Casimersen in Patients With Duchenne Muscular Dystrophy Amenable to Exon 45 Skipping: Interim Results From the Phase 3 ESSENCE Trial


Clinical Trials

Poster Number: 49


Susan Iannaccone, MD, UT Southwestern Medical Center, Han Phan, MD, Rare Disease Research, LLC / UAB, Volker Straub, MD, PhD, John Walton Muscular Dystrophy Research Centre and Newcastle Hospitals NHS Foundation Trust, UK, Francesco Muntoni, MD, Great Ormond Street Institute of Child Health, London, UK, Erica Koenig, Sarepta Therapeutics, Inc., Jyoti Malhotra, PhD, Sarepta Therapeutics, Inc., Eddie Darton, Sarepta Therapeutics, Inc., Bao Han, Sarepta Therapeutics, Inc., Eugenio Mercuri, Paediatric Neurology and Centro Clinico Nemo, Catholic University and Policlinico Gemelli, Fondazion

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.