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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. © 2013 The Authors.

Original publication

DOI

10.1016/j.nmd.2013.09.004

Type

Journal article

Journal

Neuromuscular Disorders

Publication Date

01/01/2014

Volume

24

Pages

16 - 24