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 b 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 5 11) or placebo (n 5 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 5 0.003). Eight weeks after dosing, the bimagrumab-treated patients increased thigh muscle volume (right leg 16.5% compared with placebo, p 5 0.024; left leg 17.6%, p 5 0.009) and lean body mass (15.7% compared with placebo, p 5 0.014). Subsequently, bimagrumabtreated patients had improved 6-minute walking distance, which peaked at 16 weeks (114.6%, p 5 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 b 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. Neurology ® 2014;83:2239-2246 GLOSSARY ActRII 5 activin receptors IIA and IIB; DXA 5 dual-energy x-ray absorptiometry; LBM 5 lean body mass; pSMAD2/3 5 phosphorylated SMAD2/3; QMT 5 quantitative muscle testing; sIBM 5 sporadic inclusion body myositis; 6MWD 5 6-minute walking distance; TGFb 5 transforming growth factor b; TMV 5 thigh muscle volume.Sporadic inclusion body myositis (sIBM) is a slowly progressive degenerative and inflammatory skeletal muscle disease beginning in middle or later life.1 Its clinical features include a specific pattern of muscle involvement (preferential weakness of finger flexors and knee extensors) accompanied by progressive muscle atrophy, distinctive microscopic pathology including endomysial inflammation and rimmed vacuoles, and a recently identified serum autoantibody (against cytosolic 59-nucleotidase 1A) biomarker.2-4 Despite a prominent adaptive immune response characterized by antigen-stimulated B-and T-cell maturation and prominent infiltration into muscle of immune system cells, sIBM is highly refractory to immunosuppressive therapies studied to date. 2Members of the transforming growth factor b (TGFb) superfamily of ligands signal through a heterodimeric receptor system.5 They first bind a type II receptor, such as the TGFb...

Evaluation of serum myostatin and sclerostin levels in chronic spinal cord injured patients

“…To date, bimagrumab, a selective anti-type II activin receptor monoclonal antibody preventing myostatin activity, has shown to be effective in humans with inclusion body myositis 28 , possibly becoming in the near future a therapeutic option to prevent muscular modifications in SCI and other pathological conditions.…”

Inflammatory Muscle Diseases

“…77 Trials targeting muscle-inhibiting TGF-β molecules or muscle growth factors are in progress. Bimagrumab, an antibody that inhibits the signaling of a TGF-β superfamily receptor, was shown in a small-scale study to increase muscle volume after 8 weeks, 78 which has prompted an ongoing controlled study (ClinicalTrials.gov number, NCT01925209). A small, controlled, proof-ofconcept study of arimoclomol (ClinicalTrials.gov number, NCT00769860), an agent that up-regulates heat shock protein response and attenuates cell stress, has been completed; the drug had an acceptable adverse-event profile, but whether there were clinically meaningful benefits is still unclear.…”

Sporadic inclusion body myositis: A review of recent clinical advances and current approaches to diagnosis and treatment

“…These include a current multi-centre international phase 2b/3 doubleblinded placebo-controlled randomised controlled trial of bimagrumab (clinical trials identifier NCT01925209), which is a fully humanized monoclonal antibody that blocks the activin IIA and IIB receptors that bind myostatin and other ligands, thereby allowing uninhibited muscle growth and promoting muscle hypertrophy. This approach appears to be promising as a previous phase IIa trial in 14 IBM patients demonstrated an increase in thigh muscle volume and improved performance with the 6-minute walk test after a single infusion of bimagrumab (Amato et al, 2014). A gene therapy approach using follistatin to inhibit myostatin expression is also being tested using an adeno-associated virus vector and direct intramuscular injection into the quadriceps muscle (clinical trials identifier NCT01519349) .…”

“…There has also been further recognition of racial and ethnic differences in the prevalence of the disease and of the importance of genetic factors in determining disease susceptibility. In addition, there have been advances in the search for disease biomarkers, such as the identification of the anti-cNA1 antibody (Larman et al, 2013, Pluk et al, 2013 and in the application of muscle imaging techniques such as MRI and ultrasound as tools for diagnosis and monitoring outcomes in trials of new therapies (Amato et al, 2014).…”