MUTATIONS, INCLUDING EXON DELETIONS, PREVENT DYSTROPHIN PRODUCTION.
Duchenne muscular dystrophy (DMD) is most often caused by frame-shift mutations due to deletions of one or more exons from the dystrophin gene.2 The exons following the deletion are misaligned or “out of frame,” preventing translation of a functional dystrophin protein.2
These frame-shift mutations result in production of little or no functional dystrophin, leading to a cycle of muscle cell degeneration, inflammation and fibrosis characterized by loss of muscle mass and muscle wasting.1-3
HOW DOES LIMITED DYSTROPHIN PRODUCTION AFFECT DMD?
Patients with different types of DMD and/or various dystrophin levels show varying rates of disease progression. For example, compared with some aggressive DMD phenotypes, patients with mutations amenable to exon 44 skipping* typically have slower disease progression.4,5
Some patients with DMD can still produce a tiny amount of dystrophin in their bodies—but often at such low levels that it can only be detected using highly sensitive imaging techniques.4,5 These observations regarding dystrophin support the rationale to reasonably expect that modest restoration of dystrophin could offer clinical benefit.4,6
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EXONDYS 51 is indicated for the treatment of Duchenne muscular dystrophy (DMD) in patients who have a confirmed mutation of the DMD gene that is amenable to exon 51 skipping. This indication is approved under accelerated approval based on an increase in dystrophin in skeletal muscle observed in some patients treated with EXONDYS 51. A clinical benefit of EXONDYS 51 has not been established. Continued approval for this indication may be contingent upon verification of a clinical benefit in confirmatory trials.
IMPORTANT SAFETY INFORMATION
Hypersensitivity reactions, including rash and urticaria, pyrexia, flushing, cough, dyspnea, bronchospasm, and hypotension, have occurred in patients who were treated with EXONDYS 51. If a hypersensitivity reaction occurs, institute appropriate medical treatment and consider slowing the infusion or interrupting the EXONDYS 51 therapy.
Aartsma-Rus A, Ginjaar IB, Bushby K. The importance of genetic testing for Duchenne muscular dystrophy. J Med Genet. 2016;0:1-7.
Kole R, Krainer AR, Altman S. RNA therapeutics: beyond RNA interference and antisense oligoneucleotides. Nature Reviews Drug Discovery 2012;11:125-140.
Allen DG, Whitehead NP, Froehner SC. Absence of dystrophin disrupts skeletal muscle signaling: roles of ca2+, reactive oxygen species, and nitric oxide in the development of muscular dystrophy. Physical Rev. 2016;96:253-305.
Bello L, Morgenroth LP, Gordish-Dressman H, et al. DMD genotypes and loss of ambulation in the CINRG Duchenne Natural History Study. Neurology. 2016; 87:401-409.
Dwianingsih EK, Malueka RG, Nishida A, et al. A novel splicing silencer generated by DMD exon 45 deletion junction could explain upstream exon 44 skipping that modifies dystrophinopathy. J. Hum. Genet. 2014; 59:423-429.
EXONDYS 51 [package insert]. Cambridge, MA: Sarepta Therapeutics Inc; October 2018.