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

• Published in: Neuromuscular disorders : NMD Vol. 24; no. 1; pp. 16 - 24
• Main Authors: Flanigan, Kevin M., Voit, Thomas, Rosales, Xiomara Q., Servais, Laurent, Kraus, John E., Wardell, Claire, Morgan, Allison, Dorricott, Susie, Nakielny, Joanna, Quarcoo, Naashika, Liefaard, Lia, Drury, Tom, Campion, Giles, Wright, Padraig
• Format: Journal Article
• Language: English
• Published: England Elsevier B.V 01.01.2014
• Subjects: Adolescent; Biomarkers; Child; DMD; Double-Blind Method; Drisapersen; Duchenne muscular dystrophy; Dystrophin; Exon 51; Humans; Inflammation Mediators - analysis; Male; Muscular Dystrophy, Duchenne - drug therapy; Muscular Dystrophy, Duchenne - metabolism; Neurology; Non-ambulant; Oligonucleotide; Oligonucleotides - administration & dosage; Oligonucleotides - adverse effects; Oligonucleotides - pharmacokinetics; Oligonucleotides - therapeutic use; Pharmacokinetics; Safety; Drisapersen; Duchenne muscular dystrophy; Exon 51; DMD; Oligonucleotide; Safety; Dystrophin; Non-ambulant; Pharmacokinetics
• ISSN: 0960-8966; 1873-2364; 1873-2364
• DOI: 10.1016/j.nmd.2013.09.004

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.