Objective To report safety, pharmacokinetics, exon 53 skipping, and dystrophin expression in golodirsen-treated patients with Duchenne muscular dystrophy (DMD) amenable to exon 53 skipping. Methods Part 1 was a randomized, double-blind, placebo-controlled, 12-week dose titration of once-weekly golodirsen; Part 2 is an ongoing, open-label evaluation. Safety and pharmacokinetics were primary and secondary objectives of Part 1. Primary biological outcome measures of part 2 were blinded exon skipping and dystrophin protein production on muscle biopsies (baseline, Week 48) evaluated, respectively using reverse transcription PCR and western blot and immunohistochemistry. Results Twelve patients were randomized to receive golodirsen (n=8) or placebo (n=4) in Part 1. All from Part 1 plus 13 additional patients received 30 mg/kg golodirsen in Part 2. Safety findings were consistent with those previously observed in pediatric DMD patients. Most of the study drug was excreted within 4 hours following administration. A significant increase in exon 53 skipping was associated with ~16-fold increase over baseline in dystrophin protein expression at Week 48, with a mean percent normal dystrophin protein standard of 1.019% (range, 0.09%-4.30%). Sarcolemmal localization of dystrophin was demonstrated by significantly increased dystrophin positive fibers (Week 48, p<0.001); and a positive correlation (Spearman-r=0.663; p<0.001) between dystrophin protein change from baseline, measured by western blot and immunohistochemistry.

Supplementary Materials include additional methodology details, e-tables and e-figures. Please refer to the updated file, dated June 18, 2020