Casimersen in Patients With Duchenne Muscular Dystrophy: Interim Safety and Muscle Biopsy Results From the Phase 3 ESSENCE Trial

Topic:

Clinical Trials

Poster Number: 39

Author(s):

Susan Iannaccone, MD, UTSW, Han Phan, MD, Rare Disease Research, LLC, Volker Straub, PhD, Newcastle University, Francesco Muntoni, MD, UCL Institute of Child Health and Great Ormond Street Hospital for Children, Jyoti Malhotra, Sarepta Therapeutics, Rong Chu, Sarepta Therapeutics, Inc., Eddie Darton, Sarepta Therapeutics, Inc., Eugenio Mercuri, Paediatric Neurology and Centro Clinico Nemo

Background
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.

Methods
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.

Results
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.