Pooled Analyses of Efficacy Parameters in Patients with Duchenne Muscular Dystrophy (DMD): Results from the Drisapersen (DRIS) Clinical Trial Program (P2.240)

OBJECTIVE: In a Phase III study (DMD114044), a 10m treatment difference (non-significant) on 6-minute walking distance (6MWD) in favor of DRIS was seen in the overall study population, but there was a treatment benefit of 21m in a pre-specified subset of boys aged ≤7y (n=79), suggesting that younger, less progressed boys could benefit more from DRIS in terms of ambulatory endpoints versus older boys in whom DMD is more advanced; we investigated this further through pooled and integrated analyses of clinical trial data. BACKGROUND: DRIS is a 2’-O-methyl-phosphorothioate antisense oligonucleotide designed to skip exon 51 in dystrophin pre-mRNA of boys with DMD. DESIGN/METHODS: An integrated analysis of an open-label extension (OLE; DMD114349) of two 48-wk placebo (PBO)-controlled trials (DMD114117, DMD114044). A pooled analysis of two Phase II trials (DMD114117, DMD114876): a subset of boys with similar baseline demographic and functional characteristics who received DRIS 6mg/kg/wk (n=36) was compared with PBO-treated boys (n=34; Mixed-Effect Model Repeated Measure model). RESULTS: In DMD114349, 96 wks’ DRIS resulted in a clinically meaningful difference from 48 wks’ PBO (feeder study) followed by 48 wks’ DRIS (OLE) in 6MWD of 46m (n=113; completed 48 weeks’ DMD114349). Feeder study analysis of DMD114349: treatment effect was 52m (n=30) for DMD114117 and 49m for DMD114044 (n=83) for those on DRIS for 96 wks versus PBO/delayed treatment. At Wk24 in the pooled analysis, there was a clinically meaningful and statistically significant difference in 6MWD between DRIS- and PBO-treated boys of 31m (n=70; 95[percnt]CI: 11, 51; p=0.003), based on an adjusted mean(standard error) difference of −11(7)m for placebo and +20(7)m for DRIS. CONCLUSIONS: DMD114044 enrolled boys aged ≤16y, whereas in the pooled Phase-II dataset, the oldest boys were only 13y, supporting the premise that treatment at a younger age is more immediately beneficial for preserving ambulatory capacity. Studies Supported by: GlaxoSmithKline Disclosure: Dr. Goemans has nothing to disclose. Dr. Voit has received personal compensation for activities with Prosensa. Dr. McDonald has received personal compensation for activities with PTC Therapeutics and Sarepta Therapeutics as an advisory board participant and/or consultant. Dr. Wilson has received personal compensation for activities with Prosensa as a consultant. Dr. Wardell has nothing to disclose. Dr. Campion has received personal compensation for activities with Prosensa Therapeutics as an employee.