Modeling early heterogeneity in progression in boys with Duchenne muscular dystrophy


Translational Research

Poster Number: Virtual


Yuan Fang, PhD, Binghamton University, Craig McDonald, MD, University of California Davis Health, Paula Clemens, MD, University of Pittsburgh, Heather Gordish-Dressman, PhD, Children’s National Hospital, Kate Illei, ReveraGen BioPharma, Eric Hoffman, Binghamton University, Utkarsh Dang, PhD, Department of Health Sciences, Carleton University

Duchenne muscular dystrophy (DMD) exhibits substantial variability in rates of disease progression and response to treatment. This has hindered treatment development and complicated interpretation of drug effects in clinical trials due to the inability to distinguish between an ineffective intervention and patient disease severity regardless of drug effect.
We aimed to better characterize clinical outcome trajectories of young boys with DMD (ages 4–<10 years), both treated with steroidal anti-inflammatories and untreated. We hypothesized that a multivariate combination of early-age clinical outcome measurements can explain differential disease progression. Methods Data were obtained from CINRG Duchenne Natural History Study (n=209) and vamorolone VBP15-002/003/LTE (n=46) studies. Velocities from three timed function tests (TFTs; stand from supine, run/walk 10 meters, and climb 4 stairs) were simultaneously modeled in a longitudinal latent class analysis. Results Three classes of differentially progressing early-age DMD motor trajectories were identified. Quicker decline/progression was associated with lower baseline TFT velocities, earlier loss of ability to finish a TFT, and lower predicted velocities. Earlier substantial steroid exposure was associated with greater TFT velocities while the moderate progression class was observed to have the largest difference in performance between boys treated early with steroids vs. not. Sample size calculations with the class showing the largest treatment response showed a large reduction in the required sample size as compared to using summaries from all participants. Gene variants were also investigated in post-hoc analyses, with mutations near the beginning of the DMD gene (Dp427 absent and Dp140/Dp71 present) found to be enriched in the slowest progressing class. Conclusions Our findings provide insight into the variation in DMD progression. We show class-related trajectories of motor outcomes and pharmacological response to corticosteroids and suggest that enrichment strategies and/or subgroup analyses could be considered further in designing therapeutic interventions in DMD.