Background: Casimersen is an investigational phosphorodiamidate morpholino oligomer designed for exon 45 skipping, which, in patients affected by that mutation, would result in the expression of a truncated, yet functional dystrophin protein.
Objective: The objective of this randomized, phase 1/2 trial (NCT02530905) was to evaluate the safety, tolerability, and pharmacokinetics of casimersen in male patients with Duchenne muscular dystrophy (DMD), aged 7–21 years, with confirmed mutations amenable to exon 45 skipping, who were nonambulatory or had limited ambulation (incapable of walking ≥300 meters on the 6-minute walking test [6MWT]).
Methods: Patients were randomized 2:1 to receive double-blind, intravenous casimersen in increasing doses at ≥2-week intervals (4, 10, 20, and 30 mg/kg/week) or placebo, for 12 weeks; all patients then received open-label casimersen 30 mg/kg for up to 132 weeks.
Results: Twelve patients were enrolled (casimersen, n=8; placebo, n=4), with the mean age of 13.6 years and the mean 6MWT distance of 39 meters. Eleven (92%) patients completed the study (casimersen-casimersen, n=8; placebo-casimersen, n=3). All patients experienced ≥1 treatment-emergent adverse event (TEAE). In the combined double-blind and open-label periods, most TEAEs in casimersen-treated patients (159/175; 91%) and all TEAEs in placebo-treated patients (11/11) were mild in severity. Three casimersen-treated patients experienced five serious adverse events, which were considered not related to treatment and resolved during the study. No patient discontinued the trial due to TEAEs. No patterns, trends, or abnormalities were observed in clinical laboratory parameters. All pharmacokinetic parameters for casimersen 30 mg/kg/week at Weeks 7 and 60, including concentration vs time profiles, were similar.
Conclusion: Casimersen was well tolerated in patients with DMD amenable to exon 45 skipping, with a pharmacokinetic profile that suggests little to no accumulation following weekly dosing at 30 mg/kg.