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
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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
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Journal ArticleDOI
Safety, tolerability and pharmacokinetics of eteplirsen in young boys aged 6–48 months with Duchenne muscular dystrophy amenable to exon 51 skipping
Eduardo de Oliveira Mercuri,L. Servais,N. Deconinck,H Stevenson,Xiang Ni,W P Zhang,Lilly East,S. Yonren,F. Muntoni,Nicolas Deconinck,Rudy Van Coster,Arnaud Vanlander,Andreea Mihaela Seferian,Silvana de Lucia,Teresa Gidaro,L. Vanden Brande,Laurent Servais,Janbernd Kirschner,S. Borell,Eugenio Mercuri,Claudia Brogna,Marika Pane,Lavinia Fanelli,Giulia Norcia,Francesco Muntoni,Chiara Brusa,M H Chesshyre,K. Maresh,Jaqueline Pitchforth,Lucia Schottlaender,Mariacristina Scoto,A. Silwal,Fedrica Trucco +32 more
TL;DR: In this article , the safety, tolerability and pharmacokinetics of eteplirsen in children with exon 51 skip-amenable Duchenne muscular dystrophy (DMD) were evaluated.
Journal ArticleDOI
Promising Treatments for Duchenne Muscular Dystrophy: Restoring Dystrophin Protein Expression Using Nucleic Acid Therapeutics
Guoyan Hu,Chen Chen +1 more
TL;DR: Hu et al. as discussed by the authors reviewed promising treatments for Duchenne Muscular Dystrophy: Restoring Dystrophin Protein Expression Using Nucleic Acid Therapeutics.
Journal ArticleDOI
A Brief Review of Duchenne Muscular Dystrophy Treatment Options, with an Emphasis on Two Novel Strategies
Ahlke Heydemann,Maria Siemionow +1 more
TL;DR: In this article , a review of the promising therapies for Duchenne Muscular Dystrophy is presented, followed by a description of two novel technologies that when utilized together effectively treat the disease in the mdx mouse model.
Journal ArticleDOI
Splicing Modulation as a Promising Therapeutic Strategy for Lysosomal Storage Disorders: The Mucopolysaccharidoses Example
Juliana Inês Santos,Mariana Gonçalves,Liliana Matos,Luciana Gabriela Moreira,S. Carvalho,Maria João Prata,Maria Francisca Coutinho,Sandra Alves +7 more
TL;DR: The overall rationale and general mechanisms of splicing modulation approaches are introduced and the currently marketed formulations, which have been developed for non-lysosomal genetic disorders, are highlighted.
Journal ArticleDOI
Assessing the value of delandistrogene moxeparvovec (SRP-9001) gene therapy in patients with Duchenne muscular dystrophy in the United States
Alexa Klimchak,Lauren E. Sedita,Louise R. Rodino-Klapac,Jerry R. Mendell,Craig M. McDonald,Katherine Gooch,Daniel C. Malone +6 more
TL;DR: In this article , a simulation calculated lifetime costs and equal value of life years gained (evLYG) for Duchenne muscular dystrophy (DMD), using extrapolated clinical trial results and published utilities/costs.
References
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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.
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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.
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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.