Eteplirsen in the treatment of Duchenne muscular dystrophy

Abstract

Duchenne muscular dystrophy is a fatal neuromuscular disorder affecting around one in 3,500-5,000 male births that is characterized by progressive muscular deterioration. It is inherited in an X-linked recessive fashion and is caused by loss-of-function mutations in the DMD gene coding for dystrophin, a cytoskeletal protein that stabilizes the plasma membrane of muscle fibers. In September 2016, the US Food and Drug Administration granted accelerated approval for eteplirsen (or Exondys 51), 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. Eteplirsen is applicable for approximately 14% of patients with DMD mutations. This article extensively reviews and discusses the available information on eteplirsen to date, focusing on pharmacological, efficacy, safety, and tolerability data from preclinical and clinical trials. Issues faced by eteplirsen, particularly those relating to its efficacy, will be identified. Finally, the place of eteplirsen and exon skipping as a general therapeutic strategy in Duchenne muscular dystrophy treatment will be discussed.

Keywords: Duchenne muscular dystrophy; Exondys 51; eteplirsen; exon-skipping therapy; phosphorodiamidate morpholino oligomers.

Figure 1

Eteplirsen is an exon-skipping therapeutic. Notes: Eteplirsen (green bar) specifically recognizes exon 51 of the DMD gene. Upon binding, it influences the splicing machinery to skip exon 51 from the mature mRNA transcript. This restores the reading frame of DMD, allowing for successful translation of a shortened but functional dystrophin protein. Shown above is a case where eteplirsen is used to treat a DMD patient with a deletion spanning exons 49 and 50. This creates an out-of-frame frameshift that introduces a premature stop codon and results in nonproduction of dystrophin. Abbreviations: DMD, Duchenne muscular dystrophy; mRNA, messenger RNA.

Figure 2

Chemical structures for the 2′O-methyl phosphorothioate (2′O-MePS) and phosphorodiamidate morpholino oligomer (PMO) classes of antisense oligonucleotides (AOs). Notes: Shown in relation to native DNA and RNA structures. Eteplirsen is a PMO and has the basic structure depicted above. In contrast to the negatively charged 2′O-MePS AOs, PMOs lack charge. This property is thought to be associated with the high stability of PMOs and their increased safety as a therapeutic agent.