Treatment of sporadic inclusion body myositis with bimagrumab

Abstract

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.

© 2014 American Academy of Neurology.

Figures

Figure 1. pSMAD2/3 is increased in sIBM muscle

(A) Western blots of 7 sIBM samples show increased size and density of pSMAD2/3 bands, in comparison to 5 DM, and 8 noninflammatory other muscle disease samples. Myostatin (GDF8)-treated human skeletal muscle culture was a positive control. (B) Quantitation of pSMAD2 to SMAD Western blot band intensity ratios in 50 muscle samples show statistically significant increases in sIBM samples. DM = dermatomyositis; GDF8 = growth differentiation factor 8; IBM = inclusion body myositis; OtherIM = non-IBM inflammatory myopathy; OtherMyo = noninflammatory myopathy; pSMAD2/3 = phosphorylated SMAD2/3; sIBM = sporadic inclusion body myositis.

Figure 2. Clinical trial design

Figure 3. Effect of bimagrumab compared with placebo on primary and secondary study endpoints over 24 weeks

(A–D) Changes in TMV-R, LBM, QMT-R, and 6MWD at 0, 8, 16, and 24 weeks. Sample sizes are 11 active and 3 placebo at 0 and 8 weeks, and 10 active and 2 placebo at 16 and 24 weeks. Mean and SDs of untransformed data are plotted, with SD bars provided for all means with more than 2 measurements. (E, F) Spearman correlation between change in muscle mass to week 8 (as measured by both TMV-R and LBM) and function (maximal change in 6MWD postbaseline). Sample sizes are 10 active and 2 placebo. LBM = lean body mass; QMT-R = right quadriceps quantitative muscle testing; 6MWD = 6-minute walking distance; TMV-R = right thigh muscle volume.