Golodirsen Induces Exon Skipping Leading to Sarcolemmal Dystrophin Expression in Duchenne Muscular Dystrophy Patients With Mutations Amenable to Exon 53 Skipping (S22.001)

Objective: To conduct an analysis of exon 53 skipping and dystrophin production and its cellular localization in muscle biopsies from patients in an ongoing trial of golodirsen (formerly SRP-4053). Background: Golodirsen is a phosphorodiamidate morpholino oligomer (PMO) that binds and excludes exon 53 during dystrophin mRNA processing, enabling production of internally shortened dystrophin protein. A first-in-human multicenter trial is evaluating the safety, tolerability, and efficacy of golodirsen through 144 weeks of treatment in Duchenne muscular dystrophy (DMD) patients with a genetic mutation amenable to exon 53 skipping. Design/Methods: In a preplanned interim analysis, paired muscle biopsies of the biceps brachii were obtained at baseline and Week 48 from 25 patients receiving weekly intravenous infusions of golodirsen 30 mg/kg. Biopsies were examined using a validated Western blot method to quantify dystrophin production (primary biological end point). Exon 53 skipping was evaluated using reverse transcription polymerase chain reaction (RT-PCR). An automated image analysis (MuscleMap™) used immunohistochemistry to assess dystrophin localization and sarcolemma fiber intensity. Results: Mean percent of normal dystrophin protein increased from 0.095% at baseline to 1.019% at Week 48 (range: 0.09%–4.30%), a significant mean change of +0.924% ( P P P =0.011). Analysis of mean fiber intensity demonstrated a significant increase from baseline in de novo dystrophin production ( P Conclusions: Golodirsen increased exon 53 skipping, dystrophin production, and dystrophin sarcolemma localization in all patients. Golodirsen is the second PMO shown to increase dystrophin expression and membrane localization through the initiation of exon skipping, further strengthening the potential utility of the PMO technology platform in DMD. Study Supported by: Study supported by Sarepta Therapeutics. Disclosure: Dr. Muntoni has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Participation to SAB meetings (Roche; Avexis and Biogen) and educational activities (Biogen). Dr. Muntoni has received research support from My institute receives support for Biogen and Roche sponsored clinical trials. Dr. Frank has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Sarepta Therapeutics. Dr. Sardone has nothing to disclose. Dr. Morgan has nothing to disclose. Dr. Schnell has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Sarepta Therapeutics. Dr. Charleston has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Sarepta Therapeutics. Dr. Desjardins has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Sarepta Therapeutics. Dr. Phadke has nothing to disclose. Dr. Sewry has nothing to disclose. Dr. Popplewell has nothing to disclose. Dr. Guglieri has nothing to disclose. Dr. Bushby has nothing to disclose. Dr. Carlier has nothing to disclose. Dr. Clark has nothing to disclose. Dr. Dickson has nothing to disclose. Dr. Hogrel has nothing to disclose. Dr. Straub has nothing to disclose. Dr. Mercuri has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biogen MA, Inc, Ionis Pharmaceuticals, Inc. u0026 F. Hoffman La-Roche Ltd. Dr. Voit has nothing to disclose. Dr. Kaye has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Sarepta Therapeutics. Dr. Servais has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biogen, Avexis, Sarepta, Dynacure, Pfizer, Servier. Dr. Servais has received research support from Roche, Valerion, Dynacure.