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P.132 Casimersen in patients with Duchenne muscular dystrophy amenable to exon 45 skipping: Interim results from the Phase 3 ESSENCE trial

Iannaccone S, Phan H, Straub V, Muntoni F, Wolf D, Malhotra J, Chu R, Darton E, Mercuri E
Neuromuscul Disord. 2022;32(Suppl 1):S102. doi:10.1016/j.nmd.2022.07.248
Casimersen is FDA approved for the treatment of Duchenne muscular dystrophy (DMD) in patients with a confirmed DMD gene mutation amenable to exon 45 skipping. The ongoing double-blind, placebo-controlled, Phase 3 ESSENCE trial (NCT02500381) is evaluating the efficacy and safety of casimersen and golodirsen over 96 weeks followed by a 48-week open-label period. We report results from a prespecified interim analysis of 48-week muscle biopsy data from the first 43 exon 45 skip-amenable patients. Eligible patients (7–13 years old and on a stable dose of corticosteroids) were randomized 2:1 to receive casimersen 30 mg/kg or placebo IV once weekly. In the interim biopsy analysis, 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. Patients treated with casimersen had significantly increased mean percent dystrophin-positive fibers from baseline to Week 48 (6.46% vs 15.26%; P<0.001) and compared with placebo (mean difference=8.29%; P=0.002) as shown by immunofluorescence; mean fluorescence intensity was also significantly increased in the casimersen- compared with placebo- treated patients at Week 48 (P=0.003). Restored dystrophin protein was correctly localized to the sarcolemma in casimersen-treated patients. Casimersen was well tolerated; most adverse events were mild and unrelated to casimersen, with no suggestion of kidney toxicity. The safety and efficacy of casimersen will continue to be evaluated.
Not Epub
Organism or Cell Type: 
Delivery Method: 
i.v. infusion