370-OR: Optimized Weight Loss with Bimagrumab—Reduced Fat Mass with Increased Muscle Mass by Appetite-Independent Mechanisms

Background: Obesity is managed with lifestyle changes or incretin Tx to produce wt loss that is challenging to maintain long-term, perhaps because lean mass loss accounts for 20-40% of total wt loss. Semaglutide Tx results in rapid wt loss with 35% lower caloric intake, no further wt loss after 1 yr and rapid wt regain post-Tx. Bimagrumab (bima), a mAb to ActRIIA/ActRIIB, blocks activin pathways, leading to increased lean mass/decreased fat mass in numerous clinical studies (N=1561). Effects of bima IV or SC on fat and muscle were evaluated by DXA and MRI.

Results: In a Ph2 study of bima 10 mg/kg IV q4wks vs placebo (respectively) in persons with overweight/obesity and T2DM (N=75), LS mean change at Wk 48 in body wt was −5.9 vs −0.8 kg (p<0.001; −7.5% vs −1.1%), with minimal change in daily caloric intake. DXA: LS mean change at Wk48 in total body (TB) fat mass was −7.5 vs −0.2 kg (p<0.001; −22.2% vs −0.3%), TB lean mass +1.7 vs −0.4 kg (p<0.001; +3.6% vs -0.9%), and appendicular lean mass +0.5 vs −0.3 kg (p=0.009; +2.5% vs −1.1%); fat mass loss was maintained 12 wks post-last dose. MRI: LS mean change at Wk24 in visceral adipose tissue was −1.5 vs +0.2 L (p<0.001; −36.1% vs +3.6%), absolute hepatic fat fraction (FF, %) −4.6 vs +0.2 (p=0.006; -23.6% vs +14.3%), and paravertebral muscle (PVM) mass +363.3 vs −331.0 mm² (p=0.003; +6.4% vs -4.6%); a trend for decreased PVM fat fraction and intermuscular adipose tissue was observed (p=NS). Bima improved HbA1c (%) by -0.76 vs +0.04. AEs included diarrhea, muscle spasms. In a Ph1 study comparing bima 525 mg SC (N=12) and 700 mg IV (N=8), q4wks X3, fat mass loss and lean mass (total body and appendicular) increase were similar, with fat mass loss maintained 12 wks post-last dose; SC arm had fewer AEs than IV arm.

Conclusions: Bimagrumab Tx results in decreased fat deposition in tissues and increased muscle mass despite minimal change in caloric intake, which could lead to durable, high quality wt loss. A study of bima in obesity without T2DM is ongoing (NCT05616013).