Study Design and Mechanism:

The BELIEVE phase 2b study, which evaluated a novel approach to obesity treatment by combining semaglutide with bimagrumab — a monoclonal antibody targeting activin type 2 receptor pathways. Bimagrumab acts to block muscle growth inhibition and reduce adipose lipid storage, thus promoting simultaneous muscle mass gain and fat mass loss.

This as a paradigm-shifting mechanism complementary to GLP-1-based therapies, offering expanded indications, including maintenance therapy and an option for patients with GLP-1 intolerance.

Study Protocol and Patient Population:

• This multi-center, double-blind, placebo-controlled trial enrolled 507 adults with obesity or overweight status.
• Participants were randomized across nine treatment arms, including various dose combinations of bimagrumab (10 or 30 mg/kg) and semaglutide (1.0 or 2.4 mg).
• Administration: Intravenous bimagrumab was administered at weeks 4, 16, 28, and 40; semaglutide was given subcutaneously weekly.
• Duration: 48-week primary treatment followed by a 24-week open-label extension to 72 weeks.
• Assessment: Body composition was assessed via DEXA.

Efficacy Results: Weight, Fat, and Lean Mass:

1. The combination of high-dose bimagrumab (30 mg/kg) and semaglutide (2.4 mg) produced the greatest weight loss at 22.1% by week 72.
2. Fat mass reduction was highest in the combination group (45.7%), compared to 27.8% (semaglutide alone) and 28.5% (bimagrumab alone).
3. Importantly, lean mass loss was only 2.9% with the combination versus 7.4% with semaglutide monotherapy.
4. Bimagrumab alone was associated with a 2.5% gain in lean mass.

Fat Mass vs Lean Mass Proportions and Functional Measures:

• At 48 weeks, 92.9% of weight lost in the high-dose combination group was attributable to fat loss, versus 71.5% for semaglutide and 100% for bimagrumab.
• 94% of participants in the combination group achieved ≥30% fat mass reduction.
• Functional evaluation included hand grip strength, though limitations were noted in assessing muscle quality, as no biopsies were conducted.

Biomarker and Lipid Profile Changes:

The combination therapy showed:

• 83% reduction in high-sensitivity CRP (anti-inflammatory effect)
• Increased adiponectin levels exceeding those observed with semaglutide alone
• LDL cholesterol initially rose by 15–30% in bimagrumab groups but normalized by week 72 in combination groups.

Safety Profile and Adverse Events:

1. Bimagrumab was associated with:
   1. Muscle spasms (up to 63.6% in high-dose group)
   2. Transient elevations in ALT and lipase
   3. Acne and diarrhea
2. Semaglutide groups experienced typical GI symptoms: nausea, diarrhoea, constipation, fatigue, elevation in serum lipase.
3. Discontinuation rates due to adverse events were ~9% in combination groups. No deaths were reported.

Expert Commentary and Future Directions:

• Bimagrumab's complexity as an activin receptor modulator was noted, and the necessity of Phase 3 data and pharmacovigilance was underscored.

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