Long-Term Efficacy, Safety, and Pharmacokinetics of Drisapersen in Duchenne Muscular Dystrophy: Results from an Open-Label Extension Study

PLoS One. 2016 Sep 2;11(9):e0161955. doi: 10.1371/journal.pone.0161955. eCollection 2016.

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.

Conclusion: 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.

Trial registration: ClinicalTrials.gov NCT01910649.

Publication types

  • Clinical Trial, Phase I
  • Clinical Trial, Phase II

MeSH terms

  • Adolescent
  • Child
  • Child, Preschool
  • Dystrophin / genetics
  • Dystrophin / metabolism
  • Exercise Test
  • Humans
  • Male
  • Muscle, Skeletal / metabolism
  • Muscular Dystrophy, Duchenne / drug therapy*
  • Muscular Dystrophy, Duchenne / genetics
  • Muscular Dystrophy, Duchenne / metabolism
  • Oligonucleotides / adverse effects
  • Oligonucleotides / pharmacokinetics
  • Oligonucleotides / therapeutic use*
  • Treatment Outcome
  • Walking / physiology

Substances

  • Dystrophin
  • Oligonucleotides
  • PRO051

Associated data

  • ClinicalTrials.gov/NCT01910649

Grants and funding

This study was sponsored by Prosensa Therapeutics BV, Leiden, Netherlands until 21 July 2011; subsequently, GlaxoSmithKline, Middlesex, UK, sponsored the study until the data cut reported here. This work was performed collaboratively by University Hospitals Leuven, University of Gothenburg, and Prosensa Therapeutics BV, GlaxoSmithKline and BioMarin Pharmaceutical Inc. researchers. None of the contributing authors listed on this paper were affiliated with GlaxoSmithKline at the time of the study. Prosensa Therapeuics BV provided support in the form of salaries and/or research materials for authors (JCvD, SJdK, AL, GVC, NMG), the study design, data collection, data analysis and in the preparation of the manuscript. GlaxoSmithKline provided support in the form of salaries and/or research materials for non-author collaborators (stated in the acknowledgements), the study design, data collection, data analysis and in the preparation of the manuscript. BioMarin Pharmaceutical Inc., Leiden, The Netherlands, provided support in the form of salaries and/or research materials for authors (JCvD, SJdK, AL, GVC), the data collection and analysis, and in the decision to publish, or preparation of the manuscript. Spica Consultants Ltd, Marlborough, UK, provided support in the form of salaries (RJW) and data analysis and preparation of the manuscript, but did not play a role in the study design and data collection. The specific roles of these authors are articulated in the “Author Contributions” section.