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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Associated Conditions
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

TargetActionsOrganism
ADMD-001 gene (exon 51 target site)
binding
Humans
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

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Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
Exondys 51Injection50 mg/1mLIntravenousSarepta Therapeutics, Inc.2016-09-19Not applicableUS flag
Exondys 51Injection50 mg/1mLIntravenousSarepta Therapeutics, Inc.2016-09-19Not applicableUS flag

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
  1. 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]
  2. 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]
  3. 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]
  4. FDA Approved Drug Products: EXONDYS 51 (eteplirsen) injection, for intravenous use [Link]
KEGG Drug
D09900
PubChem Substance
347910319
RxNav
1810569
ChEMBL
CHEMBL2108278
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Eteplirsen

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3CompletedTreatmentDuchenne's Muscular Dystrophy (DMD)1
3RecruitingTreatmentDuchenne's Muscular Dystrophy (DMD)1
2Active Not RecruitingTreatmentDuchenne's Muscular Dystrophy (DMD)1
2CompletedTreatmentDuchenne's Muscular Dystrophy (DMD)5
2Enrolling by InvitationTreatmentDuchenne's Muscular Dystrophy (DMD)1
1, 2CompletedTreatmentDuchenne's Muscular Dystrophy (DMD)2

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
InjectionIntravenous50 mg/1mL
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US9018368No2015-04-282025-06-28US flag
US9416361No2016-08-162021-05-04US flag
US9506058No2016-11-292034-03-14US flag
US8486907No2013-07-162025-06-28US flag
US9243245No2016-01-262028-10-27US flag
US10364431No2019-07-302034-03-14US flag
US10337003No2019-07-022034-03-14US flag
USRE47751No2019-12-032025-06-28US flag
USRE47769No2019-12-172025-06-28US flag
US10533174No2020-01-142021-05-04US flag
US10781451No2020-09-222025-06-28US flag
USRE48468No2021-03-162028-10-27US flag

Properties

State
Solid
Experimental Properties
Not Available

Targets

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Kind
Nucleotide
Organism
Humans
Pharmacological action
Yes
Actions
Binding
References
  1. 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]
  2. 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