Resmetirom effects on metabolic dysfunction associated steatohepatitis (MASH) with liver fibrosis in patients with mash genetic risk alleles

Introduction: MAESTRO-NASH is an ongoing 54-month, randomized, double-blind, placebo-controlled Phase 3 trial evaluating the efficacy of resmetirom in patients with biopsy-confirmed nonalcoholic steatohepatitis (NASH/MASH) and fibrosis. 966 patients with biopsy-confirmed NASH were randomized 1:1:1 to resmetirom 80 mg, resmetirom 100 mg, or placebo administered once daily.

Histologic endpoints were assessed after 52 weeks. Dual primary endpoints at Week 52 were achieved with both resmetirom 80 mg and 100 mg: NASH resolution with no worsening of fibrosis (NR) or≥1-stage reduction in fibrosis with no worsening of NAS (FI). In this analysis, we examined the impact of baseline PNPLA3 ,TM6SF2 and MBOAT7 genotypes on the response to resmetirom on serial liver biopsy and MRI-PDFF (magnetic resonance imaging proton density fat fraction).

Objectives and Methods: In the Phase 3 study (MGL-3196-11), PNPLA3 rs738409, TM6SF2 rs58542926 and MBOAT7 rs6141738 were genotyped in patients consenting to DNA collection and genetic testing for the response to resmetirom on serial liver biopsy and MRI-PDFF. The NASH resolution and fibrosis improvement responses on liver biopsy and the MRI-PDFF (median percent change from baseline at Week 52) response were analyzed within each treatment arm, comparing wild type, heterozygote and homozygote for each genetic risk allele.

Results: Across three treatment arms, 740 patients had genotyping and serial liver biopsy data. The frequency of PNPLA3GG (wild type), PNPLA3 CG (heterozygous), and GG (homozygous) genotypes across 3 treatment arms were 30-32%, 45-50% and 20-24% respectively. The frequency of TM6SF2 CC (wild type), TM6SF2 CT (heterozygous), and TM6SF2 TT (homozygous) genotypes were 79-82%, 15-21% and 0-3% across 3 treatment arms. The frequency of MBOAT7 CC (wild type), MBOAT7 CT (heterozygous) and MBOAT7 TT (homozygous) genotypes were 28-29%, 47-50%, and 21-24% across 3 treatment arms. There were no differences observed in the level of response on biopsy or MRI-PDFF to resmetirom or placebo treatment in patients with genetic risk alleles for PNPLA3 and TM6SF2 or TMC4 (not shown).

Conclusion: MASH risk alleles were prevalent in the MAESTRO-NASH population and did not influence the treatment response to resmetirom.

Publikationsverlauf

Artikel online veröffentlicht:
04. September 2025