ESSENCE: Semaglutide bests placebo in MASH resolution, fibrosis improvement at 72 weeks
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Key takeaways:
- Semaglutide 2.4 mg outperformed placebo in MASH resolution (62.9% vs. 34.1%) and improvement in fibrosis (37% vs. 22.5%) at 72 weeks.
- Safety profile was consistent with previous phase 2 trials.
SAN DIEGO — Semaglutide was superior to placebo in metabolic dysfunction-associated steatohepatitis resolution and improvement in fibrosis at 72 weeks, with a safety profile consistent with previous studies, according to late-breaking data.
“Semaglutide is a glucagon-like peptide-1 receptor agonist [that] has been extensively studied across a broad spectrum of cardiometabolic diseases,” Philip N. Newsome, PhD, FRCPE, director of Roger Williams Institute of Liver Studies at King’s College London, told attendees at The Liver Meeting. “In a phase 2 randomized clinical trial, it demonstrated a benefit in terms of resolution of MASH in patients with histologically proven MASH and stage 2 or 3 fibrosis.”
In his presentation, Newsome reported interim efficacy and safety results from the ongoing phase 3 ESSENCE trial, which is comparing once-weekly, subcutaneous semaglutide vs. placebo in patients with biopsy-defined MASH and fibrosis stage 2 or 3.
The analysis included the first 800 patients to complete 72 weeks of treatment, who were randomly assigned 2:1 to semaglutide 2.4 mg (Ozempic, Wegovy; Novo Nordisk; n = 534) or placebo (n = 266), along with standard of care. Patients in the semaglutide group were up-titrated every 4 weeks to achieve the 2.4 mg target dose at 16 weeks. Liver biopsies were performed at weeks 0 and 72.
The primary endpoints were MASH resolution with no worsening of fibrosis and improvement of fibrosis with no worsening of MASH. Secondary confirmatory endpoints included MASH resolution with at least one-stage improvement in fibrosis and change in body weight, as well as patient-reported change in bodily pain, evaluated via the 36-item Short Form Health Survey.
According to Newsome, there was a “highly significant difference” in the proportion of patients who achieved MASH resolution with no worsening of fibrosis in favor of semaglutide (62.9% vs. 34.1%; estimated proportion difference [EDP] = 28.9 percentage points; 95% CI, 21.3-36.5). Similarly, a higher proportion of patients receiving semaglutide achieved fibrosis improvement with no worsening of MASH (37% vs. 22.5%; EDP = 14.4 percentage points; 95% CI, 7.5-21.4).
Semaglutide also outperformed placebo in the secondary dual endpoint of MASH resolution with one-stage fibrosis improvement (32.8% vs. 16.2%; EDP = 16.6 percentage points; 95% CI, 10.2-22.9), which was “highly statistically significant,” Newsome said.
In addition, there was a statistically significant reduction in body weight with semaglutide vs. placebo (–10.5% vs. –2%); however, there was no significant improvement in bodily pain.
Results also demonstrated improvement in liver enzymes with semaglutide, as well as in noninvasive fibrosis tests and cardiometabolic risk parameters.
In a safety analysis of 1,195 patients at 96 weeks, there was no increase in discontinuations or fatal or serious adverse events among patients receiving semaglutide, although gastrointestinal side effects were more common.
Specific safety concerns related to semaglutide included an increase in gallbladder disorders, but there was no evidence of drug-induced liver injury.
“[Semaglutide] is the first GLP-1 receptor agonist to demonstrate efficacy in a phase 3 trial of patients with MASH, [with] superiority confirmed against placebo, for both the primary endpoints, but also the dual endpoint and noninvasive markers of liver fibrosis,” Newsome told attendees. “It’s nice to see demonstration of metabolic benefit in patients with MASH... and reassuringly, the safety profile is in keeping with previous phase 2 clinical trials and the larger body of data with semaglutide.”