Comparison of MAESTRO-NASH and ESSENCE: Effects of Resmetirom and Semaglutide Relative to Placebo on Primary and Secondary Liver Biopsy Endpoints Using Aligned Endpoints and Statistical Methods

The MAESTRO-NASH and ESSENCE trials are ongoing studies evaluating new therapies in patients with MASH.^1,2 The MAESTRO-NASH trial enrolled 966 patients including 917 with fibrosis stage 2/3, who were randomly assigned to resmetirom 100 mg (n=323), resmetirom 80 mg (n=322), or placebo (n=321). At week 52, the trial met its dual primary endpoints with both doses of resmetirom demonstrating significantly improvements over placebo in the proportion of patients attaining NASH resolution with no worsening of fibrosis with at least 2-point reduction in nonalcoholic fatty liver disease activity score (NAS) (P<.001 for both vs placebo), and at least 1-stage improvement in fibrosis with no worsening of NAS (P<.001 for both vs placebo).¹

The ESSENCE trial enrolled 1197 patients with biopsy-defined MASH and fibrosis stage 2/3 who were randomly assigned to once weekly subcutaneous semaglutide at 2.4 mg (n=534) or placebo (n=266). In an analysis of the first 800 patients, the trial met its primary endpoint, with significantly higher proportions of patients in the semaglutide arm attaining resolution of steatohepatitis without worsening of liver fibrosis (P<.001 vs placebo) and attaining significantly greater reductions in liver fibrosis without worsening of steatohepatitis (P<.001 vs placebo).²

In an exploratory cross-trial analysis, Loomba and colleagues compared responses to drug treatment and placebo in the MAESTRO-NASH and ESSENCE trials using aligned biopsy endpoints and statistical tools. Baseline characteristics between patients with fibrosis stage 2/3 were similar across both trials; the mean age was 56 years in both trials; 57% of patients in both trials were female, and the mean BMI was 35.6 kg/m² in MAESTRO-NASH and 34.6 kg/m² in ESSENCE.

When placebo responses were imputed for missing data, the improvements with treatment over placebo in the likelihood of attaining at least 1-stage improvements in fibrosis with no worsening of NAS were similar with resmetirom 100 mg in MAESTRO-NASH (15% difference over placebo, approximate 2.4-fold improvement) as with semaglutide in ESSENCE (14% difference over placebo, approximate 2-fold improvement).

In MAESTRO-NASH, 36% of patients receiving resmetirom 100 mg attained the FDA endpoint of NASH resolution, compared with 13% in the placebo arm (23% difference), whereas in the ESSENCE trial, rates of NASH resolution were 63% with semaglutide and 34% with placebo (29% difference). However, using the more stringent endpoint of NASH resolution with at least 2-point NAS reduction, rates of resolution in the MAESTRO-NASH trial were 30% with resmetirom and 9% with placebo (21% difference) and in the ESSENCE trial were 44% with semaglutide and 19% with placebo (25% difference) (Figure 7).

Figure 7.

Achievement of biopsy endpoint MASH resolution in patients with fibrosis stages 2 to 3 treated with resmetirom or placebo in the MAESTRO-NASH trial vs semaglutide or placebo in the ESSENCE trial.

FDA, US Food and Drug Administration; MASH, metabolic dysfunction-associated steatohepatitis; NAS, nonalcoholic fatty liver disease activity score.

Adapted from Loomba R, et al. AASLD abstract 4093. Presented at: The Liver Meeting; November 7-11, 2025; Washington, DC.³

The proportion of patients attaining a 2-point NAS reduction was 51% with resmetirom 100 mg in MAESTRO-NASH and 50% with semaglutide in ESSENCE, compared with 25% in both placebo arms. Investigators concluded that the similar rates of 2-point NAS reduction in the placebo arms suggest that the high rate of MASH resolution of 34% reported in the ESSENCE trial can be attributed to low NAS in the reassessed baseline biopsies.

When considering outcomes for MASLD studies, one of the most challenging findings has been that the placebo arms also get better over time. That response can blunt the perceived efficacy in the study. This study nicely demonstrated that both resmetirom and semaglutide led to around a 15% improvement over placebo when looking at the baseline characteristics of the liver biopsies in the intervention as well as placebo arms. When the authors evaluated for this 2-point change in NAS, the placebo groups did have a similar response in both studies, showing that both of these agents worked.

—Nancy S. Reau, MD

ABSTRACT SUMMARY A Randomized, Placebo-Controlled, Phase 2 Study of the Safety and Efficacy of Combination Treatment With Semaglutide, Cilofexor, and Firsocostat in Patients With Compensated Cirrhosis Due to MASH (WAYFIND).

The WAYFIND trial evaluated the combination of semaglutide plus the fixed-dose combination of cilofexor (cilo), a nonsteroidal gut-restricted selective farnesoid X receptor agonist, and firsocostat (fir), a liver-targeted acetyl-coenzyme A carboxylase inhibitor, in patients with compensated cirrhosis (F4c) due to MASH (Abstract 0148). The trial enrolled 453 patients with a mean age of 62 years; 64.5% were female and 68.2% had diabetes mellitus. The study did not meet its primary endpoint, showing no significant difference in rates of fibrosis improvement without MASH worsening at week 72 with semaglutide plus cilo/fir compared with placebo as assessed by central pathologists (13.7% vs 8.3%; P=.2289). When liver biopsies were assessed by PathAI, rates of fibrosis improvement without MASH were significantly higher with semaglutide plus cilo/fir compared with placebo (16.0% vs 6.0%; nominal P=.0011) and were also higher with semaglutide vs placebo (12.4% vs 6.0%; P=.0093) and with cilo/fir alone vs placebo (12.9% vs 6.0%; P=.0066). Noninvasive fibrosis tests were also superior with semaglutide, cilo/fir, and the combination compared with placebo. Investigators noted that the combination regimen was well tolerated; no treatment-related serious AEs were reported.

The proportion of patients attaining ballooning reduction was numerically higher for patients in the resmetirom 100 mg arm in the MAESTRO-NASH trial than for patients in the semaglutide arm in the ESSENCE trial (66% vs 61%); rates in the placebo arms in both trials were 31% and 40%, respectively, indicating a greater difference from placebo in the resmetirom trial.

Regarding safety, resmetirom was associated with higher rates of diarrhea and nausea vs placebo, and semaglu-tide was associated with higher rates of nausea, diarrhea, constipation, and vomiting vs placebo. In both trials, the incidence of serious AEs was similar between treatment and placebo arms.