Brian Tseng

Treatment of sporadic inclusion body myositis with bimagrumab

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.

Mortality and Causes of Death in Patients with Sporadic Inclusion Body Myositis: Survey Study Based on the Clinical Experience of Specialists in Australia, Europe and the USA

Background: There is a paucity of data on mortality and causes of death (CoDs) in patients with sporadic inclusion body myositis (sIBM), a rare, progressive, degenerative, inflammatory myopathy that typically affects those aged over 50 years. Objective: Based on patient records and expertise of clinical specialists, this study used questionnaires to evaluate physicians’ views on clinical characteristics of sIBM that may impact on premature mortality and CoDs in these patients. Methods: Thirteen physicians from seven countries completed two questionnaires online between December 20, 2012 and January 15, 2013. Responses to the first questionnaire were collated and presented in the second questionnaire to seek elaboration and identify consensus. Results: All 13 physicians completed both questionnaires, providing responses based on 585 living and 149 deceased patients under their care. Patients were reported to have experienced dysphagia (60.2%) and injurious falls (44.3%) during their disease. Over half of physicians reported that a subset of their patients with sIBM had a shortened lifespan (8/13), and agreed that bulbar dysfunction/dysphagia/oropharyngeal involvement (12/13), early-onset disease (8/13), severe symptoms (8/13), and falls (7/13) impacted lifespan. Factors related to sIBM were reported as CoDs in 40% of deceased patients. Oropharyngeal muscle dysfunction was ranked as the leading feature of sIBM that could contribute to death. The risk of premature mortality was higher than the age-matched comparison population. Conclusions: In the absence of data from traditional sources, this study suggests that features of sIBM may contribute to premature mortality and may be used to inform future studies.

Development of the sporadic inclusion body myositis physical functioning assessment.

Introduction: Sporadic inclusion body myositis (sIBM) is a progressive idiopathic inflammatory myopathy characterized by atrophy and weakness of proximal and distal muscle groups that results in a loss of independence and the need for assistive devices and supportive care. To assess treatment benefit of new therapies, a patient‐reported outcome measure of physical function was developed. Methods: The tool was rigorously developed in accordance with the United States Food and Drug Administration (FDA) patient‐reported outcomes (PRO) guidance. A single‐visit, observational study was conducted. Standard qualitative analytical methods were employed to analyze interview data and generate questionnaire items. Results: Twenty concept elicitation and 19 cognitive debriefing interviews were conducted, and 6 expert physicians were consulted. The tool consists of 11 items scored on a 0–10 numerical rating scale. Subjects completed the questionnaire utilizing either paper or electronic administration. Conclusion: We have developed a PRO tool in alignment with FDA PRO guidance for use in the functional assessment of treatment benefit in sIBM. Muscle Nerve, 2016 Muscle Nerve 54: –, 2016 Muscle Nerve 54: 653–657, 2016

Truncal fat distribution correlates with decreased vital capacity in Duchenne muscular dystrophy.

Duchenne muscular dystrophy (DMD) is an X‐linked recessive disorder associated with progressive muscle weakness and respiratory failure. Oral corticosteroids are the mainstay of treatment, but are associated with obesity with a central distribution. This study is designed to determine the relationship between body mass index, central adiposity, and lung function in subjects with DMD.

Psychometric validation of a patient-reported measure of physical functioning in sporadic inclusion body myositis

Introduction: To assess self‐reported physical functioning in patients with sporadic inclusion body myositis (sIBM), the sIBM Physical Functioning Assessment (sIFA) was developed. This research establishes the validity, reliability, and responsiveness of the sIFA in patients with sIBM. Methods: Data from 3 small, noninterventional, observational studies were analyzed. Several measures of physical function were included to assess validity. Reliability (Cronbach alpha, test–retest intraclass correlations), construct validity (correlations, analyses of variance), and responsiveness (effect size estimates) were evaluated. Results: Cronbach alphas (range = 0.86–0.91) and test–retest reliability (0.91) were highly satisfactory. Correlations with other measures provided evidence of convergent validity. sIBM patients able to walk without assistive devices scored significantly better on the sIFA (means = 36.0–47.05) than those who required power mobility or wheelchairs (means = 54.9–71.5), demonstrating the discriminating ability of the sIFA. Effect size estimates of responsiveness suggested mild functional progression. Conclusions: Psychometric analyses of the sIFA demonstrate satisfactory reliability, validity, and responsiveness. Muscle Nerve 54: 658–665, 2016

Regulatory and Ethical Issues in Pediatric Clinical Research: Recommendations From a Panel Discussion

Nilima Kshirsagar,MD, PhD, FNAS, FNAMS, FRCP (UK), FCP (USA)1, Soumya Swaminathan,Dip NB/MNAMS,MD,MBBS2, Pramod Jog,MD,DNB, FIAP3, Samir Dalwai,MD,DCH,DNB, FCPS, LLB4, Roli Mathur, PhD5, Chandra Shekhar,MD, MBBS5, Bernd Meibohm, PhD, FCP, FAAPS6, Y. K.Gupta,MBBS,MD, FAMS, FNASc, FIPS,FIAN7,Nusrat Shafiq,MD8,Gangadhar Sunkara, PhD9, V.G. Somani, PhD, MPharm10, Prasad Kulkarni,MD,MBBS11, Brian Tseng,MD, PhD12, and Dhvani Mehta,MPhil13

AB0687 Non-Invasive Assessment of Muscle Quality by MRI as a Potential Marker of Disease Modification in Bimagrumab-Treated SIBM Patients

Background Bimagrumab is a monoclonal antibody that inhibits ligand binding to the activin receptor IIA/B thereby stimulating muscle growth. In a proof of concept study, bimagrumab increased thigh muscle volume (TMV) by 6.5% (p=0.024) and decreased intramuscular adipose tissue (IMAT) by 3% (p=n.s.) after 8 weeks of treatment. Objectives Using qualitative muscle MRI to characterize disease severity and modification in sporadic inclusion body myositis (sIBM) patients treated with bimagrumab. Methods 14 patients were randomized to single IV dose (30 mg/kg) of bimagrumab (n=11) or placebo (n=3). Disease severity was assessed by visual scoring of PD images. TMV, IMAT, subcutaneous (SC) adipose tissue volume, and individual muscle volume (IMV) were determined from proton-density (PD) MR images using semi-automated segmentation approaches. In addition, the relative fat fraction (%FF) and apparent coefficient of diffusion (ADC) were measured from three-point Dixon and diffusion-weighted images, respectively. Results After 8 weeks of treatment, mean score for disease activity (21.5±0.6) remained unchanged. Although insignificant, decrease in %FF (−7% vs baseline) was seen at Week-8 in 4 patients while SC and IMAT volumes were slightly reduced. At baseline, fat-infiltrated muscles had lower ADC values than previously reported (1.46±0.11 vs 1.62±0.14 x10-3 mm2/sec) and a trend towards normal values was observed after treatment. At baseline, IMAT content was greater in anterior than in posterior thigh muscles (49% vs 23%, p<0.01). Individual muscle volumes (IMV) increased more in the posterior (+8%) than in anterior thigh compartment (+4%, p<0.01). At Week-16, further decrease in IMAT in all muscles (-7% vs baseline, p<0.05) correlated well with the change from baseline in IMV at Week-8 (r=0.57, p<0.05). Conclusions MRI may be used in a comprehensive non-invasive way to demonstrate potential of bimagrumab as a disease-modifying therapy which may potentially lead to restoration of normal muscle quality and composition. References Amato AA et al. Neurology. 2014;83(24):2239-46. Qi J et al. J Magn Reson Imaging. 2008;27(1):212-7. Acknowledgements Study Supported By: Novartis Pharma AG Disclosure of Interest D. Laurent Shareholder of: Novartis, Employee of: Novartis Institutes for Biomedical Research, Basel, Switzerland, B. Tseng Employee of: Novartis Institutes for Biomedical Research, Cambridge, USA, S. Greenberg Grant/research support from: Novartis Pharma AG, P. Houston Employee of: Novartis Pharma AG, Basel, Switzerland, D. Papanicolaou Employee of: Novartis Pharmaceuticals Corporation, East Hanover, USA, R. Roubenoff Employee of: Novartis Institutes for Biomedical Research, Basel, Switzerland.