title: Long-Term Efficacy, Safety, and Pharmacokinetics of Drisapersen in Duchenne Muscular Dystrophy: Results from an Open-Label Extension Study.
abstract: BACKGROUND
  Drisapersen induces exon 51 skipping during dystrophin pre-mRNA splicing and allows synthesis of partially functional dystrophin in Duchenne muscular dystrophy (DMD) patients with amenable mutations.
  
  
  METHODS
  This 188-week open-label extension of the dose-escalation study assessed the long-term efficacy, safety, and pharmacokinetics of drisapersen (PRO051/GSK2402968), 6 mg/kg subcutaneously, in 12 DMD subjects. Dosing was once weekly for 72 weeks. All subjects had a planned treatment interruption (weeks 73-80), followed by intermittent dosing (weeks 81-188).
  
  
  RESULTS
  Subjects received a median (range) total dose of 5.93 (5.10 to 6.02) mg/kg drisapersen. After 177 weeks (last efficacy assessment), median (mean [SD]) six-minute walk distance (6MWD) improved by 8 (-24.5 [161]) meters for the 10 subjects able to complete the 6MWD at baseline (mean age [SD]: 9.5 [1.9] years). These statistics include 2 subjects unable to complete the test at later visits and who scored "zero". When only the 8 ambulant subjects at week 177 were taken into account, a median (mean [SD]) increase of 64 (33 [121]) meters in 6MWD was observed. Of 7 subjects walking ≥330 m at extension baseline, 5 walked farther at week 177. Of 3 subjects walking <330 m, 2 lost ambulation, while 1 declined overall but walked farther at some visits. Over the 188 weeks, the most common adverse events were injection-site reactions, raised urinary α1-microglobulin and proteinuria. Dystrophin expression was detected in all muscle biopsies obtained at week 68 or 72.
  
  
  CONCLUSIONS
  Drisapersen was generally well tolerated over 188 weeks. Possible renal effects, thrombocytopenia and injection-site reactions warrant continued monitoring. Improvements in the 6MWD at 12 weeks were sustained after 3.4 years of dosing for most patients. For a small, uncontrolled study, the outcomes are encouraging, as natural history studies would anticipate a decline of over 100 meters over a 3-year period in a comparable cohort.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT01910649.
authors: University Hospitals Leuven, Leuven, Belgium.
authors: Nathalie M
authors: NM
authors: Goemans
authors: University of Gothenburg, Gothenburg, Sweden.
authors: Már
authors: M
authors: Tulinius
authors: University Hospitals Leuven, Leuven, Belgium.
authors: Marleen
authors: M
authors: van den Hauwe
authors: University of Gothenburg, Gothenburg, Sweden.
authors: Anna-Karin
authors: AK
authors: Kroksmark
authors: University Hospitals Leuven, Leuven, Belgium.
authors: Gunnar
authors: G
authors: Buyse
authors: Spica Consultants Ltd, Marlborough, United Kingdom.
authors: Rosamund J
authors: RJ
authors: Wilson
authors: BioMarin Pharmaceutical Inc., Leiden, Netherlands.
authors: Judith C
authors: JC
authors: van Deutekom
authors: BioMarin Pharmaceutical Inc., Leiden, Netherlands.
authors: Sjef J
authors: SJ
authors: de Kimpe
authors: BioMarin Pharmaceutical Inc., Leiden, Netherlands.
authors: Afrodite
authors: A
authors: Lourbakos
authors: BioMarin Pharmaceutical Inc., Leiden, Netherlands.
authors: Giles
authors: G
authors: Campion
mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D016189:Dystrophin / Q000235:genetics / Q000378:metabolism; D005080:Exercise Test; D006801:Humans; D008297:Male; D018482:Muscle, Skeletal / Q000378:metabolism; D020388:Muscular Dystrophy, Duchenne / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D009841:Oligonucleotides / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016896:Treatment Outcome; D016138:Walking / Q000502:physiology
chemical_list: D016189:Dystrophin; D009841:Oligonucleotides; C525434:PRO051