Abstract
Objective: This double-blind, randomized, placebo-controlled Phase 2 study (NCT01462292) assessed the 24-week efficacy, safety, tolerability, and pharmacokinetics of two different subcutaneous drisapersen doses, and the 24-week off-dose persistent effect, in ambulant Duchenne muscular dystrophy (DMD) patients. Methods: Male DMD patients (≥5 years; time to rise from floor ≤15 s) were randomized to drisapersen 3 mg/kg/week, 6 mg/kg/week or placebo. The primary efficacy endpoint was change from baseline in 6-minute walking distance (6MWD) at week 24. Secondary endpoints included changes in timed function tests, muscle strength, and pulmonary function tests. Results: Fifty-one patients were randomized to placebo (N = 16), drisapersen 3 mg/kg/week (N = 17) or 6 mg/kg/week (N = 18). All but 2 patients had baseline rise from floor time <7 s. This study was exploratory and not prospectively powered; however, a difference in mean 6MWD versus placebo in favor of drisapersen 6 mg/kg/week was observed at week 24 (27.1 m; P = 0.069) and maintained 24 weeks off-treatment (27.9 m; P = 0.177). The 3 mg/kg/week group showed no statistically significant difference in mean 6MWD versus placebo. For some secondary endpoints, a more positive response in favor of drisapersen 6 mg/kg/week compared to placebo was shown. Drisapersen had a long half-life with steady state reached after approximately 36 weeks. Most common adverse events in both drisapersen groups were related to injection site reactions and subclinical proteinuria. Interpretation: Drisapersen 6 mg/kg/week for 24 weeks resulted in a treatment benefit in 6MWD, largely maintained 24 weeks off-treatment. This study provided insights for further studies to optimize dosage regimen.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 913-926 |
| Number of pages | 14 |
| Journal | Annals of Clinical and Translational Neurology |
| Volume | 5 |
| Issue number | 8 |
| DOIs | |
| State | Published - Aug 2018 |
Bibliographical note
Funding Information:This study (NCT01462292; DMD114876) was sponsored by GlaxoSmithKline (Research Triangle Park, NC, United States). The project described was supported by Award Number Grant UL1TR001070 from the National Center For Advancing Translational Sciences (Nationwide Children’s Hospital/Ohio State University). The authors would like to thank all non-author collaborators from the DEMAND V Study Group (see Supplementary Materials), Shaun Jones (GlaxoSmithKline, London, UK) and Marlene Jordan (GlaxoSmithKline, Research Triangle Park, NC, United States) and the group of coordinating physiotherapists who performed the training and quality control of the functional endpoints. We thank Ismar Healthcare for their support with editing of the manuscript, which was funded by BioMarin Pharmaceutical Inc.
Funding Information:
This study (NCT01462292; DMD114876) was sponsored by GlaxoSmithKline (Research Triangle Park, NC, United States). The project described was supported by Award Number Grant UL1TR001070 from the National Center For Advancing Translational Sciences (Nationwide Children’s Hospital/Ohio State University).
Funding Information:
C.M.M. acts as a consultant for BioMarin, Sarepta Therapeutics, PTC Therapeutics, Eli Lilly, Pfizer, Akashi Therapeutics, Catabassis, Marathon, Italfarmaco, Capricor, and Santhera Pharmaceuticals. B.W. received personal fees and non-financial support from the Drisapersen Expert Advisory meeting in London and Sarepta’s Advisory Board meeting in Phoenix, Arizona. K.M.F. serves as a site investigator on trials supported by PTC Therapeutics and Akashi Therapeutics, and has received personal fees from Sarepta Therapeutics and a grant from CureDuch-enne outside the submitted work. R.W. receives consultant fees from BioMarin. S.K. is an employee of BioMarin Pharmaceutical Inc. A.L. is an employee of BioMarin Pharmaceutical Inc. Z.L. is an employee of BioMarin Pharmaceutical Inc. G.C. is an employee of BioMarin Pharmaceutical Inc. and holder of stock and options.
Funding Information:
This study (NCT01462292; DMD114876) was sponsored by GlaxoSmithKline (Research Triangle Park, NC, United States). The project described was supported by Award Number Grant UL1TR001070 from the National Center For Advancing Translational Sciences (Nationwide Children's Hospital/Ohio State University). The authors would like to thank all non-author collaborators from the DEMAND V Study Group (see Supplementary Materials), Shaun Jones (GlaxoSmithKline, London, UK) and Marlene Jordan (GlaxoSmithKline, Research Triangle Park, NC, United States) and the group of coordinating physiotherapists who performed the training and quality control of the functional endpoints. We thank Ismar Healthcare for their support with editing of the manuscript, which was funded by BioMarin Pharmaceutical Inc.
Publisher Copyright:
© 2018 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc on behalf of American Neurological Association.