Apitegromab cuts muscle loss nearly in half in adults losing weight on tirzepatide

Incretin-based drugs such as tirzepatide produce dramatic weight loss, but lean mass accounts for roughly 25-40% of the weight lost. Lean mass is mostly skeletal muscle, which supports metabolic rate, insulin sensitivity, strength and independence as people age. Preserving it during pharmacologic weight loss is therefore a major unmet need. Myostatin, a TGF-beta family protein, restrains muscle growth, but earlier myostatin-targeting drugs failed, partly because they lacked selectivity. Apitegromab is a fully human antibody that binds precursor forms of myostatin and blocks its activation without touching other TGF-beta members. It has already improved motor function in spinal muscular atrophy trials.

EMBRAZE was a randomized, double-blind, placebo-controlled phase 2 trial at seven US sites. It enrolled 102 adults with overweight or obesity (BMI 27 to 45) from June to September 2024. Participants received tirzepatide, titrated by 2.5 mg every 4 weeks to a maximum of 15 mg weekly, plus either intravenous apitegromab 10 mg/kg every 4 weeks (n=51) or placebo (n=51) for 24 weeks. About 82% were women, and mean age was roughly 43. People with diabetes, cardiovascular disease and many other conditions were excluded. Lean mass was measured by DEXA, with an extra assessment at week 32.

The primary endpoint was met. Among the 87 completers with week 24 scans (43 apitegromab, 44 placebo), lean mass fell 1.6 kg with apitegromab versus 3.5 kg with placebo, a difference of 1.9 kg (80% CI 1.2-2.7; nominal P=0.0014). That is 54.9% less lean mass loss than placebo. Total weight loss was similar (11.2 vs 12.5 kg; P=0.29). Lean mass made up 14.6% of total weight loss with apitegromab versus 30.2% with placebo, while fat made up 85.3% versus 69.5%.

Absolute fat loss was not significantly different (8.5 vs 8.0 kg; P=0.57). Visceral, subcutaneous and trunk fat changes were also similar. At week 32, eight weeks after both treatments stopped, a lean mass advantage of 0.9 kg persisted (80% CI 0.3-1.5; nominal P=0.048). Pharmacokinetic data showed apitegromab and latent myostatin levels reached a plateau by about week 16, consistent with target engagement and saturation at this dose. No notable differences emerged in cardiometabolic markers or physical function.

Adverse events occurred in 76% of the apitegromab group and 71% of the placebo group. Serious events occurred in 1 participant per arm, and none was judged related to apitegromab. Nausea (39% vs 31%), fatigue (25% vs 12%) and headache (22% vs 10%) were more frequent with apitegromab, mostly mild. One apitegromab participant stopped after a creatine phosphokinase rise following vigorous strength training. Three participants (6%) had transient low-titer anti-drug antibodies, without hypersensitivity reactions.

This is proof of concept, not evidence of better function or outcomes. Efficacy analyses used completers. The significance level was a lenient two-sided 20% with no multiplicity correction, and the trial was small and mostly female. Physical activity was not objectively tracked, and DEXA cannot separate muscle from water-influenced lean tissue. Whether the preserved lean mass translates into strength, mobility or long-term health remains untested.