Eteplirsen
Identification
- Summary
Eteplirsen is an antisense oligonucleotide used to treat Duchenne muscular dystrophy (DMD) in patients with a confirmed mutation of the DMD gene that is amenable to exon 51 skipping.
- Brand Names
- Exondys
- Generic Name
- Eteplirsen
- DrugBank Accession Number
- DB06014
- Background
Eteplirsen is a synthetic antisense oligonucleotide and a phosphorodiamidate morpholino oligomer. It consists of a six-membered morpholino ring replacing the five-membered ribofuranosyl rings found in natural DNA and RNA.4
Duchenne muscular dystrophy is a rare genetic disorder characterized by progressive muscle deterioration and premature death most commonly due to respiratory or cardiac complications.3 It is caused by loss-of-function mutations in the DMD gene coding for dystrophin, an essential protein involved in maintaining the structural integrity and function of muscle fibres. Eteplirsen was first approved by the FDA in September 2016 for the treatment of Duchenne muscular dystrophy (DMD) in patients with a confirmed mutation of the DMD gene, which codes for dystrophin, that is amenable to exon 51 skipping. Eteplirsen directly works on the DMD gene to promote dystrophin production. Eteplirsen was the first treatment for DMD approved by the FDA.2
- Type
- Biotech
- Groups
- Approved, Investigational
- Biologic Classification
- Gene Therapies
Antisense oligonucleotides - Synonyms
- (P-deoxy-P-(dimethylamino)](2',3'-dideoxy-2',3'-imino-2',3'-seco)(2'a→5')(C-m5U-C-C-A-A-C-A-m5U-C-A-A-G-G-A-A-G-A-m5U-G-G-C-A-m5U-m5U-m5U-C-m5U-A-G),5'-(P-(4-((2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)carbonyl)-1-piperazinyl)-N,N-dimethylphosphonamidate) RNA
- Eteplirsen
- External IDs
- AVI-4658
Pharmacology
- Indication
Eteplirsen 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 eteplirsen.4
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Indication Type Indication Combined Product Details Approval Level Age Group Patient Characteristics Dose Form Management of Duchenne muscular dystrophy •••••••••••• ••••••••• •••••••• •• •••• •• •••••••• ••••••••• - Contraindications & Blackbox Warnings
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- Pharmacodynamics
Eteplirsen is a disease-modifying agent that aims to slow down the progression of Duchenne muscular dystrophy (DMD), but does not cure the disease itself.1 While it is unclear how to properly estimate dystrophin production in muscle tissue in clinical studies, eteplirsen increases the levels of dystrophin protein in patients with DMD. Patients treated with eteplirsen produce mRNA for a truncated dystrophin protein.4 Internally truncated dystrophin protein is often found in patients with Becker muscular dystrophy, a less severe form of dystrophinopathy caused by defective DMD gene variants leading to in-frame mutations and production of functional, truncated versions of dystrophin.2 Eteplirsen aims to render the disease less severe and attenuate the rate of functional decline.3
- Mechanism of action
Dystrophin is a membrane-associated protein that links cytoskeletal actin in muscle fibres with the surrounding extracellular matrix by forming a network with sarcolemmal glycoproteins. This linkage strengthens muscle structure during stressful contraction and relaxation cycles. The loss of dystrophin leads to mechanical damage of muscle fibres and eventually muscle degeneration. Duchenne muscular dystrophy (DMD) is caused by deletion mutations in exons 43 to 55 of the DMD gene coding for dystrophin, which is the largest known human gene. These mutations disrupt the open reading frame and cease the normal production of dystrophin.2 About 60% of DMD cases are caused by deletions of at least one exon in DMD 2 and about 13-14% of patients with DMD have exon 51 amenable deletions.1,2 Deletions ending at exon 50 and starting at exon 52 represents the largest group of patients to which single exon skipping is applicable.2
Eteplirsen mediates its effect by inducing exon skipping in defective gene variants. Eteplirsen selectively binds to exon 51 of dystrophin pre-mRNA, excluding this exon during mRNA processing in patients with genetic mutations that are amenable to exon 51 skipping. Through exon skipping, eteplirsen restores the open reading frame of the DMD gene and allows the production of functional dystrophin.1,4
Target Actions Organism ADMD-001 gene (exon 51 target site) bindingHumans - Absorption
Following single or multiple intravenous infusions, the peak plasma concentrations (Cmax) of eteplirsen occurred near the end of infusion (i.e., 1.1 to 1.2 hours across a dose range of 0.5 mg/kg/week to 50 mg/kg/week). The inter-subject variability for eteplirsen Cmax and AUC range from 20 to 55%.4
- Volume of distribution
Following weekly intravenous infusion of eteplirsen at 30 mg/kg, the mean apparent volume of distribution (Vss) was 600 mL/kg. No accumulation is seen with once-weekly dosing.4 Eteplirsen is not widely distributed.2
- Protein binding
In vitro, eteplirsen is 6 to 17% bound to plasma proteins.4
- Metabolism
Eteplirsen does not undergo hepatic metabolism.4 As with other phosphorodiamidate morpholino oligomers, it is not favorable to metabolism.2
- Route of elimination
Renal clearance of eteplirsen accounts for approximately 67-70% of the administered dose within 24 hours of intravenous administration.2,4
- Half-life
The elimination half-life (t1/2) of eteplirsen was three to four hours.4
- Clearance
The total clearance of eteplirsen was 339 mL/hr/kg following 12 weeks of therapy with 30 mg/kg/week.4
- Adverse Effects
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- Toxicity
There is no information on the LD50 of eteplirsen. There is no experience with overdose of eteplirsen.4
- Pathways
- Not Available
- Pharmacogenomic Effects/ADRs
- Not Available
Interactions
- Drug Interactions
- This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.Not Available
- Food Interactions
- No interactions found.
Products
- Drug product information from 10+ global regionsOur datasets provide approved product information including:dosage, form, labeller, route of administration, and marketing period.Access drug product information from over 10 global regions.
- Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Exondys 51 Injection 50 mg/1mL Intravenous Sarepta Therapeutics, Inc. 2016-09-19 Not applicable US Exondys 51 Injection 50 mg/1mL Intravenous Sarepta Therapeutics, Inc. 2016-09-19 Not applicable US
Categories
- ATC Codes
- M09AX06 — Eteplirsen
- Drug Categories
- Classification
- Not classified
- Affected organisms
- Not Available
Chemical Identifiers
- UNII
- AIW6036FAS
- CAS number
- 1173755-55-9
References
- General References
- Mendell JR, Rodino-Klapac LR, Sahenk Z, Roush K, Bird L, Lowes LP, Alfano L, Gomez AM, Lewis S, Kota J, Malik V, Shontz K, Walker CM, Flanigan KM, Corridore M, Kean JR, Allen HD, Shilling C, Melia KR, Sazani P, Saoud JB, Kaye EM: Eteplirsen for the treatment of Duchenne muscular dystrophy. Ann Neurol. 2013 Nov;74(5):637-47. doi: 10.1002/ana.23982. Epub 2013 Sep 10. [Article]
- Lim KR, Maruyama R, Yokota T: Eteplirsen in the treatment of Duchenne muscular dystrophy. Drug Des Devel Ther. 2017 Feb 28;11:533-545. doi: 10.2147/DDDT.S97635. eCollection 2017. [Article]
- Khan N, Eliopoulos H, Han L, Kinane TB, Lowes LP, Mendell JR, Gordish-Dressman H, Henricson EK, McDonald CM: Eteplirsen Treatment Attenuates Respiratory Decline in Ambulatory and Non-Ambulatory Patients with Duchenne Muscular Dystrophy. J Neuromuscul Dis. 2019;6(2):213-225. doi: 10.3233/JND-180351. [Article]
- FDA Approved Drug Products: EXONDYS 51 (eteplirsen) injection, for intravenous use [Link]
- External Links
- KEGG Drug
- D09900
- PubChem Substance
- 347910319
- 1810569
- ChEMBL
- CHEMBL2108278
- RxList
- RxList Drug Page
- Drugs.com
- Drugs.com Drug Page
- Wikipedia
- Eteplirsen
Clinical Trials
- Clinical Trials
Phase Status Purpose Conditions Count 3 Active Not Recruiting Treatment Duchenne Muscular Dystrophy (DMD) 1 3 Completed Treatment Duchenne Muscular Dystrophy (DMD) 1 2 Completed Treatment Duchenne Muscular Dystrophy (DMD) 6 2 Terminated Treatment Duchenne Muscular Dystrophy (DMD) 1 1, 2 Completed Treatment Duchenne Muscular Dystrophy (DMD) 2
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Injection Intravenous 50 mg/1mL - Prices
- Not Available
- Patents
Patent Number Pediatric Extension Approved Expires (estimated) Region US9018368 No 2015-04-28 2025-06-28 US US9416361 No 2016-08-16 2021-05-04 US US9506058 No 2016-11-29 2034-03-14 US US8486907 No 2013-07-16 2025-06-28 US US9243245 No 2016-01-26 2028-10-27 US US10364431 No 2019-07-30 2034-03-14 US US10337003 No 2019-07-02 2034-03-14 US USRE47751 No 2019-12-03 2025-06-28 US USRE47769 No 2019-12-17 2025-06-28 US US10533174 No 2020-01-14 2021-05-04 US US10781451 No 2020-09-22 2025-06-28 US USRE48468 No 2021-03-16 2028-10-27 US
Properties
- State
- Solid
- Experimental Properties
- Not Available
Targets
References
- Mendell JR, Rodino-Klapac LR, Sahenk Z, Roush K, Bird L, Lowes LP, Alfano L, Gomez AM, Lewis S, Kota J, Malik V, Shontz K, Walker CM, Flanigan KM, Corridore M, Kean JR, Allen HD, Shilling C, Melia KR, Sazani P, Saoud JB, Kaye EM: Eteplirsen for the treatment of Duchenne muscular dystrophy. Ann Neurol. 2013 Nov;74(5):637-47. doi: 10.1002/ana.23982. Epub 2013 Sep 10. [Article]
- Lim KR, Maruyama R, Yokota T: Eteplirsen in the treatment of Duchenne muscular dystrophy. Drug Des Devel Ther. 2017 Feb 28;11:533-545. doi: 10.2147/DDDT.S97635. eCollection 2017. [Article]
Drug created at November 18, 2007 18:29 / Updated at February 01, 2022 02:38