Pharmacokinetics and safety of single doses of drisapersen in non-ambulant subjects with Duchenne muscular dystrophy: Results of a double-blind randomized clinical trial

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• 作者：Kevin M. Flanigan ; Thomas Voit ; Xiomara Q. Rosales ; Laurent Servais ; John E. Kraus ; Claire Wardell ; Allison Morgan ; Susie Dorricott ; Joanna Nakielny ; Naashika Quarcoo ; Lia Liefaard ; Tom Drury ; Giles Campion ; Padraig Wright
• 关键词：Drisapersen ; Duchenne muscular dystrophy ; DMD ; Dystrophin ; Exon 51 ; Non-ambulant ; Oligonucleotide ; Pharmacokinetics ; Safety
• 刊名：Neuromuscular Disorders
• 出版年：January, 2014
• 年：2014
• 卷：24
• 期：1
• 页码：16-24
• 全文大小：753 K

文摘

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鈥?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 猢? years, in wheelchairs for 猢? to 猢? 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.