Effect of resmetirom or placebo in NASH (MASH) fibrosis patients with<5% or≥5% weight loss and/or on baseline GLP-1 therapy in the MAESTRO-NASH 52-week serial liver biopsy study

Background MAESTRO-NASH (NCT03900429) 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) 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 improvement in fibrosis with no worsening of NAS (FI). At baseline 12-16% of patients in the treatment groups were on stable GLP-1 therapy. The effects of resmetirom or placebo with or without weight loss on liver biopsy endpoints and/or GLP-1 baseline therapy were evaluated.

Methods Patients in this serial liver biopsy trial were counseled on moderate diet and exercise at each study visit. Patients on baseline GLP-1 therapy and/or with<or≥5% weight loss at 52 weeks were evaluated for achievement of NASH resolution (NR) and fibrosis improvement (FI) liver biopsy endpoints or percent change from baseline in MRI-PDFF at Week 52.

Results Baseline GLP-1 therapy had been in place for>6 months, 96% in diabetics, the most common dose was 1 mg semaglutide. Patients on GLPs compared to not on GLPs had MRI-PDFF 16% vs 18%; higher percentage diabetic, higher glucose and HbA1C; more common statin use; lower lipids, liver enzymes, ELF and FIB-4. Seventeen% of randomized patients achieved≥5% weight loss at Week 52, 17-22% in the resmetirom arms and 12% on placebo. GLP-1 treatment was not associated with weight loss: 14% of patients with≥5% weight loss were on GLPs; 15% of patients with<5% weight loss were on GLPs.≥5% weight loss enhanced NR by>20% in resmetirom and placebo groups; the difference between resmetirom and placebo was 25% higher NR in resmetirom at 100 mg (not impacted). FI was increased by ~10% in all treatment arms. GLP-1 treatment had no effect on either NR or FI in resmetirom arms. In the placebo arm, GLP treatment resulted in lower NR and FI responses; both FI and NR were<3% in placebo patients on GLPs who had<5% weight loss, lower than placebo patients not on GLPs with<5% weight loss. MRI-PDFF response was greater in patients with≥5% weight loss in both resmetirom and placebo arms and not changed by GLP treatment.

Conclusion A small amount of weight loss (≥5%) enhances the effect of resmetirom on NASH resolution (>50%) and fibrosis improvement ~40% on serial liver biopsy. Stable GLP-1 therapy did not impact liver biopsy endpoints or cause weight loss. In the placebo group, stable GLP-1 therapy did not result in weight loss, and biopsy response rates in GLP-treated placebo patients were similar or slightly lower than placebo patients not on GLP therapy.

 

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Interessenkonflikt

JS: reports consultancy fees from Astra Zeneca, Apollo Endosurgery, Bayer, Boehringer Ingelheim, BMS, Gilead Sciences, GSK, Intercept Pharmaceuticals, Ipsen, Inventiva Pharma, Madrigal, MSD, Northsea Therapeutics, Novartis, Novo Nordisk, Pfizer, Roche, Sanofi, Siemens Healthineers. Research Funding: Gilead Sciences, Boehringer Ingelheim, Siemens Healthcare GmbH. Stock Options: AGED diagnostics, Hepta Bio. Speaker Honorarium: Boehringer Ingelheim, Echosens, MedPublico GmbH, Novo Nordisk, Madrigal Pharmaceuticals, Histoindex, MedPublico GmbH.

Publication History

Article published online:
28 May 2025