期刊
NEUROMUSCULAR DISORDERS
卷 24, 期 1, 页码 16-24出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.nmd.2013.09.004
关键词
Drisapersen; Duchenne muscular dystrophy; DMD; Dystrophin; Exon 51; Non-ambulant; Oligonucleotide; Pharmacokinetics; Safety
资金
- GlaxoSmithKline
- NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES [UL1TR001070] Funding Source: NIH RePORTER
Duchenne muscular dystrophy (DMD) is a progressive, lethal neuromuscular disorder caused by the absence of dystrophin protein due to mutations of the dystrophin gene. Drisapersen is a 2'-O-methyl-phosphorothioate oligonucleotide designed to skip exon 51 in dystrophin pre-mRNA to restore the reading frame of the mRNA. This study assessed safety, tolerability, and pharmacokinetics of drisapersen after a single subcutaneous administration in non-ambulatory subjects. Eligible subjects were non-ambulant boys aged >= 9 years, in wheelchairs for >= 1 to <= 4 years, with a diagnosis of DMD resulting from a mutation correctable by drisapersen treatment. Four dose cohorts were planned (3, 6, 9 and 12 mg/kg), but study objectives were met with the 9 mg/kg dose. Less than proportional increase in exposure was demonstrated over the 3-9 mg/kg dose range, though post hoc analysis showed dose proportionality was more feasible over the 3-6 mg/kg range. Single doses of drisapersen at 3 and 6 mg/kg did not result in significant safety or tolerability concerns; however, at the 9 mg/kg dose, pyrexia and transient elevations in inflammatory parameters were seen. The maximum tolerated dose of 6 mg/kg drisapersen was identified for further characterization in multiple dose studies in the non-ambulant DMD population. (C) 2013 The Authors. Published by Elsevier B.V. All rights reserved.
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