Eteplirsen

Structural formula
General
Non-proprietary name	Eteplirsen
other names	(P-deoxy-P- (dimethylamino)] (2 ', 3'-dideoxy-2', 3'-imino-2 ', 3'-seco) (2'a → 5') (C-m5U-CCAACA -m5U-CAAGGAAGA-m5U-GGCA-m5U-m5U-m5U-C-m5U-AG), 5 '- (P- (4 - ((2- (2- (2-hydroxyethoxy) ethoxy) ethoxy) carbonyl) - 1-piperazinyl) -N, N-dimethylphosphonamidate) RNA
Molecular formula	C 365 H 569 N 177 O 122 P 30
External identifiers / databases
CAS number 1173755-55-9 ChemSpider 34983391 DrugBank DB06014 Wikidata Q5402585
Drug information
ATC code	M09 AX06
properties
Molar mass	10305.738 g · mol -1
safety instructions
Please note the exemption from the labeling requirement for drugs, medical devices, cosmetics, food and animal feed GHS hazard labeling no classification available
As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Eteplirsen (trade name: Exondys 51 ; manufacturer: Sarepta Therapeutics Inc. ) is a drug from the group of antisense therapeutics that is used to treat Duchenne muscular dystrophy (DMD) .

In the United States received Exondys 51 in September 2016 accelerated approval ( fast track ) by the US Food and Drug Administration (FDA) . Approval was refused in Europe. A comprehensive overview of the drug and its clinical studies was published in early 2017 in the online-only journal Drug Design, Development and Therapy .

Duchenne muscular dystrophy (DMD)

→ Main article : Duchenne muscular dystrophy

Duchenne muscular dystrophy is the most common hereditary muscular disease in childhood. It occurs at a frequency of around 1: 5000 per male newborn and thus falls by definition into the category of rare diseases ("orphan diseases "). Due to the x-linked inheritance, almost only boys are affected. In about 1/3 of all cases, however, the disease is also caused by a spontaneous mutation of the dystrophin gene. The disease begins in infancy with weakness in the pelvic and thigh muscles, progresses rapidly and ends, usually in young adults, always fatal as soon as the heart and respiratory muscles are broken down.

A cure is not yet possible. Eteplirsen is the first drug approved for the treatment of DMD - initially only in the USA. Eteplirsen targets mutations in a region that are involved in 13% of DMD cases.

application areas

Eteplirsen is approved for the treatment of Duchenne muscular dystrophy (DMD). The drug is administered intravenously or subcutaneously .

Mechanism of action

Duchenne muscular dystrophy is caused by mutations in the gene for dystrophin . These are often deletions , for example in exon 50. Dystrophin is essential for the function of the muscle .

Eteplirsen is a phosphorodiamidate morpholino oligomer (PMO) that selectively binds to exon 51 of the pre-mRNA . It is an antisense oligonucleotide with a high molecular weight. The sequence is complementary to the section in the pre-mRNA. Eteplirsen is an RNA analogue that contains a morpholine ring instead of ribose and a phosphorodiamidate linker instead of the phosphodiester.

Eteplirsen restores the protein expression of the dystrophin protein by skipping or removing exon 51 in the pre-mRNA during splicing ( exon skipping ). As a result, exon 51 is no longer contained in the mRNA and is not translated . The body is now able to produce a shortened but partially functional protein. Skipping exon 51 changes the downstream reading frame of dystrophin.

It does not cure the disease, but it does reduce the severity.

Admission and Studies

Several clinical studies have been conducted to test eteplirsen: of these

• one in the UK with local injection in the foot,
• one in the UK with systemic injection at low doses and
• one in the US at higher systemic doses that evolved into a rollover extension study.

In the phase II study with 12 boys, dystrophin production was increased in 72% of the participants. The question arose whether an increase in the dose - which is possible due to the lower toxicity of Eteplirsen compared to Drisapersen - would benefit the non- responders and whether this could lead to increased side effects. A phase III study has started in the USA.

In a UK study ( AVI-4658 ) in 2011, Eteplirsen was given to 19 children with Duchenne muscular dystrophy. The researchers found that higher doses of the drug led to an increase in dystrophin. They conclude that drugs that "skip" the body in this way could be used to treat about 83% of cases of Duchenne muscular dystrophy. Eteplirsen only targets mutations in one region that is affected 13% of the time. This study demonstrated the potential of this approach to increase dystrophin levels in the short term. The main objective of the study was to determine the appropriate dosage of the drug, so the safety profile and effects of the drug need to be confirmed in larger, longer-term studies, especially since patients will have to take it for the rest of their lives (or until a better treatment becomes available is).

So far, approval has only been granted for the USA. Approval was refused in Europe.

In July 2012, the company that developed Eteplirsen changed the name from AVI BioPharma (previously AntiVirals) to Sarepta Therapeutics. As a result, various studies are running on AVI.

Web links

• Scientific assessment report on Exondys of the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency of September 12, 2018 (PDF, English)

See also

• RNA interference

Individual evidence

1. ↑ This substance has either not yet been classified with regard to its hazardousness or a reliable and citable source has not yet been found.
2. ↑ ^{a b c d} FDA grants accelerated approval to first drug for Duchenne muscular dystrophy , PM FDA dated September 19, 2016, accessed on July 3, 2018
3. ↑ ^{a b} Rejected human medicinal products in the EU Community Register , accessed on March 5, 2019.
4. ↑ Kenji Rowel Q Lim et al .: Eteplirsen in the treatment of Duchenne muscular dystrophy . In: Drug Design, Development and Therapy . 11, February 2017, pp. 533-545. doi : 10.2147 / DDDT.S97635 .
5. ↑ ^{a b c} Sebahattin Cirak et al .: 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 . In: The Lancet . 378, No. 9791, 2011, pp. 595-605. doi : 10.1016 / S0140-6736 (11) 60756-3 . PMID 21784508 . PMC 3156980 (free full text).
6. ↑ Karen Anthony et al .: Exon Skipping Quantification by qRT-PCR in Duchenne Muscular Dystrophy Patients Treated with the Antisense Oligomer Eteplirsen . In: Hum Gene Ther Methods. . 23, No. 5, October 1, 2012, pp. 336-45. doi : 10.1089 / hgtb.2012.117 . PMID 23075107 .
7. ^ Gary Roper, Manager Clinical Research Governance Organization, Imperial College London: Safety and Efficacy Study of Antisense Oligonucleotides in Duchenne Muscular Dystrophy . In: ClinicalTrials.gov . US Government, NIH.
8. ↑ Maria Kinali et al .: 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 . In: Lancet Neurol. . 8, No. 10, August 25, 2009, pp. 918-28. doi : 10.1016 / S1474-4422 (09) 70211-X . PMID 19713152 . PMC 2755039 (free full text).
9. Jump up ↑ Professor Francesco Muntoni, University College of London Institute of Child Health: Dose-Ranging Study of AVI-4658 to Induce Dystrophin Expression in Selected Duchenne Muscular Dystrophy (DMD) Patients . In: ClinicalTrials.gov . US Government, NIH.
10. ↑ Sarepta Therapeutics: Efficacy Study of AVI-4658 to Induce Dystrophin Expression in Selected Duchenne Muscular Dystrophy Patients . In: ClinicalTrials.gov . US Government, NIH.
11. ↑ Jerry Mendell et al .: Eteplirsen for the treatment of duchenne muscular dystrophy . In: Ann. Neurol. . 74, No. 5, 2013, pp. 637-647. doi : 10.1002 / ana.23982 .
12. ↑ Sarepta Therapeutics: Efficacy, Safety, and Tolerability Rollover Study of Eteplirsen in Subjects With Duchenne Muscular Dystrophy . In: ClinicalTrials.gov . US Government, NIH. Retrieved October 30, 2012.
13. ^ Sarepta Therapeutics: Confirmatory Study of Eteplirsen in DMD Patients (PROMOVI) . In: ClinicalTrials.gov . US Government, NIH.
14. ↑ A. Mende: Approval for agents against Duchenne dystrophy , Pharmazeutische Zeitung, edition 39/2016.
15. ↑ Exondys on the European Medicines Agency website
16. ↑ FAQs , Company WebSite, accessed July 3, 2018

This article is about a health issue. It is not used for self-diagnosis and does not replace a diagnosis by a doctor. Please note the information on health issues !