OBJECTIVE: To study activin signaling and its blockade in sporadic inclusion 
body myositis (sIBM) through translational studies and a randomized controlled 
trial.
METHODS: We measured transforming growth factor β signaling by SMAD2/3 
phosphorylation in muscle biopsies of 50 patients with neuromuscular disease (17 
with sIBM). We tested inhibition of activin receptors IIA and IIB (ActRII) in 14 
patients with sIBM using one dose of bimagrumab (n = 11) or placebo (n = 3). The 
primary outcome was the change in right thigh muscle volume by MRI at 8 weeks. 
Lean body mass, strength, and function were secondary outcomes. Twelve of the 
patients (10 bimagrumab, 2 placebo) participated in a subsequent 16-week 
observation phase.
RESULTS: Muscle SMAD2/3 phosphorylation was higher in sIBM than in other muscle 
diseases studied (p = 0.003). Eight weeks after dosing, the bimagrumab-treated 
patients increased thigh muscle volume (right leg +6.5% compared with placebo, p 
= 0.024; left leg +7.6%, p = 0.009) and lean body mass (+5.7% compared with 
placebo, p = 0.014). Subsequently, bimagrumab-treated patients had improved 
6-minute walking distance, which peaked at 16 weeks (+14.6%, p = 0.008) compared 
with placebo. There were no serious adverse events; the main adverse events with 
bimagrumab were mild acne and transient involuntary muscle contractions.
CONCLUSIONS: Transforming growth factor β superfamily signaling, at least 
through ActRII, is implicated in the pathophysiology of sIBM. Inhibition of 
ActRII increased muscle mass and function in this pilot trial, offering a 
potential novel treatment of sIBM.
CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that for 
patients with inclusion body myositis, bimagrumab increases thigh muscle volume 
at 8 weeks.