DMD genotypes and motor function in Duchenne muscular dystrophy

Abstract

Background and Objectives

Clinical trials of genotype-targeted treatments in Duchenne muscular dystrophy (DMD) tra-

ditionally compare treated patients with untreated patients with the same DMD genotype class.

This avoids confounding of drug efficacy by genotype effects but also shrinks the pool of eligible controls, increasing challenges for trial enrollment in this already rare disease. To evaluate the suitability of genotypically unmatched controls in DMD, we quantified effects of genotype class on 1-year changes in motor function endpoints used in clinical trials. Methods More than 1,600 patient-years of follow-up (>700 patients) were studied from 6 real-world/ natural history data sources (UZ Leuven, PRO-DMD-01 shared by CureDuchenne, iMDEX, North Star UK, Cincinnati Children’s Hospital Medical Center, and the DMD Italian Group), with genotypes classified as amenable to skipping exons 44, 45, 51, or 53, or other skippable, nonsense, and other mutations. Associations between genotype class and 1-year changes in North Star Ambulatory Assessment total score (DNSAA) and in 10-m walk/run velocity (D10MWR) were studied in each data source with and without adjustment for baseline prognostic factors. Results The studied genotype classes accounted for approximately 2% of variation in DNSAA outcomes after 12 months, whereas other prognostic factors explained >30% of variation in large data sources. Based on a meta-analysis across all data sources, pooled effect estimates for the studied skip-amenable mutation classes were all small in magnitude (<2 units in DNSAA total score in 1-year follow up), smaller than clinically important differences in NSAA, and were precisely estimated with standard errors <1 unit after adjusting for nongenotypic prognostic factors.