Safety and Efficacy of Intravenous Bimagrumab in Inclusion Body Myositis
abstract
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Access this abstract now Full Text Available for ClinicalKey SubscribersBACKGROUND
Inclusion body myositis is an idiopathic inflammatory myopathy and the most common myopathy affecting people older than 50 years. To date, there are no effective drug treatments. We aimed to assess the safety, efficacy, and tolerability of bimagrumab-a fully human monoclonal antibody-in individuals with inclusion body myositis.
METHODS
We did a multicentre, double-blind, placebo-controlled study (RESILIENT) at 38 academic clinical sites in Australia, Europe, Japan, and the USA. Individuals (aged 36-85 years) were eligible for the study if they met modified 2010 Medical Research Council criteria for inclusion body myositis. We randomly assigned participants (1:1:1:1) using a blocked randomisation schedule (block size of four) to either bimagrumab (10 mg/kg, 3 mg/kg, or 1 mg/kg) or placebo matched in appearance to bimagrumab, administered as intravenous infusions every 4 weeks for at least 48 weeks. All study participants, the funder, investigators, site personnel, and people doing assessments were masked to treatment assignment. The primary outcome measure was 6-min walking distance (6MWD), which was assessed at week 52 in the primary analysis population and analysed by intention-to-treat principles. We used a multivariate normal repeated measures model to analyse data for 6MWD. Safety was assessed by recording adverse events and by electrocardiography, echocardiography, haematological testing, urinalysis, and blood chemistry.
FINDINGS
Between Sept 26, 2013, and Jan 6, 2016, 251 participants were enrolled to the study, of whom 63 were assigned to each bimagrumab group and 62 were allocated to the placebo group. At week 52, 6MWD change from baseline did not differ between any bimagrumab dose and placebo (least squares mean treatment difference for bimagrumab 10 mg/kg group, 17·6 m, SE 14·3, 99% CI -19·6 to 54·8; p=0·22; for 3 mg/kg group, 18·6 m, 14·2, -18·2 to 55·4; p=0·19; and for 1 mg/kg group, -1·3 m, 14·1, -38·0 to 35·4; p=0·93). 63 (100%) participants in each bimagrumab group and 61 (98%) of 62 in the placebo group had at least one adverse event. Falls were the most frequent adverse event (48 [76%] in the bimagrumab 10 mg/kg group, 55 [87%] in the 3 mg/kg group, 54 [86%] in the 1 mg/kg group, and 52 [84%] in the placebo group). The most frequently reported adverse events with bimagrumab were muscle spasms (32 [51%] in the bimagrumab 10 mg/kg group, 43 [68%] in the 3 mg/kg group, 25 [40%] in the 1 mg/kg group, and 13 [21%] in the placebo group) and diarrhoea (33 [52%], 28 [44%], 20 [32%], and 11 [18%], respectively). Adverse events leading to discontinuation were reported in four (6%) participants in each bimagrumab group compared with one (2%) participant in the placebo group. At least one serious adverse event was reported by 21 (33%) participants in the 10 mg/kg group, 11 (17%) in the 3 mg/kg group, 20 (32%) in the 1 mg/kg group, and 20 (32%) in the placebo group. No significant adverse cardiac effects were recorded on electrocardiography or echocardiography. Two deaths were reported during the study, one attributable to subendocardial myocardial infarction (secondary to gastrointestinal bleeding after an intentional overdose of concomitant sedatives and antidepressants) and one attributable to lung adenocarcinoma. Neither death was considered by the investigator to be related to bimagrumab.
INTERPRETATION
Bimagrumab showed a good safety profile, relative to placebo, in individuals with inclusion body myositis but did not improve 6MWD. The strengths of our study are that, to the best of our knowledge, it is the largest randomised controlled trial done in people with inclusion body myositis, and it provides important natural history data over 12 months.
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Additional Info
Disclosure statements are available on the authors' profiles:
Safety and Efficacy of Intravenous Bimagrumab in Inclusion Body Myositis (RESILIENT): A Randomised, Double-Blind, Placebo-Controlled Phase 2b Trial
Lancet Neurol 2019 Sep 01;18(9)834-844, MG Hanna, UA Badrising, O Benveniste, TE Lloyd, M Needham, H Chinoy, M Aoki, PM Machado, C Liang, KA Reardon, M de Visser, DP Ascherman, RJ Barohn, MM Dimachkie, JAL Miller, JT Kissel, B Oskarsson, NC Joyce, P Van den Bergh, J Baets, JL De Bleecker, C Karam, WS David, M Mirabella, SP Nations, HH Jung, E Pegoraro, L Maggi, C Rodolico, M Filosto, AI Shaibani, K Sivakumar, NA Goyal, M Mori-Yoshimura, S Yamashita, N Suzuki, M Katsuno, K Murata, H Nodera, I Nishino, CD Romano, VSL Williams, J Vissing, LZ Auberson, M Wu, A de Vera, DA Papanicolaou, AA AmatoFrom MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
Hanna et al conducted a double-blind, placebo-controlled, phase IIb, multicenter study (RESILIENT) to assess the safety and efficacy of intravenous bimagrumab in patients with inclusion body myositis (IBM). Bimagrumab is a monoclonal antibody that binds to muscle activin-2 receptors with greater affinity than their natural ligands activin and myostatin, which function as negative regulators of muscle growth. By inhibiting myostatin, bimagrumab can increase muscle weight in mice and cultured myotubes, but has no demonstrable effect on increasing muscle strength. On this background, the authors randomized 251 IBM patients to monthly three-dosing regimens of bimagrumab (10, 3, and 1 mg/kg) or placebo for 52 weeks. No change in 6MWD, the study’s primary endpoint, was noted with any bimagrumab dose compared with placebo. All patients continued to worsen with further deterioration in quantitative muscle strength testing, more falls, and worsening swallowing. A slight increase in lean body mass (measured by non-validated x-ray absorptiometry) was visually imperceptible and of no clinical relevance.
This is the largest clinical trial in IBM patients and the most disappointing because so much effort was invested for a drug that could only increase body mass but not muscle strength. The negative results were not, therefore, unexpected. IBM is a complex myopathy with many inflammatory/degenerative factors contributing to its relentless progression. Patients develop incapacitating weakness with muscular atrophy requiring drugs aimed at increasing mobility and strength, rather than the size of their atrophic muscles, and stopping disease progression. Powerful agents aimed at inflammation or degeneration have so far failed, but future drugs combining both effects are in the offing for future trials. In spite of the totally negative results, the RESILIENT study provides useful data for yearly disease progression. It also sends a message that muscle mass–building drugs aimed at sarcopenia are unsuitable not only for IBM but also for other neuromuscular disorders with devastating weakness and atrophy.