Small Differences in Motor Function Outcomes of Duchenne Muscular Dystrophy Genotypes Prompt Implications for New Trials


A meta-analysis displayed a small magnitude of pooled effect estimates for the studied skip-amenable mutation classes in Duchenne muscular dystrophy at 1 year follow up.

Francesco Muntoni, MD, pediatric neurologist, Great Ormond Street Institute of Child Health, University College London, & Great Ormond Street Hospital Trust, London, United Kingdom

Francesco Muntoni, MD,

A recent multi-institution, meta-analysis study suggested that often targeted Duchenne Muscular Dystrophy (DMD) genotype classes have small and estimated precise effects on 1 year motor function outcomes.1 These findings suggest viability of trial designs that include genotypically mixed or unmatched controls up to 12 months for motor function outcomes, easing challenging recruitments and reducing patients with placebos.

In the analysis, investigators observed DMD genotypes classified as amenable to skipping exons 44, 45, 51 or 53, other skippable, nonsense, and other mutations. Pooled effect estimates for studied skip-amenable mutation classes were all small in magnitude (less than 2 units in North Star Ambulatory Assessment total score [ΔNSAA] total score in 1 year follow up), with smaller than clinically critical differences in NSAA. Notably, skip-amenable mutation classes were estimated precisely with standard errors less than 1 unit after adjustment for non-genotypic prognostic factors across all data sources.

Lead author Francesco Muntoni, MD, pediatric neurologist, Great Ormond Street Institute of Child Health, University College London, & Great Ormond Street Hospital Trust, London, United Kingdom, and colleagues wrote, “Such trial designs, including multi-genotype platform trials and hybrid designs, should ensure baseline balance between treatment and control groups for the most important prognostic factors, while accounting for small remaining genotype effects quantified in the present study.”1

At least 700 patients with DMD diagnosis and over 1600 patient-years of follow-up were studied from 6 data sources. The time periods of collected data were between 2011 and 2016 for Leuven, 2012 and 2016 for PRO-DMD-01, 2012 and 2018 for iMDEX, 2005 and 2015 for NSUK, 2004 and 2016 for CCHMC, and 2008 and 2013 for DMD Italian Group. In each data source, associations between genotype class and 1-year changes in ΔNSAA and in 10-meter walk/run velocity (Δ10MWR) were studied with and without baseline prognostic factors. Approximately every 6 or 12 months, clinical assessment of the data sources were conducted.

“As genetically targeted therapies for DMD increasingly advance to clinical trials, recruitment of patients with specific genetic subtypes within this already rare disease becomes a bottleneck for drug development,” Muntoni, et al noted.1

Approximately 2% of variation in ΔNSAA outcomes after 12 months were accounted as the studied genotype classes. Other prognostic factors explained more than 30% of variation in all data sources. The median age (men, n = 962) for those who completed 10MWR of more than 10 seconds was significantly younger in patients skipping exon 51 compared with all other skip-amenable mutations (12.2 vs. 13.7 years, log-rank P <.001). Also, the median age at 10MWR was significantly older in exon 44 skip-amenable vs. all other skip-amenable mutations (13.8 vs. 13.3 years; log-rank P <.05).

READ MORE: REGENXBIO's Clinical Trial for Duchenne Therapy RGX-202 Begins Patient Recruitment

In the PRO-DMD-01 and CCHMC, the addition of multiple baseline prognostic factors in the fully adjusted model explained the most variation in ΔNSAA (R2 of 36% and 39%, respectively), more than doubling the intermediate adjusted model that accounted only for baseline age and NSAA total score with genotype class (R2 of 15% and 16%, respectively). In iMDEX, Leuven, and DMD Italian Group, 3 smaller data sources, each of which had fewer than 5 ΔNSAA intervals in at least two of the genotype classes, explained variation due to genotype classes ranging from 6% to 21%.

Patients with exon 51 skip-amenable mutations had a mean difference in ΔNSAA of -1.3 unit (95% CI, -2.3 to -0.4) compared with other skip-amenable patients. Notably, patients with exon 44 skip-amenable mutations reported mean differences of 0.3 (95% CI, -0.5-1.1) and 0.9 (95% CI, 0.5-1.4) units on ΔNSAA, relative to other skip-amenable and all others.

Limitations of the analysis included the small sample size of DMD nonsense mutations and genotype frequencies, which were not reflective of natural prevalence. Patients were required to have nonmissing data which excluded 25% of patients who would have been eligible otherwise. All data sources had a large majority of White patients and thus, lack representatives from other races and ethnicities. In addition, the study may not generalize to long-term follow-up or other genotypes since it focused on 1-year changes. All mutations of interest for drug development could not be adequately studied even in the large database collected.

Muntoni et al noted, "Precision is critical because a trial design that aims to account for differences in genotypes must consider uncertainty in the effects of those genotypes on outcomes, thereby adding to the overall level of noise against which a signal for drug effect needs to be statistically detected.”1

1. Muntoni F, Signorovitch J, Sajeev G, et al. DMD Genotypes and Motor Function in Duchenne Muscular Dystrophy: A Multi-institution Meta-analysis With Implications for Clinical Trials. Neurology. 2023;10.1212/WNL.0000000000201626. doi:10.1212/WNL.0000000000201626
2. Aartsma-Rus A, Fokkema I, Verschuuren J, et al. Theoretic applicability of antisense-mediated exon skipping for Duchenne muscular dystrophy mutations. Hum Mutat. 2009;30(3):293-299. doi:10.1002/humu.20918
3. Fletcher S, Adams AM, Johnsen RD, Greer K, Moulton HM, Wilton SD. Dystrophin isoform induction in vivo by antisense-mediated alternative splicing. Mol Ther. 2010;18(6):1218-1223. doi:10.1038/mt.2010.45
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