Randomized phase 2 trial and open-label extension of domagrozumab in Duchenne muscular dystrophy

Abstract

We report results from a phase 2, randomized, double-blind, 2-period trial (48 weeks each) of domagrozumab and its open-label extension in patients with Duchenne muscular dystrophy (DMD). Of 120 ambulatory boys (aged 6 to < 16 years) with DMD, 80 were treated with multiple ascending doses (5, 20, and 40 mg/kg) of domagrozumab and 40 treated with placebo. The primary endpoints were safety and mean change in 4-stair climb (4SC) time at week 49. Secondary endpoints included other functional tests, pharmacokinetics, and pharmacodynamics. Mean (SD) age was 8.4 (1.7) and 9.3 (2.3) years in domagrozumab-and placebo-treated patients, respectively. Difference in mean (95% CI) change from baseline in 4SC at week 49 for domagrozumab vs placebo was 0.27 (-7.4 to 7.9) seconds (p = 0.94). There were no significant between-group differences in any secondary clinical endpoints. Most patients had ≥1 adverse event in the first 48 weeks; most were mild and not treatment-related. Median serum concentrations of domagrozumab increased with administered dose within each dose level. Non-significant increases in muscle volume were observed in domagrozumab-vs placebo-treated patients. Domagrozumab was generally safe and well tolerated in patients with DMD. Efficacy measures did not support a significant treatment effect. Clinicaltrials.gov identifiers: NCT02310763 and NCT02907619

Quantitative Muscle Mri Biomarkers in Duchenne Muscular Dystrophy: Cross-Sectional Correlations with Age and Functional Tests

“…This article outlines imaging protocols and methods that were scalable and applied in a Phase II, multicenter, global clinical trial (NCT02310763) to evaluate domagrozumab in ambulatory boys with DMD [ 24 ]. Using baseline data from this trial, we evaluated the correlation between an array of functional tests and quantitative MRI assessments of the thigh.…”

Monoclonal Antibodies as Neurological Therapeutics

“…Monoclonal antibody-mediated blockade of myostatin, a member of the transforming growth factor-β (TGF-β) family of ligands, has been shown to increase muscle mass and volume in wild type mice and non-human primates and to increase muscle mass and improve function in murine models of DMD [226]. However, a phase 2 randomized placebo-controlled trial of domagrozumab, a humanized anti-myostatin mAb in 6 to 16 year-old children with DMD did not exhibit a significant treatment effect in its primary efficacy measure (time to 4 stair-climb) [227].…”

Genome editing for Duchenne muscular dystrophy: a glimpse of the future?

“…These include, but are not limited to, inflammation prevention, muscle growth and regeneration, fibrosis, and improving mitochondrial function. The agents under investigation include a novel steroid [2], NF-κB- [3] and myostatininhibitors [4], idebenone [5], an anti-CTGF antibody [6], a histone deacetylase inhibitor [7], and cardiosphere-derived cells [8]. For utrophin modulation, AAV-mediated gene therapy with GALGT2 [9] is currently being investigated to upregulate utrophin expression [10,11].…”