A phase Ib/IIa, open-label, multiple ascending-dose trial of domagrozumab in fukutin-related protein limb-girdle muscular dystrophy.

INTRODUCTION/AIMS: In this study we report the results of a phase Ib/IIa, open-label, multiple ascending-dose trial of domagrozumab, a myostatin inhibitor, in patients with fukutin-related protein (FKRP)-associated limb-girdle muscular dystrophy. METHODS: Nineteen patients were enrolled and assigned to one of three dosing arms (5, 20, or 40 mg/kg every 4 weeks). After 32 weeks of treatment, participants receiving the lowest dose were switched to the highest dose (40 mg/kg) for an additional 32 weeks. An extension study was also conducted. The primary endpoints were safety and tolerability. Secondary endpoints included muscle strength, timed function testing, pulmonary function, lean body mass, pharmacokinetics, and pharmacodynamics. As an exploratory outcome, muscle fat fractions were derived from whole-body magnetic resonance images. RESULTS: Serum concentrations of domagrozumab increased in a dose-dependent manner and modest levels of myostatin inhibition were observed in both serum and muscle tissue. The most frequently occurring adverse events were injuries secondary to falls. There were no significant between-group differences in the strength, functional, or imaging outcomes studied. DISCUSSION: We conclude that, although domagrozumab was safe in patients in limb-girdle muscular dystrophy type 2I/R9, there was no clear evidence supporting its efficacy in improving muscle strength or function.

Longitudinal functional and imaging outcome measures in FKRP limb-girdle muscular dystrophy.

BACKGROUND: Pathogenic variants in the FKRP gene cause impaired glycosylation of α-dystroglycan in muscle, producing a limb-girdle muscular dystrophy with cardiomyopathy. Despite advances in understanding the pathophysiology of FKRP-associated myopathies, clinical research in the limb-girdle muscular dystrophies has been limited by the lack of normative biomarker data to gauge disease progression. METHODS: Participants in a phase 2 clinical trial were evaluated over a 4-month, untreated lead-in period to evaluate repeatability and to obtain normative data for timed function tests, strength tests, pulmonary function, and body composition using DEXA and whole-body MRI. Novel deep learning algorithms were used to analyze MRI scans and quantify muscle, fat, and intramuscular fat infiltration in the thighs. T-tests and signed rank tests were used to assess changes in these outcome measures. RESULTS: Nineteen participants were observed during the lead-in period for this trial. No significant changes were noted in the strength, pulmonary function, or body composition outcome measures over the 4-month observation period. One timed function measure, the 4-stair climb, showed a statistically significant difference over the observation period. Quantitative estimates of muscle, fat, and intramuscular fat infiltration from whole-body MRI corresponded significantly with DEXA estimates of body composition, strength, and timed function measures. CONCLUSIONS: We describe normative data and repeatability performance for multiple physical function measures in an adult FKRP muscular dystrophy population. Our analysis indicates that deep learning algorithms can be used to quantify healthy and dystrophic muscle seen on whole-body imaging. TRIAL REGISTRATION: This study was retrospectively registered in clinicaltrials.gov (NCT02841267) on July 22, 2016 and data supporting this study has been submitted to this registry.

The NIH Toolbox for cognitive surveillance in Duchenne muscular dystrophy.

OBJECTIVE: We performed a prospective, cross-sectional cognitive assessment in subjects with Duchenne Muscular Dystrophy (DMD) and their biological mothers. METHODS: Thirty subjects with out-of-frame mutations in the dystrophin (DMD) gene, and 25 biological mothers were evaluated using the National Institutes of Health Toolbox Cognition Battery (NIHTB-CB). A parent completed the Behavior Rating Inventory of Executive Functioning (BRIEF), a standardized rating scale of executive functioning, for their child. Mothers completed self-reports of BRIEF and Neuro Quality-of-Life (NeuroQoL) Cognitive Function. RESULTS: Overall, the subjects with DMD scored approximately one standard deviation (SD) below age-corrected norms on the NIHTB-CB Total Cognition score. They scored 1.5 SD below age-corrected norms in Fluid Cognition, which evaluates the cognitive domains of executive function, working memory, episodic memory, attention, and processing speed. Their performance was consistent with age expectations (i.e., within 1 SD below age-corrected norms) in Crystalized Cognition, which evaluates vocabulary and reading. Subjects with DMD had higher T-scores in several domains of BRIEF, demonstrating greater difficulty in executive functioning. The biological mothers had overall average or above average T-scores on NIHTB-CB. Mothers who were carriers of DMD mutation performed lower overall compared to mothers who were not carriers of DMD mutation (Cohen's d = -1.1). Carrier mothers performed lower than average (1.5 SD) in Executive Function, measured by Flanker Inhibitory Control and Attention. Biological mothers scored within expected score ranges for adults in BRIEF and NeuroQoL. INTERPRETATION: The NIHTB-CB, combined with standardized self-reported measures, can be a sensitive screening tool for cognitive surveillance in DMD.