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 patients amenable to exon 45 skipping.
Eligible patients (7–13 years old and on a stable dose of corticosteroids) were randomized 2:1 to receive intravenous casimersen 30 mg/kg or placebo once weekly.
In the interim biopsy analysis, casimersen- but not placebo-treated patients demonstrated statistically 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 statistically significant 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 was 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 statistically significant 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 increase was also statistically significant in the casimersen- compared with placebo-treated patients at week 48 (P=0.003). Representative immunofluorescence images from casimersen- and placebo-treated patients will be presented. Conclusion Casimersen-treated patients had significantly increased exon skipping from baseline and dystrophin production with correct localization to the sarcolemma. 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.