Nimacimab Plus Semaglutide Achieves Superior Weight Loss in Phase 2a Trial
Key Insights
Adults receiving nimacimab plus semaglutide achieved 2.95 percentage points greater weight loss than semaglutide alone at 26 weeks in the CBeyond phase 2a trial.
The combination therapy preserved more lean mass, with only 24% of weight loss attributed to lean mass compared to 28% with semaglutide alone.
Nimacimab plus semaglutide showed reduced weight regain during follow-up, with 18.1% weight regain versus 49.8% for semaglutide alone.
A peripherally acting cannabinoid receptor 1 (search) antibody combined with semaglutide demonstrated superior weight loss efficacy compared to semaglutide alone in adults with overweight or obesity, according to data from the CBeyond phase 2a trial presented at ObesityWeek.
The study enrolled 136 adults with overweight or obesity without diabetes (mean age 45.6 years; 84.6% women) who were randomly assigned to receive once-weekly 200 mg nimacimab alone, placebo, 200 mg nimacimab plus semaglutide 2.4 mg, or semaglutide alone for 26 weeks, followed by a 13-week follow-up period.
Enhanced Weight Loss Efficacy
Adults receiving nimacimab plus semaglutide achieved significantly greater weight reduction at 26 weeks compared to those receiving semaglutide alone, with a mean difference of -2.95 percentage points (95% CI, -5.7 to -0.2; P = 0.0372) in intention-to-treat analysis.
The combination therapy also demonstrated superior body composition changes. From baseline to 26 weeks, the nimacimab plus semaglutide group achieved a 21.12% fat mass loss and 6.48% lean mass reduction, compared to 15.35% fat mass reduction and 5.68% decrease in lean mass with semaglutide alone. Notably, the proportion of weight loss attributed to lean mass was lower with the combination therapy at 24% versus 28% with semaglutide alone.
Waist circumference reduction was also more pronounced in the combination group, with an 11.28 cm decline compared to 7.61 cm decrease for semaglutide alone (P = 0.0492).
Reduced Weight Regain
During the off-treatment follow-up period from 26 to 38 weeks, the nimacimab plus semaglutide group demonstrated significantly less weight regain at 18.1% compared to 49.8% for adults receiving semaglutide alone. "It appears as though the addition of the nimacimab slowed down the regain of body fat and body weight," said Louis J. Aronne, MD, the Sanford I. Weill Professor of Metabolic Research at Weill Cornell Medicine.
Differentiated Mechanism of Action
Nimacimab represents a novel approach to cannabinoid receptor 1 (search) modulation, differing significantly from previously investigated agents. "Nimacimab is an antibody that is peripherally restricted," Aronne explained. "There's minimal penetration into the brain and compared to small molecules, the difference is quite significant. It's also a negative allosteric modulator, which makes it retain its potency even in the presence of competition."
This peripheral restriction addresses safety concerns that led to the discontinuation of earlier cannabinoid receptor 1 (search) inhibitors rimonabant and taranabant, both of which were associated with increased risk for suicidality despite demonstrating at least 5% weight loss in 50% or more of participants in phase 2 or phase 3 trials.
Safety Profile
Adverse events were reported in 80.9% of study participants overall, with rates of 91.7% in the semaglutide alone group, 82.5% in the nimacimab alone group, 78.6% in the nimacimab plus semaglutide group, and 75% in the placebo group. The most common treatment-emergent adverse events were nausea (18.4%), dizziness (15.4%), injection site erythema (13.2%), and headache (10.3%).
Gastrointestinal adverse events were more common with semaglutide than nimacimab, with nimacimab demonstrating similar rates to placebo. Psychiatric adverse events were rare, with two reported in the semaglutide alone group, one in the nimacimab alone group, and one in the placebo group. All psychiatric adverse events were mild or moderate in severity.
Future Development
The favorable safety profile may enable exploration of higher doses in future studies. "Further dose-ranging studies are needed to demonstrate the optimal dose of nimacimab for both monotherapy and combination treatment," Aronne noted. Participants who completed the 26-week treatment period were invited to participate in an ongoing 26-week extension study.