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Clinical data
Trade names Exondys 51
Routes of
Intravenous infusion
ATC code
  • None
Legal status
Legal status
CAS Number
Chemical and physical data
Formula C364H569N177O122P30
Molar mass 10305.738
3D model (JSmol)

Eteplirsen (Exondys 51, Sarepta Therapeutics Inc.), also called AVI-4658, is a drug designed for treatment, but not a cure, of some mutations that cause Duchenne muscular dystrophy (DMD), a genetic degenerative muscle disease. Eteplirsen only targets mutations in a region implicated in 13% of DMD cases.[1] After a controversial debate surrounding the efficacy of the drug, eteplirsen received accelerated approval from the US Food and Drug administration in late 2016.[2][3] A year's worth of treatment with Eteplirsen is expected to cost approximately $300,000.[4] A comprehensive review of the molecule and its clinical trials was published in early 2017.[5]

Mechanism of action[edit]

Duchenne muscular dystrophy is caused when a mutation in the DMD gene changes the DMD RNA so that it no longer codes for functional dystrophin protein, usually due to a mutation that alters the reading frame of the RNA downstream of the mutation. If an exon with an appropriate number of bases lies near the mutation, by removing that exon the downstream reading frame can be corrected and production of partially functional dystrophin can be restored. This is the general strategy used for designing exon-skipping oligos for DMD; as there are 79 exons in the longest splice form of the dystrophin transcript, many different oligos are needed to address the range of mutations present in the population of people with DMD.

Eteplirsen is a morpholino antisense oligomer which triggers excision of exon 51 during pre-mRNA splicing of the dystrophin RNA transcript. Skipping exon 51 changes the downstream reading frame of dystrophin;[6] giving eteplirsen to a healthy person would result in production of dystrophin mRNA which would not code for functional dystrophin protein but, for DMD patients with particular frameshifting mutations, giving eteplirsen can restore the reading frame of the dystrophin mRNA and result in production of functional (although modified by having an internal deletion consisting of both the patient's original defect, as well as the therapeutically skipped exon) dystrophin.[7] Eteplirsen is given by intravenous infusion for systemic treatment of DMD.

Exon skipping is induced by eteplirsen, a charge-neutral, phosphorodiamidate morpholino oligomer (PMO) that selectively binds to exon 51 of dystrophin pre-mRNA, restoring the phase of the reading frame and enabling production of functional, but truncated, dystrophin.[8] The uncharged nature of the PMO helps make it resistant to biological degradation.[9] This truncated dystrophin protein produced by eteplirsen causes a less severe form of dystrophinopathy, much like Becker muscular dystrophy. PMO technology to treat other genotypes amenable to exon skipping could potentially treat an estimated 70 to 80% of all DMD patients with dystrophin gene deletion. Eteplirsen's proposed mechanism of action is to bind to pre-mRNA needed to make a particular muscle protein, dystrophin, and rearrange the splicing of the RNA so that more dystrophin is made. By increasing the quantity of an abnormal, but potentially functional, dystrophin protein, the objective is to slow or prevent the progression of DMD.[8][10]

Clinical studies[edit]

Several clinical trials have been conducted to test eteplirsen, one in the UK involving local injection to the foot,[11][12] one in the UK involving systemic injection at low doses[1][13] and one in the USA at higher systemic doses[14] that progressed to a rollover extension study.[10][15] In the phase II study of 12 boys, dystrophin production was increased in 72% of the participants. It is questioned whether increasing the dose — which is feasible due to the lower toxicity of eteplirsen compared to drisapersen — would benefit the non-responders and whether this could result in any increased side effects. A phase III study has begun in the USA.[16]

In 2011, in a UK study eteplirsen (AVI-4658) was given to 19 children with Duchenne muscular dystrophy; researchers found that higher doses of the drug led to an increase in dystrophin. Researchers believe that drugs which are designed to make the body “skip over” mutations in this way could be used to treat approximately 83% of Duchenne muscular dystrophy cases. Eteplirsen only targets mutations in a region implicated in 13% of cases. This study demonstrated the potential of this approach for increasing the levels of dystrophin in the short term. The trial’s principal aim was to work out the appropriate dosages of the drug, therefore the drug’s safety profile and effects will need to be confirmed in larger, longer-term studies, particularly as patients would need to take it for the rest of their lives (or until a better treatment is available).[1]

A similar drug was also in clinical trials, drisapersen, which is a 2'-O-methyl phosphorothioate antisense oligo that, like eteplirsen, triggers skipping of dystrophin exon 51. In January 2016, the FDA rejected drisapersen (Kyndrisa) for lack of efficacy, effectively shifting focus to eteplirsen.[17]

Current status[edit]

Eterplirsen has received accelerated approval from the US FDA.[2]

Both eteplirsen and the similar drug drisapersen filed New Drug Application (NDA) for review with the US Food and Drug Administration (FDA).[18] The Prescription Drug User Fee Act (PDUFA) goal dates for these were December 27, 2015 for drisapersen and February 26, 2016 for eteplirsen. Following FDA rejection of drisapersen, the agency announced a three-month time extension for its review of eteplirsen. The FDA panel decision was controversial because the FDA staff and the panel used a stricter standard of evidence than Sarepta and patient groups used. The FDA panel said that it was required by law to apply the standard of “substantial evidence” of effectiveness. This required randomized, controlled trials showing effectivenes of a meaningful clinical outcome, such as the ability to function in daily life. Sarepta and the patient groups wanted to use the standard of historical controls, personal testimonies, and the presence of altered dystrophin in the body. On April 25, 2016, the Advisory Committee Panel voted against approval;.[19] In June 2016, FDA requested for additional data from Sarepta, to confirm findings of dystrophin production by Eteplirsen. Janet Woodcock, director of the FDA’s Center for Drug Evaluation and Research, overruled the panel, and FDA Commissioner Robert Califf deferred to her decision. Eterplirsen received accelerated approval on September 19, 2016.[20]

Pharmacokinetic (PK) properties and potential side effects[edit]

On January 22, 2016 the FDA Briefing Document containing information about eteplirsen (ND 206488) was submitted to the Peripheral and Central Nervous System Advisory Committee Meeting. The most common treatment for DMD is glucocorticoid use, which do not sufficiently ameliorate symptoms or address the underlying genetic mutation and lack of functional dystrophin. Part of the document included the following information pertaining to the pharmacokinetic properties of eteplirsen:[8]

  • Clinical safety data shows that there has been no adverse effects from treatment with Eteplirsen-based off the doses administered in several trials.
  • In general, dose-proportionality and linearity in PK properties may be concluded following weekly doses of 0.5~20 mg/kg in Phase 1 dose-ranging study and 30 and 50 mg/kg in efficacy trials. There was insignificant drug accumulation following weekly dosing across this dose range of 0.5~50 mg/kg
  • Eteplirsen is not metabolized by hepatic microsomes and was not a potent inducer or inhibitor of the major human CYP enzymes, and was not a substrate, nor did it have any major inhibitory potential for any of the key human drug transporters at the concentration range given in clinical trials. Based on these findings, it is expected to have a low potential for drug-drug interactions (DDI) in humans.
  • Eteplirsen was found to be metabolically stable in vitro with no evidence of metabolism or metabolite formation.
  • Most of the metabolism of eteplirsen is done through the kidneys.
  • Following single or multiple IV infusion, the peak plasma concentrations (Cmax) of eteplirsen occurred near the end of infusion and plasma concentration-time profiles of eteplirsen were generally similar and showed multi-phasic decline; the majority of drug elimination occurred within 24 hours.
  • Plasma protein binding of eteplirsen in human is relatively low, ranging 6.1~16.5% and is independent of concentration studied.

Nature and sequence of oligo and target[edit]

Eteplirsen is a morpholino phosphorodiamidate antisense oligomer.

20% G,
43% CG,
Predicted Tm: 88.9 °C at 10 µM oligo.




  1. ^ a b c Cirak, Sebahattin; Arechavala-Gomeza, Virginia; Guglieri, Michela; Feng, Lucy; Torelli, Silvia; Anthony, Karen; Abbs, Stephen; Garralda, Maria Elena; Bourke, John; Wells, Dominic J; Dickson, George; Wood, Matthew JA; Wilton, Steve D; Straub, Volker; Kole, Ryszard; Shrewsbury, Stephen B; Sewry, Caroline; Morgan, Jennifer E; Bushby, Kate; Muntoni, Francesco (2011). "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". The Lancet. 378 (9791): 595–605. PMC 3156980Freely accessible. PMID 21784508. doi:10.1016/S0140-6736(11)60756-3. Lay summaryNHS Choices (July 25, 2011). 
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  3. ^ "Railroading at the FDA" (PDF). Nature Biotechnology. 34 (11): 1078. November 2016. doi:10.1038/nbt.3733. Retrieved 29 November 2016. 
  4. ^ Kounang, Nadia (4 October 2016). "The families that fought for controversial new drug". CNN. Retrieved 29 November 2016. 
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  6. ^ Anthony, Karen; Feng, Lucy; Arechavala-Gomeza, Virginia; Guglieri, Michela; Straub, Volker; Bushby, Katherine; Cirak, Sebahattin; Morgan, Jennifer; Muntoni, Francesco (17 Oct 2012). "Exon Skipping Quantification by qRT-PCR in Duchenne Muscular Dystrophy Patients Treated with the Antisense Oligomer Eteplirsen". Hum Gene Ther Methods. 23 (5): 336–45. PMID 23075107. doi:10.1089/hgtb.2012.117. 
  7. ^ Moulton, HM; Moulton, JD (17 Feb 2010). "Morpholinos and Their Peptide Conjugates: Therapeutic Promise and Challenge for Duchenne Muscular Dystrophy". Biochim Biophys Acta. 1798 (12): 2296–303. PMID 20170628. doi:10.1016/j.bbamem.2010.02.012. 
  8. ^ a b c d
  9. ^
  10. ^ a b Mendell, Jerry; Rodino-Klapac, Louise R; Sahenk, Zarife; Roush, Kandice; Bird, Loren; Lowes, Linda P; Alfano, Lindsay; Gomez, Ann Maria; Lewis, Sarah; Kota, Janaiah; Malik, Vinod; Shontz, Kim; Walker, Christopher M; Flanigan, Kevin M; Kean, John R; Allen, Hugh D; Shilling, Chris; Melia, Kathleen R; Sazani, Peter; Saoud, Jay B; Kaye, Edward M; Kaye, Edward M. (2013). "Eteplirsen for the treatment of duchenne muscular dystrophy". Ann. Neurol. 74 (5): 637–647. doi:10.1002/ana.23982. 
  11. ^ Gary Roper, Manager Clinical Research Governance Organisation, Imperial College London. "Safety and Efficacy Study of Antisense Oligonucleotides in Duchenne Muscular Dystrophy". US Government, NIH. Retrieved 30 October 2012. 
  12. ^ Kinali, M; Arechavala-Gomeza, V; Feng, L; Cirak, S; Hunt, D; Adkin, C; Guglieri, M; Ashton, E; Abbs, S; Nihoyannopoulos, P; Garralda, ME; Rutherford, M; McCulley, C; Popplewell, L; Graham, IR; Dickson, G; Wood, MJ; Wells, DJ; Wilton, SD; Kole, R; Straub, V; Bushby, K; Sewry, C; Morgan, JE; Muntoni, F (25 Aug 2009). "Local restoration of dystrophin expression with the morpholino oligomer AVI-4658 in Duchenne muscular dystrophy: A single-blind, placebo-controlled, dose-escalation, proof-of-concept study". Lancet Neurol. 8 (10): 918–28. PMC 2755039Freely accessible. PMID 19713152. doi:10.1016/S1474-4422(09)70211-X. 
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  17. ^ FDA rejects BioMarin's muscle wasting drug; Sarepta drug in focus. Jan 2016
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  20. ^ Column: To appease a patient lobby, did the FDA approve a $300,000 drug that doesn't work? Michael Hiltzik, Los Angeles Times, October 28, 2016