title: Pharmacokinetics and safety of single doses of drisapersen in non-ambulant subjects with Duchenne muscular dystrophy: results of a double-blind randomized clinical trial.
abstract: 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 ⩾9years, in wheelchairs for ⩾1 to ⩽4years, with a diagnosis of DMD resulting from a mutation correctable by drisapersen treatment. Four dose cohorts were planned (3, 6, 9 and 12mg/kg), but study objectives were met with the 9mg/kg dose. Less than proportional increase in exposure was demonstrated over the 3-9mg/kg dose range, though post hoc analysis showed dose proportionality was more feasible over the 3-6mg/kg range. Single doses of drisapersen at 3 and 6mg/kg did not result in significant safety or tolerability concerns; however, at the 9mg/kg dose, pyrexia and transient elevations in inflammatory parameters were seen. The maximum tolerated dose of 6mg/kg drisapersen was identified for further characterization in multiple dose studies in the non-ambulant DMD population.
authors: Center for Gene Therapy, Nationwide Children's Hospital, Columbus, OH, United States.
authors: Kevin M
authors: KM
authors: Flanigan
authors: Institut de Myologie, Université Pierre et Marie Curie Paris 6, UM 76, INSERM U 974, CNRS UMR 7215, France.
authors: Thomas
authors: T
authors: Voit
authors: Center for Gene Therapy, Nationwide Children's Hospital, Columbus, OH, United States.
authors: Xiomara Q
authors: XQ
authors: Rosales
authors: Institut de Myologie, Université Pierre et Marie Curie Paris 6, UM 76, INSERM U 974, CNRS UMR 7215, France.
authors: Laurent
authors: L
authors: Servais
authors: GlaxoSmithKline, Research Triangle Park, NC, United States. Electronic address: john.e.kraus@gsk.com.
authors: John E
authors: JE
authors: Kraus
authors: GlaxoSmithKline, Stockley Park, UK.
authors: Claire
authors: C
authors: Wardell
authors: Prosensa Therapeutics BV, Leiden, The Netherlands.
authors: Allison
authors: A
authors: Morgan
authors: Prosensa Therapeutics BV, Leiden, The Netherlands.
authors: Susie
authors: S
authors: Dorricott
authors: GlaxoSmithKline, Stockley Park, UK.
authors: Joanna
authors: J
authors: Nakielny
authors: GlaxoSmithKline, Stockley Park, UK.
authors: Naashika
authors: N
authors: Quarcoo
authors: GlaxoSmithKline, Stevenage, UK.
authors: Lia
authors: L
authors: Liefaard
authors: GlaxoSmithKline, Stockley Park, UK.
authors: Tom
authors: T
authors: Drury
authors: Prosensa Therapeutics BV, Leiden, The Netherlands.
authors: Giles
authors: G
authors: Campion
authors: GlaxoSmithKline, London, UK.
authors: Padraig
authors: P
authors: Wright
mesh_terms: D000293:Adolescent; D015415:Biomarkers; D002648:Child; D004311:Double-Blind Method; D006801:Humans; D018836:Inflammation Mediators / Q000032:analysis; D008297:Male; D020388:Muscular Dystrophy, Duchenne / Q000188:drug therapy* / Q000378:metabolism; D009841:Oligonucleotides / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*
chemical_list: D015415:Biomarkers; D018836:Inflammation Mediators; D009841:Oligonucleotides; C525434:PRO051
keywords: DMD; Drisapersen; Duchenne muscular dystrophy; Dystrophin; Exon 51; Non-ambulant; Oligonucleotide; Pharmacokinetics; Safety