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

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.