Long-Term Safety and Efficacy Data of Golodirsen in Ambulatory Patients with Duchenne Muscular Dystrophy Amenable to Exon 53 Skipping: A First-in-human, Multicenter, Two-Part, Open-Label, Phase 1/2 Trial

Abstract

The aim of this Phase 1/2, 2-part, multicenter trial was to report clinical safety and efficacy of long-term golodirsen treatment among ambulatory patients with exon 53 skip-amenable Duchenne muscular dystrophy (DMD). Part 1 was a 12-week, randomized, double-blind, placebo-controlled, dose-titration study followed by 9-week safety review. Part 2 was a 168-week, open-label evaluation of golodirsen 30 mg/kg. Part 1 primary endpoint was safety. Part 2 primary endpoints were dystrophin protein expression and 6-minute walk test (6MWT); secondary endpoints were percent predicted forced vital capacity (FVC%p) and safety. Post hoc ambulation analyses used mutation-matched external natural history controls. All patients from Part 1 (golodirsen, n = 8; placebo, n = 4) plus 13 additional patients entered Part 2; 23 completed the study. Adverse events were generally mild, nonserious, and unrelated to golodirsen, with no safety-related discontinuations or deaths. Golodirsen increased dystrophin protein (16.0-fold; P < 0.001) and exon skipping (28.9-fold; P < 0.001). At 3 years, 6MWT change from baseline was -99.0 m for golodirsen-treated patients versus -181.4 m for external controls (P = 0.067), and loss of ambulation occurred in 9% versus 26% (P = 0.21). FVC%p declined 8.4% over 3 years in golodirsen-treated patients, comparing favorably with literature-reported rates. This study provides evidence for golodirsen biologic activity and long-term safety in a declining DMD population and suggests functional benefit versus external controls. Clinical Trial Registration number: NCT02310906.

Keywords: Duchenne muscular dystrophy; exon skipping; golodirsen.

FIG. 1.

(A) Study design. Part 1 was a double-blind, placebo-controlled, dose-titration period; each dose level was administered for ≥2 weeks. Part 2 was an open-label extension period, including all patients from Part 1 plus 13 new patients amenable to exon 53 skipping. The untreated arm consisted of patients not amenable to exon 53 skipping and, per protocol, was not a control group but was included to evaluate DMD natural history and exploratory biomarkers. Adapted with permission from Frank et al. [21]. DOI: https://doi.org/10.1212/WNL.0000000000009233. (B) Patient disposition. ^aPatients continued on treatment as randomized through enrollment and DSMB review. ^bReasons included enrollment in a therapeutic study (n = 2) and personal reasons (n = 1). B, biopsy; DMD, Duchenne muscular dystrophy; DSMB, Data Safety Monitoring Board.

FIG. 2.

(A) Mean dystrophin protein by western blot, (B) exon skipping by RT-PCR, (C) dystrophin protein by immunohistochemistry, and (D) percentage of F/D myosin-positive fibers were measured at baseline and after 48 weeks of golodirsen treatment. F/D, fetal/developmental; ns, not significant; RT-PCR, reverse transcription polymerase chain reaction.

FIG. 3.

Ambulatory function: (A) 6MWT distance and (B) loss of ambulation over 3 years in golodirsen-treated patients and matched exon 53 skip-amenable natural history external controls. 6MWT, 6-minute walk test.