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Background Semaglutide is being investigated for its potential to treat MASH in the ongoing ESSENCE trial ( NCT04822181).Methods ESSENCE, a phase 3 trial involving 1200 participants with biopsy-defined F2/F3 MASH, randomised participants 2:1 to once-weekly subcutaneous semaglutide 2.4 mg or placebo for 240 weeks. An analysis at week 72 (part 1) of the first 800 participants evaluated co-primary end-points: resolution of steatohepatitis with no worsening of liver fibrosis, and improvement in liver fibrosis with no worsening of steatohepatitis.A secondary analysis of part 1 evaluated treatment response through assessment of histology and non-invasive tests (NITs). Those with available measurements for NITs and histology results (N = 394) were assessed for disease activity-related response: decrease in alanine transaminase (ALT) levels (≥ 25% from baseline) or improvement in FibroScan-AST (FAST) score (≥ 0.22 points from baseline). For NITs and fibrosis-related histology (N = 494), response was assessed by decrease in vibration-controlled transient elastography (LSM-VCTE) ≥ 30% from baseline or enhanced liver fibrosis (ELF) score decrease (≥ 0.5units from base-line).Results Among the 800 participants (semaglutide [n=534; 169 F2, 365 F3] or placebo [n=266; 81 F2, 185 F3]), mean (standard deviation) age was 56.0 (11.6) years. Resolution of steatohepatitis with no worsening of fibrosis was achieved by 62.9% (semaglutide) vs 34.3% (placebo) with an estimated difference in responder proportions (EDP) of 28.7% (95% CI, 21.1 to 36.2; P<0.001). Improvement in liver fibrosis with no worsening of steatohepatitis was achieved by 36.8% (semaglutide) and 22.4% (placebo) (EDP, 14.4%; 95% CI, 7.5 to 21.3; P<0.001).In the secondary analysis, evaluating disease activity in the semaglutide (n = 269) and place-bo (n = 125) arms, 90.3% vs 59.2% met at least one treatment response criteria of disease activity, respectively. The percentage that met all response criteria (ALT, FAST, histology) was 45.7% (semaglutide) vs 10.4% (placebo).In the semaglutide arm (n = 332), 84.3% met at least one of the treatment response criteria related to fibrosis, compared with 54.9% in the placebo arm (n = 162). The percentage that met all response criteria (ELF, LSM-VCTE, histology) was 16% (semaglutide) vs 5.6% (pla-cebo).The incidence of serious adverse events in the safety analysis set was similar in both arms.Conclusions In participants with F2-F3 MASH, semaglutide 2.4 mg demonstrated superiority vs placebo for improvement of histological activity and fibrosis markers. Secondary analysis showed a higher proportion of participants who received semaglutide met the NIT and histology-based definitions of treatment response vs placebo.