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Clinical data
Trade namesExondys 51
Routes of
Intravenous infusion
ATC code
Legal status
Legal status
CAS Number
Chemical and physical data
Molar mass10305.738 g/mol

Eteplirsen (brand name Exondys 51) is a medication to treat, but not a cure, some types of Duchenne muscular dystrophy (DMD), caused by a specific mutation. Eteplirsen only targets specific mutations and thus is only useful in just over 1% of cases.[1]

After a 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 is expected to cost approximately $300,000.[4]

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;[5] 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.[6] 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.[7] The uncharged nature of the PMO helps make it resistant to biological degradation.[8] 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.[7][9]


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).[10] 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 effectiveness 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;.[11] 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.[12]

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

On January 22, 2016 the FDA Briefing Document containing information about eteplirsen 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:[7]

  • 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. ^ Scoto, M; Finkel, R; Mercuri, E; Muntoni, F (August 2018). "Genetic therapies for inherited neuromuscular disorders". The Lancet. Child & Adolescent Health. 2 (8): 600–609. doi:10.1016/S2352-4642(18)30140-8. PMID 30119719.
  2. ^ a b "FDA grants accelerated approval to first drug for Duchenne muscular dystrophy". Press Announcements. U.S. Food & Drug Administration. September 19, 2016. Retrieved September 19, 2016.
  3. ^ "Railroading at the FDA" (PDF). Nature Biotechnology. 34 (11): 1078. November 2016. doi:10.1038/nbt.3733. PMID 27824847. Retrieved 29 November 2016.
  4. ^ Kounang, Nadia (4 October 2016). "The families that fought for controversial new drug". CNN. Retrieved 29 November 2016.
  5. ^ 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. doi:10.1089/hgtb.2012.117. PMID 23075107.
  6. ^ 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. doi:10.1016/j.bbamem.2010.02.012. PMID 20170628.
  7. ^ a b c d
  8. ^ Leppert, Brian J.; Kole, Ryszard (2012-07-26). "Targeting mRNA Splicing as a Potential Treatment for Duchenne Muscular Dystrophy". Discovery Medicine. 14 (74): 59–69. PMID 22846203.
  9. ^ 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. PMID 23907995.
  10. ^ "FDA Accepts Sarepta's NDA for Eteplirsen". Rare Disease Report.
  11. ^ Pollack, Andrew (2016-04-25). "Advisers to F.D.A. Vote Against Duchenne Muscular Dystrophy Drug". The New York Times.
  12. ^ 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