Summary: This paper reports the design and the baseline characteristics of the first 800 randomised participants in the two-part, phase 3 ESSENCE trial (NCT04822181) of subcutaneous semaglutide 2.4 mg versus placebo in biopsy-proven, non-cirrhotic MASH with fibrosis stage 2 or 3. The cohort had a mean age of 56 years, 57.1% were female, mean BMI was 34.6 kg/m2, 55.5% had type 2 diabetes, and more than 99% met at least one MASLD cardiometabolic criterion. No efficacy or histological outcomes are reported in this publication.
PICO Summary
| Element | Detail |
|---|---|
| Population | First 800 randomised adults with biopsy-proven, non-cirrhotic MASH and fibrosis stage 2 (31.3%) or stage 3 (68.8%); two-part, phase 3, randomised, double-blind, multicentre trial. Baseline: mean age 56 (SD 11.6) years, 57.1% female, mean BMI 34.6 (SD 7.2) kg/m2, 55.5% with type 2 diabetes, and more than 99% meeting at least one MASLD cardiometabolic criterion. |
| Intervention | Subcutaneous semaglutide 2.4 mg once weekly (allocation arm sizes not reported in this baseline/design paper). |
| Comparison | Matched placebo (allocation arm sizes not reported in this baseline/design paper). |
| Outcome | No efficacy or histological results are reported. This publication describes the trial design and baseline cohort only. The pre-specified Part 1 primary endpoints are (1) resolution of steatohepatitis with no worsening of fibrosis and (2) improvement in fibrosis with no worsening of steatohepatitis; Part 2 is based on clinical outcomes. No effect estimates, confidence intervals, p-values, or ARR/NNT are available, as no between-arm comparison has been performed in this report. |
Expert Commentary
This publication should be read for what it is: a design and baseline-characteristics report, not an efficacy readout. No outcome has been demonstrated here, and any claim that semaglutide improved liver histology cannot be supported by this paper. What the report does establish is reassuring in a narrow sense. The enrolled population is well-characterised and clinically meaningful, being weighted toward fibrosis stage 3 (68.8%), with a high prevalence of type 2 diabetes (55.5%) and obesity, and nearly universal MASLD cardiometabolic burden. That composition suggests the trial is sampling the higher-risk MASH patients in whom an effective therapy would matter most. The chief limitation for interpretation is simply that there is nothing to interpret yet regarding benefit; the histological and clinical endpoints were unreported at this stage, so efficacy and safety remain open questions to be answered when Part 1 and Part 2 data mature. Readers should also note the heavy manufacturer involvement, with several authors employed by the trial sponsor, which warrants the usual caution once results appear. Can I use this with my patients? Not yet, since this paper offers no treatment effect to act on; it only confirms that a rigorous phase 3 evaluation in biopsy-proven MASH is underway and adequately enrolled. Clinicians awaiting an evidence-based MASH pharmacotherapy should watch for the outcome publications rather than extrapolate from this baseline description.
References
Newsome PN, Sanyal AJ, Engebretsen KA, Kliers I, Østergaard L, Vanni D, et al. Semaglutide 2.4 mg in participants with metabolic dysfunction-associated steatohepatitis: baseline characteristics and design of the phase 3 ESSENCE trial. Aliment Pharmacol Ther. 2024;60(11-12):1525-1533. doi:10.1111/apt.18331