Background: Casimersen is FDA-approved for treatment of Duchenne muscular dystrophy in patients with exon 45 skip-amenable mutations. ESSENCE is an ongoing, double-blind, placebo-controlled, Phase 3 trial (NCT02500381) evaluating the efficacy and safety of casimersen and golodirsen over 96 weeks followed by a 48-week open-label period.
Objective: We report results from a prespecified interim analysis of 48-week muscle biopsy data in casimersen- and placebo-treated patients.
Methods: Eligible patients (aged 7–13 years, on a stable dose of corticosteroids, forced vital capacity percent predicted ?50%, 6-minute walk distance ?300–?450 m) were randomized 2:1 to receive casimersen 30 mg/kg or placebo IV once weekly.
Results: Casimersen- but not placebo- treated patients demonstrated significant increases in exon 45 skipping assessed by droplet digital PCR compared with baseline (n=27, P<0.001 and n=16, P=0.808 respectively). Western blot analysis showed significantly increased mean dystrophin levels from baseline after 48 weeks of casimersen (0.93% vs 1.74% of normal; P<0.001) and compared with placebo (mean difference=0.59%; P=0.004). Increased dystrophin positively correlated with exon skipping (Spearman rank correlation=0.627; P<0.001), demonstrating mechanistic association between de novo dystrophin production and exon 45 skipping. Immunofluorescence staining suggested correct sarcolemmal localization of the restored dystrophin in casimersen-treated patients. Casimersen was well tolerated; most adverse events were mild and unrelated to casimersen, with no suggestion of kidney toxicity.
Conclusion: Interim analysis shows casimersen significantly increased exon skipping and dystrophin expression in exon 45 skip-amenable patients at 48 weeks and was well tolerated. The safety and efficacy of casimersen will continue to be evaluated.