John E Kraus1, Claire Wardell1, Katie Rolfe1, Joanna Nakielny1, Naashika Quarcoo1, Lia Liefaard1, Steve Hood1, Allison Morgan2, Afrodite Lourbakos2, Sjef de Kimpe2, Rosamund Wilson2, Giles Campion2 1GlaxoSmithKline, R&D, Research Triangle Park, NC, 27709, 2Prosensa, R&D, Leiden, 2333 CH, Netherlands

Introduction: Duchenne muscular dystrophy (DMD) is a progressive neuromuscular disorder, ultimately lethal, caused by the absence of dystrophin protein due to mutations of the dystrophin gene. The aim of oligonucleotide therapy is to manipulate the post-transcriptional splicing process of the premRNA to restore the reading frame of the mRNA, resulting in a shortened dystrophin protein. Drisapersen is a 2'-O-methyl-phosphothioate oligo designed to skip exon 51 in the dystrophin pre-mRNA. Here we report results of an exploratory, unpowered, double blind, placebo-controlled clinical study of drisapersen.

Methods: Subjects with DMD met the following inclusion criteria: ≥5 years old; ambulant; corticosteroid-treated; rise from the floor ≤7 sec; and a dystrophin mutation correctable by exon 51 skipping. 53 subjects were randomized to 2 drisapersen dosing regimens or matched placebo (2:1). Dosing regimens: continuous (6mg/kg/wk) and intermittent (10-week cycles of 9 doses at 6mg/kg over 6 wks, and 4 wks off drug). Treatment was administered subcutaneously for 48 weeks. The primary objective was to assess the efficacy (6 Minute Walk Distance [6MWD] = primary outcome) of 2 different drisapersen dosing regimens over 24 weeks. Secondary objectives included 6MWD at 48 weeks, various timed function tests, the North Star Ambulatory Assessment [NSAA], muscle strength and safety.

Results: The continuous treatment arm (n=18) showed a clinically meaningful and statistically significant difference from placebo (n=18) on 6MWD at 24 weeks (mean, 35.09m; [95%CI, 7.59-62.60m], p=0.014), with trends supportive of efficacy in other timed function tests and the NSAA. A clinically meaningful difference from placebo (35.84m [-0.11-71.78m], p=0.051) was maintained at 48 weeks. The intermittent treatment arm (n=17) did not separate from placebo at week 24, though by week 48 there was a clinically meaningful difference from placebo on 6MWD (27.08m [-9.83-63.99m], p=0.147), supported by trends in timed function tests and the NSAA. There was little change in muscle strength at either time point for either treatment arm. Drisapersen was generally welltolerated, with the majority of adverse events related to injection site reactions and proteinuria. All patients completed the study.

Discussion: The primary objective was achieved - the continuous treatment arm showed a clinically meaningful and statistically significant difference from placebo on 6MWD at week 24. At week 48, both treatment arms showed a clinically meaningful difference from placebo on 6MWD (supported by improvement in other secondary endpoints). Drisapersen may represent an important treatment option for boys with DMD having mutations correctable by exon 51 skipping.