期刊
MUSCLE & NERVE
卷 64, 期 3, 页码 285-292出版社
WILEY
DOI: 10.1002/mus.27347
关键词
casimersen; Duchenne muscular dystrophy; exon skipping; phosphorodiamidate morpholino oligomer; RNA oligonucleotide
资金
- Sarepta Therapeutics, Inc
Duchenne muscular dystrophy (DMD) is caused by mutations in the DMD gene, while casimersen is designed to produce truncated but functional dystrophin in patients amenable to exon 45 skipping. This study demonstrated that casimersen was well tolerated in DMD patients and showed dose-proportional plasma exposure, supporting further research in this population.
Introduction/Aims Duchenne muscular dystrophy (DMD) is caused by mutations in the DMD gene resulting in the absence of dystrophin. Casimersen is a phosphorodiamidate morpholino oligomer designed to bypass frameshift DMD mutations and produce internally truncated, yet functional, dystrophin protein in patients amenable to exon 45 skipping. Our primary study objective was to evaluate safety and tolerability of casimersen; the secondary objective was to characterize the plasma pharmacokinetics. Methods This multicenter, phase 1/2 trial enrolled 12 participants (aged 7-21 years, who had limited ambulation or were nonambulatory) and comprised a 12-week, double-blind dose titration, then an open-label extension for up to 132 weeks. During dose titration, participants were randomized 2:1 to weekly casimersen infusions at escalating doses of 4, 10, 20, and 30 mg/kg (>= 2 weeks per dose), or placebo. Results Participants received casimersen for a mean 139.6 weeks. Treatment-emergent adverse events (TEAEs) occurred in all casimersen- and placebo-treated participants and were mostly mild (over 91.4%) and unrelated to casimersen or its dose. There were no deaths, dose reductions, abnormalities in laboratory parameters or vital signs, or casimersen-related serious AEs. Casimersen plasma concentration increased with dose and declined similarly for all dose levels over 24 hours postinfusion. All pharmacokinetic parameters were similar at weeks 7 and 60. Discussion Casimersen was well tolerated in participants with DMD amenable to exon 45 skipping. Most TEAEs were mild, nonserious, and unrelated to casimersen. Plasma exposure was dose proportional with no suggestion of plasma accumulation. These results support further studies of casimersen in this population.
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