Open AccessJournal Article
Eteplirsen for the Treatment of Duchenne Muscular Dystrophy (DMD) (S42.001)
Jay S. Charleston,F.J. Schnell,Johannes Dworzak,Cas Donoghue,J Lynch,Sarah Lewis,Lei Chen,Louise R. Rodino-Klapac,Zarife Sahenk,Jon Voss,U. DeAlwis,D. Frank,H Eliopoulos,J. Mendell +13 more
Reads0
Chats0
TLDR
The present study used a double‐blind placebo‐controlled protocol to test eteplirsen's ability to induce dystrophin production and improve distance walked on the 6‐minute walk test.Abstract:
Objective: Phosphorodiamidate morpholino oligomers (PMOs) are synthetic nucleic acid analogs that can be designed to sequence-specifically block spliceosomes from binding to dystrophin pre-mRNA, resulting in omission of the targeted exon from the transcript and restoration of the reading frame with the goal of enabling synthesis of internally-shortened dystrophin. Background: DMD, a rare, X-linked genetic disease results in progressive muscle degeneration and premature death. DMD is primarily caused by whole exon deletions in the dystrophin gene resulting in a shift of the mRNA reading frame that prevents production of functional dystrophin protein. Design/Methods: As of June 3, 2016, 81 of 150 treated patients had received weekly eteplirsen for ≥1 year. Results: PMO eteplirsen received accelerated approval in the US for patients with a dystrophin gene mutation amenable to exon 51 skipping based on an increase in dystrophin in skeletal muscle in some patients. Mean dystrophin increases as measured by Western blot were observed following 180 weeks of treatment in the pivotal Phase II Studies 201/202 when compared to untreated DMD controls (N=11; +0.85%, p=0.007) and at Week 48 in Phase III Study PROMOVI when compared to baseline (N=12; +0.28%, p=0.008). Immunohistochemistry analysis at Week 180 in Study 201/202 also showed mean increases in dystrophin as measured by % dystrophin-positive fibers (N=11; +16.27%, p 4.5 years of treatment. Conclusions: Eteplirsen is the first exon skipping therapy approved for the treatment of Duchenne muscular dystrophy amenable to exon 51 skipping. Lessons learned from the eteplirsen clinical development program can aid in development of PMO therapies targeting additional exons. Study Supported by: Sarepta Therapeutics, Inc. Disclosure: Dr. Charleston has received personal compensation for activities with Sarepta Therapeutics as an employee. Dr. Schnell has received personal compensation for activities with Sarepta Therapeutics as a full time employee. Dr. Dworzak has received personal compensation for activities with Sarepta Therapeutics as an employee. Dr. Donoghue has received personal compensation for activities with Sarepta Therapeutics as an employee. Dr. Lynch has received personal compensation for activities with Sarepta Therapeutics, Inc. as an employee. Dr. Lewis has nothing to disclose. Dr. Chen has nothing to disclose. Dr. Rodino-Klapac has nothing to disclose. Dr. Sahenk has nothing to disclose. Dr. Voss has received personal compensation for activities with Sarepta Therapeutics as an employee. Dr. DeAlwis has received personal compensation for activities with Sarepta Therapeutics as an employee. Dr. Frank has received personal compensation for activities with Sarepta Therapeutics, Inc. as an employee. Dr. Eliopoulos has received personal compensation for activities with Sarepta Therapeutics as an employee. Dr. Mendell has received personal compensation for activities with Sarepta Therapeutics, Inc.read more
Citations
More filters
Journal ArticleDOI
Eteplirsen in the treatment of Duchenne muscular dystrophy
TL;DR: Eteplirsen is a drug that acts to promote dystrophin production by restoring the translational reading frame of DMD through specific skipping of exon 51 in defective gene variants, which is applicable for approximately 14% of patients with DMD mutations.
Journal ArticleDOI
Current Clinical Applications of In Vivo Gene Therapy with AAVs.
Jerry R. Mendell,Jerry R. Mendell,Samiah Al-Zaidy,Louise R. Rodino-Klapac,Kimberly Goodspeed,Steven J. Gray,Christine N. Kay,Sanford L. Boye,Shannon E. Boye,Lindsey A. George,Stephanie Salabarria,Manuela Corti,Barry J. Byrne,Jacques P. Tremblay +13 more
TL;DR: This review is limited to gene therapy using adeno-associated virus (AAV) because the gene delivered by this vector does not integrate into the patient genome and has a low immunogenicity.
Journal ArticleDOI
Pharmacology of Antisense Drugs
TL;DR: This review focuses on some of the advances that have taken place in translating antisense technology from the bench to the clinic.
Journal ArticleDOI
Safety and efficacy of drisapersen for the treatment of Duchenne muscular dystrophy (DEMAND II): an exploratory, randomised, placebo-controlled phase 2 study.
Thomas Voit,Haluk Topaloglu,Volker Straub,Francesco Muntoni,Nicolas Deconinck,Giles G Campion,Sjef J. de Kimpe,Michelle Eagle,Michela Guglieri,Steve S Hood,Lia Liefaard,Afrodite Lourbakos,Allison A Morgan,Joanna Nakielny,Naashika Quarcoo,Valeria Ricotti,Katie Rolfe,Laurent Servais,C. Wardell,Rosamund Wilson,Padraig Wright,Padraig Wright,John E. Kraus +22 more
TL;DR: Continuous drisapersen resulted in some benefit in 6MWD versus placebo at week 25 in patients in the intention-to-treat population for whom data were available, andAmbulation improvements in this young population with early-stage Duchenne muscular dystrophy are encouraging but need to be confirmed in larger studies.
Journal ArticleDOI
Functional correction in mouse models of muscular dystrophy using exon-skipping tricyclo-DNA oligomers
Aurélie Goyenvalle,Graziella Griffith,Arran Babbs,Samir El Andaloussi,Samir El Andaloussi,Kariem Ezzat,Aurélie Avril,Branislav Dugovic,Rémi Chaussenot,Rémi Chaussenot,Arnaud Ferry,Thomas Voit,Helge Amthor,Claudia Bühr,Stefan Schürch,Matthew J.A. Wood,Kay E. Davies,Cyrille Vaillend,Cyrille Vaillend,Christian J. Leumann,Luis Garcia +20 more
TL;DR: Although current naked AONs do not enter the heart or cross the blood-brain barrier to any substantial extent, it is shown that systemic delivery of tcDNA-AONs promotes a high degree of rescue of dystrophin expression in skeletal muscles, the heart and, to a lesser extent, the brain.
References
More filters
Journal ArticleDOI
Diagnosis and management of Duchenne muscular dystrophy, part 1: diagnosis, and pharmacological and psychosocial management
Katharine Bushby,Richard S. Finkel,David J. Birnkrant,Laura E. Case,Paula R. Clemens,Linda H. Cripe,Ajay Kaul,Kathi Kinnett,Craig M. McDonald,Shree Pandya,James Poysky,Frederic Shapiro,Jean Tomezsko,Carolyn M. Constantin +13 more
TL;DR: These recommendations provide a framework for recognising the multisystem primary manifestations and secondary complications of DMD and for providing coordinated multidisciplinary care.
Journal ArticleDOI
Profiles of neuromuscular diseases. Duchenne muscular dystrophy.
Craig M. McDonald,Richard T. Abresch,Gregory T. Carter,William M. Fowler,E. R. Johnson,David D. Kilmer,B. J. Sigford +6 more
TL;DR: A tremendous heterogeneity of severity among males with Becker's muscular dystrophy is suggested, with mean intellectual and neuropsychologic function within normal limits, but with a large variability in intelligence quotient scores.
Journal ArticleDOI
Dystrophin and mutations: one gene, several proteins, multiple phenotypes
TL;DR: Current understanding of the genotype-phenotype relation for mutations in the dystrophin gene and their implications for gene functions are focused on.
Journal ArticleDOI
Exon skipping and dystrophin restoration in patients with Duchenne muscular dystrophy after systemic phosphorodiamidate morpholino oligomer treatment: an open-label, phase 2, dose-escalation study.
Sebahattin Cirak,Virginia Arechavala-Gomeza,Michela Guglieri,Lucy Feng,Silvia Torelli,Karen Anthony,Stephen Abbs,M. E. Garralda,John P. Bourke,Dominic J. Wells,George Dickson,Matthew J.A. Wood,Steve D. Wilton,Volker Straub,Ryszard Kole,Stephen B. Shrewsbury,Caroline Sewry,Jennifer E. Morgan,Kate Bushby,Francesco Muntoni +19 more
TL;DR: The safety and biochemical efficacy presented show the potential of AVI-4658 to become a disease-modifying drug for Duchenne muscular dystrophy.
Journal ArticleDOI
Local Dystrophin Restoration with Antisense Oligonucleotide PRO051
Judith C.T. van Deutekom,Anneke A.M. Janson,Ieke B. Ginjaar,Wendy S. Frankhuizen,Annemieke Aartsma-Rus,Mattie Bremmer-Bout,Johan T. den Dunnen,Klaas Koop,Anneke J. van der Kooi,Nathalie Goemans,Sjef J. de Kimpe,Peter F. Ekhart,Edna H. Venneker,Gerard Johannes Platenburg,Jan J.G.M. Verschuuren,Gert-Jan B. van Ommen +15 more
TL;DR: Intramuscular injection of antisense oligonucleotide PRO051 induced dystrophin synthesis in four patients with Duchenne's muscular dystrophy who had suitable mutations, suggesting that further studies might be feasible.