Increased dystrophin production with golodirsen in patients with Duchenne muscular dystrophy
Diane E. Frank, Frederick J. Schnell, Cody Akana, Saleh El-Husayni, Cody A. Desjardins, Jennifer E. Morgan, Jay S. Charleston, Valentina Sardone, Joana Domingos, George Dickson, Volker Straub, Michela Guglieri, Eugenio Mercuri, Laurent Servais, Francesco Muntoni, on behalf of the SKIP-NMD Study Group
Abstract
<h3>Objective</h3> To report safety, pharmacokinetics, exon 53 skipping, and dystrophin expression in golodirsen-treated patients with Duchenne muscular dystrophy (DMD) amenable to exon 53 skipping. <h3>Methods</h3> 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. <h3>Results</h3> 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 patients with DMD. 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, <i>p</i> < 0.001) and a positive correlation (Spearman <i>r</i> = 0.663; <i>p</i> < 0.001) with dystrophin protein change from baseline, measured by Western blot and immunohistochemistry. <h3>Conclusion</h3> Golodirsen was well-tolerated; muscle biopsies from golodirsen-treated patients showed increased exon 53 skipping, dystrophin production, and correct dystrophin sarcolemmal localization. <h3>Clinicaltrials.gov identifier</h3> NCT02310906. <h3>Classification of evidence</h3> This study provides Class I evidence that golodirsen is safe and Class IV evidence that it induces exon skipping and novel dystrophin as confirmed by 3 different assays.