH biomarkers in the MAESTRO-NASH trial were not significantly impacted by the presence of common MASH risk genotypes, suggesting that resmetirom's mechanism of action may help mitigate the deleterious effects of MASH risk variants.
CLINICAL TRIAL: Number: NCT03900429 IMPACT AND IMPLICATIONS: Resmetirom has recently been approved for the treatment of metabolic dysfunction-associated steatohepatitis (MASH). It leads to MASH resolution and improvement of fibrosis in patients with non-cirrhotic MASH. Patients with MASH have higher prevalence of certain genetic variants which can be associated with more severe disease. In this study we evaluated the relationship between the presence of select MASH risk genotypes (e.g. PNPLA3, TM6SF2, or HSD17B13) or the combined total of MASH genetic risk alleles on the response to resmetirom and placebo in 738 patients with non-cirrhotic MASH with serial liver biopsies at baseline and week 52. Within the limitation of study sample size, resmetirom's benefits on MASH resolution, fibrosis improvement and hepatic steatosis were independent of the presence of MASH genetic risk genotypes either alone or in combination.