1. Pharmacokinetics and safety of single doses of drisapersen in non-ambulant subjects with Duchenne muscular dystrophy: Results of a double-blind randomized clinical trial
- Author
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Joanna Nakielny, A. Morgan, Naashika Quarcoo, Thomas Voit, C. Wardell, Xiomara Q. Rosales, Lia Liefaard, Kevin M. Flanigan, John E. Kraus, G. Campion, Laurent Servais, Tom Drury, Susie Dorricott, and Padraig Wright
- Subjects
Male ,Duchenne muscular dystrophy ,medicine.medical_specialty ,Adolescent ,Population ,Clinical Neurology ,Oligonucleotides ,Urology ,Non-ambulant ,Article ,law.invention ,Dystrophin ,Double-Blind Method ,Randomized controlled trial ,Pharmacokinetics ,law ,Oligonucleotide ,Exon 51 ,DMD ,Post-hoc analysis ,Humans ,Medicine ,Genetics(clinical) ,Pediatrics, Perinatology, and Child Health ,Child ,education ,Genetics (clinical) ,Drisapersen ,education.field_of_study ,biology ,business.industry ,medicine.disease ,Muscular Dystrophy, Duchenne ,Neurology ,Tolerability ,Pediatrics, Perinatology and Child Health ,biology.protein ,Physical therapy ,Neurology (clinical) ,Inflammation Mediators ,Safety ,business ,Biomarkers ,Oligonucleotide, Pharmacokinetics - 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 ≥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.
- Published
- 2014