Casimersen Shows Safe and Effective Profile in Multiple DMD Studies


Most treatment-emergent adverse events were mild in severity across both studies, with no evidence of renal toxicity, cardiac signals, or deaths.

Nancy L. Kuntz, MD

Nancy L. Kuntz, MD

Results from a phase 1/2 study (Study 4045-101; NCT02530905) and interim data from the phase 3 ESSENCE study (NCT02500381) demonstrate that treatment with casimersen (Amondys 45; Sarepta Therapeutics) is safe and efficacious to treat patients with Duchenne Muscular Dystrophy (DMD) and further supports future evaluations.

The data was presented virtually at the Muscular Dystrophy Association (MDA) Clinical and Scientific Conference 2021, March 15-18, by Nancy L. Kuntz, MD, pediatric neurologist, Ann & Robert H. Lurie Children’s Hospital of Chicago in Illinois.

Treatment with casimersen 30 mg/kg was well tolerated in patients diagnosed with genotype-confirmed DMD amenable to exon 45 skipping, with most treatment-emergent adverse events (TEAEs) mild in severity during the double-blind period (89%) and combined double-blind and open-label casimersen treatment periods (91%).

Treatment-related TEAEs included 1 case of moderate iron deficiency and 1 case of mild flushing in 2 casimersen-treated patients. Furthermore, 3 casimersen-treated patients experienced 5 serious AEs, which were considered not related to treatment and were resolved during the study.

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The design of Study 4045-101 includes a 12-week double-blind dose-titration period, where patients are randomized 2:1 to either casimersen or placebo, followed by an open-label extension period that lasts up to 132 weeks. In total, 11 (92%) patients completed the study and mean total time on study was 144 weeks (standard deviation [SD], 3.45), with total casimersen treatment was 139 weeks (SD, 9.26).

Kuntz and colleagues found no evidence of renal toxicity, cardiac signals, or deaths in the study. All pharmacokinetic parameters were similar for casimersen 30 mg/kg/week at Weeks 7 and 60, suggesting little to no accumulation in plasma with weekly dosing. Furthermore, no patterns, trends, or abnormalities were observed in hematology, coagulopathy, chemistry, or other clinical laboratory parameters.

ESSENCE is an ongoing, 96-week, double-blind, placebo-controlled phase 3 study with a subsequent 48-week open-label period. The interim results presented showed a greater change from baseline in the casimersen arm compared to placebo in dystrophin expression (P = .004).

Researchers saw increases in exon 45 skipping (P <.001) vs baseline in all 27 patients who received casimersen, representing a 100% response rate. ESSENSE included ambulatory patients with DMD amenable to exon 45 skipping or exon 53 skipping, whereas study 4045-101 solely included patients with DMD amenable to exon 45 skipping who had limited ambulation or were nonambulatory.

In February, casimersen received FDA approval for treating patients with DMD who have a confirmed mutation amenable to exon 45 skipping. Keeping with the accelerated approval pathway casimersen is on, the continued approval was contingent on the confirmation of a clinical benefit in confirmatory trials such as ESSENCE.2

At the time, Sarepta noted that casimersen met the full satisfactory standards for safety and effectiveness and is, therefore, not considered investigational or experimental. Kidney toxicity had been observed after the administration of some antisense oligonucleotides—such as potentially fatal glomerulonephritis—though it had not been observed in clinical studies of casimersen to date. It was advised that kidney function should be monitored in patients administered the drug.

For more coverage of MDA 2021, click here.

1. Kuntz NL, Wagner KR, East L, et al. Casimersen treatment in eligible patients with Duchenne muscular dystrophy: safety, tolerability, and pharmacokinetics over 144 weeks of treatment. Presented at MDA Clinical and Scientific Conference 2021; March 15-18.
2. Sarepta Therapeutics Announces FDA Approval of AMONDYS 45™ (casimersen) Injection for the Treatment of Duchenne Muscular Dystrophy (DMD) in Patients Amenable to Skipping Exon 45. News release. February 25, 2021. Accessed February 25, 2021.
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