Bimagrumab and Semaglutide in Obesity: Phase 2 Findings

Key Takeaways

• In obesity, bimagrumab-containing regimens, especially combination regimens, were associated with larger fat-mass and visceral-adiposity reductions and better lean-mass preservation than semaglutide alone.
• A high-dose combination was associated with the greatest reported weight loss, and active regimens outperformed placebo at week 48.
• Adverse events generally matched known drug profiles, discontinuations varied by regimen, and no deaths were reported.

In the randomized phase 2 BELIEVE study, adults with obesity lost 17.8 kg at week 48 with high-dose bimagrumab plus semaglutide, compared with 14.2 kg with semaglutide 2.4 mg alone. The nine-arm, placebo-controlled trial evaluated bimagrumab, semaglutide, and their combinations during the prespecified 48-week primary period. Bimagrumab-containing therapy also showed a distinct body-composition pattern, with the high-dose combination producing the greatest weight reduction.

507 adults were randomized after 730 were screened across 26 sites in the United States, Australia, and New Zealand. The multicenter, randomized, placebo-controlled design used blinded assignment to bimagrumab or placebo and open-label semaglutide, with participants assigned to nine groups in a 1:1:1:1:1:1:1:1:1 ratio to bimagrumab, semaglutide, or both. Bimagrumab 10 or 30 mg/kg was infused at randomization and week 4, then every 12 weeks, and semaglutide 1.0 or 2.4 mg was given weekly with dose escalation. The primary treatment period lasted 48 weeks, followed by a 24-week open-label extension through week 72 and planned withdrawal follow-up to week 104. Eligible adults were aged 18 to 80 years, with BMI at least 30 kg/m2 or 27 kg/m2 with a comorbidity, without treated diabetes or HbA1c 6.5% or higher.

The prespecified primary endpoint was absolute change from baseline in body weight at week 48. Least-squares mean change at that time was −9.3 kg with bimagrumab 30 mg/kg, −14.2 kg with semaglutide 2.4 mg, −17.8 kg with the high-dose combination, and −3.3 kg with placebo. All active regimens were numerically better than placebo at week 48, and all except bimagrumab 10 mg/kg were superior to placebo (nominal P<0.001); the high-dose combination exceeded semaglutide 2.4 mg alone (nominal P<0.05). Before extension results were assessed, at least 15% weight loss occurred in 23.3%, 43.4%, and 63.9% of participants receiving bimagrumab 30 mg/kg, semaglutide 2.4 mg, and the high-dose combination, respectively.

Week 72 weight analyses were secondary and post hoc rather than part of the prespecified primary endpoint. Weight change at that time was −12.0 kg with bimagrumab 30 mg/kg, −16.5 kg with semaglutide 2.4 mg, and −24.2 kg with the high-dose combination. At least 15% weight loss was reported in 21.8%, 51.8%, and 84.9%, respectively, across those three groups. Estimated visceral adipose tissue at week 72 fell 58.2% with the high-dose combination, versus 35.8% with semaglutide 2.4 mg and 45.1% with bimagrumab 30 mg/kg. Using the week 48 efficacy estimand, lean mass changed +2.3% to +2.7% with bimagrumab, −5.3% to −7.9% with semaglutide, and −1.1% to −2.6% with combinations, consistent with preferential fat reduction.

Treatment-emergent adverse events occurred in 91.1% to 98.2% of active groups versus 74.5% with placebo. Muscle spasms, diarrhea, and acne were linked to bimagrumab, while nausea, diarrhea, constipation, and fatigue were linked to semaglutide. Adverse-event discontinuations were 14.0% to 21.4% with bimagrumab, 3.6% to 8.8% with semaglutide, 5.3% to 12.5% with combinations, and 3.6% with placebo. Serious adverse events occurred across groups, no deaths were reported, and three pancreatitis serious adverse events were distributed one each to placebo, bimagrumab 10 mg/kg, and semaglutide 1.0 mg.