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<jats:sec><jats:title>Objective</jats:title><jats:p>To report safety, pharmacokinetics, exon 53 skipping, and dystrophin expression in golodirsen-treated patients with Duchenne muscular dystrophy (DMD) amenable to exon 53 skipping.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>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.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>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, <jats:italic>p</jats:italic> &lt; 0.001) and a positive correlation (Spearman <jats:italic>r</jats:italic> = 0.663; <jats:italic>p</jats:italic> &lt; 0.001) with dystrophin protein change from baseline, measured by Western blot and immunohistochemistry.</jats:p></jats:sec><jats:sec><jats:title>Conclusion</jats:title><jats:p>Golodirsen was well-tolerated; muscle biopsies from golodirsen-treated patients showed increased exon 53 skipping, dystrophin production, and correct dystrophin sarcolemmal localization.</jats:p></jats:sec><jats:sec><jats:title> identifier</jats:title><jats:p>NCT02310906.</jats:p></jats:sec><jats:sec><jats:title>Classification of evidence</jats:title><jats:p>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.</jats:p></jats:sec>

Original publication




Journal article




Ovid Technologies (Wolters Kluwer Health)

Publication Date



10.1212/WNL.0000000000009233 - 10.1212/WNL.0000000000009233