Anthony A Amato1, Kumaraswamy Sivakumar1, Namita Goyal1, William S David1, Mohammad Salajegheh1, Jens Praestgaard1, Estelle Lach-Trifilieff1, Anne-Ulrike Trendelenburg1, Didier Laurent1, David J Glass1, Ronenn Roubenoff1, Brian S Tseng2, Steven A Greenberg2. 1. From Brigham and Women's Hospital and Harvard Medical School (A.A.A., M.S., S.A.G.), Boston; Boston Children's Hospital (S.A.G.); Harvard-Massachusetts Institute of Technology (S.A.G.), Division of Health Sciences and Technology, Cambridge, MA; Barrow Neurological Institute (K.S.), Phoenix AZ; Massachusetts General Hospital (N.G., W.S.D.), Boston; Novartis Institutes for Biomedical Research (E.L.-T., A.-U.T., D.L., D.J.G., R.R., B.S.T.), Cambridge, MA and Basel, Switzerland; and Novartis Pharmaceuticals Corporation (J.P.), East Hanover, NJ. 2. From Brigham and Women's Hospital and Harvard Medical School (A.A.A., M.S., S.A.G.), Boston; Boston Children's Hospital (S.A.G.); Harvard-Massachusetts Institute of Technology (S.A.G.), Division of Health Sciences and Technology, Cambridge, MA; Barrow Neurological Institute (K.S.), Phoenix AZ; Massachusetts General Hospital (N.G., W.S.D.), Boston; Novartis Institutes for Biomedical Research (E.L.-T., A.-U.T., D.L., D.J.G., R.R., B.S.T.), Cambridge, MA and Basel, Switzerland; and Novartis Pharmaceuticals Corporation (J.P.), East Hanover, NJ. sagreenberg@partners.org brian.tseng@novartis.com.
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) orplacebo (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.
RCT Entities:
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.
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