Amato, Anthony A, Sivakumar, Kumaraswamy, Goyal, Namita, David, William S, Salajegheh, Mohammad, Praestgaard, Jens, Trifilieff, Estelle, Trendelenburg, Anne-Ulrike, Laurent, Didier, Glass, David, Roubenoff, Ronenn, Tseng, Brian and Greenberg, Steven A (2014) Treatment of sporadic inclusion body myositis with bimagrumab. Neurology, 83 (24). pp. 2239-2246. ISSN 1526-632X

Abstract

Background: Sporadic inclusion body myositis (sIBM) is the most common acquired muscle disease of people over age 50, and has no effective therapy. Bimagrumab is a monoclonal antibody that blocks activin type II receptors (ActRII), and hence the signaling of particular muscle-inhibiting TGFβ superfamily members, including myostatin and activin.

Methods: We measured TGFβ signaling by SMAD2/3 phosphorylation in muscle biopsies of 50 patients with neuromuscular disease (17 with sIBM). We tested ActRII inhibition 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 (TMV) by MRI at 8 weeks. Lean body mass (LBM), strength, and function were secondary outcomes. Twelve of the patients (10 bimagrumab, 2 placebo) participated in a subsequent 16-week observation phase.

Results: SMAD2/3 phosphorylation was higher in sIBM muscle than other muscle diseases tested (P=0.003). Eight weeks after dosing, the bimagrumab-treated patients increased TMV (right leg + 6.5% compared to placebo, P=0.024; left leg +7.6%, P = 0.009) and LBM (+5.7% compared to 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 to placebo. There were no serious adverse events; the main adverse events with bimagrumab were mild acne and transient involuntary muscle contractions.

Conclusions: TGFβ 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.

Item Type:	Article
Keywords:	sporadic inclusion body myositis, sIBM, bimagrumab, BYM338, activin type II receptors, SMAD, clinical trial
Date Deposited:	09 May 2016 23:45
Last Modified:	09 May 2016 23:45
URI:	https://oak.novartis.com/id/eprint/11300