Eteplirsen

Identification

Name

Eteplirsen

Accession Number

DB06014

Description

Eteplirsen is a phosphoramidite morpholino sequence complementary to a portion of exon 51. ¹ It exerts it's mechanism of action by forcing the exclusion of exon 51 from the mature DMD mRNA. ¹

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

External IDs

AVI-4658

Pharmacology

Indication

Eteplirsen is indicated for treatment of certain individuals with Duchenne muscular dystrophy (DMD). Its use is limited to those with a confirmed mutation of the DMD gene which would benefit from exon 51 skipping. Based on clinical studies showing increased dystrophin production in skeletal muscle in some patients given this drug, the above indication was approved under accelerated approval. Further confirmatory trials are required to demonstrate clinical benefit of eteplirsen.

Associated Conditions

Duchenne's Muscular Dystrophy (DMD)

Contraindications & Blackbox Warnings

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Pharmacodynamics

The defining characteristic of DMD is lack of dystrophin, which is a protein that plays a vital role in maintaining muscle cell membrane integrity. (2) This is caused by a mutation in the DMD gene which leads to disruption of the translational reading frame, and ultimately in a non-functional protein. (2) Eteplirsen, is a targeted oligonucleotide that causes exon skipping of exon 51 and restores the translational reading frame. (2) The expected result is production of an internally deleted but functional dystrophin protein. (2)
Three clinical studies were done to evaluate eteplirsen. All patients in studies had a confirmed mutation of the DMD gene susceptible to exon 51 skipping. All patients treated with the drug produced messenger ribonucleic acid (mRNA) coding for an internally truncated dystrophin protein. In study 3, after 48 weeks of treatment with eteplirsen, the average dystrophin protein level was 0.44% of normal (what would be found in a healthy subject) compared to 0.16% of normal prior to treatment. There was a median increase of 0.1% in truncated dystrophin.

Mechanism of action

Eteplirsen, is a targeted oligonucleotide that causes exon skipping of exon 51 and restores the translational reading frame. (2) The expected result is production of an internally deleted but functional dystrophin protein. (2)

Target	Actions	Organism
ADMD-001 gene (exon 51 target site)	binding	Humans

Absorption

Not Available

Volume of distribution

Mean apparent volume of distribution = 600 mL/kg (value found following weekly intravenous infusion at a dose of 30mg/kg)

Protein binding

Studies suggest that plasma protein binding of eteplirsen is 6-17% in humans.

Metabolism

Metabolism of eteplirsen does not appear to occur in human hepatic microsomes.

Route of elimination

Two-thirds of eteplirsen is renally eliminated within 24 hours of intravenous administration.

Half-life

Mean half-life (dose of 30 mg/kg) = 3.3 hours, and mean half-life (dose of 50 mg/kg) = 3.2 hours (3)

Clearance

The kidneys are responsible for 65-70% of total eteplirsen clearance. (3) After 12 weeks of treatment at a dose of 30 mg/kg/week, total clearance was found to be 339 mL/hr/kg.

Adverse Effects

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Toxicity

Potential adverse effects of eteplirsen were determined in 2 studies: 1. A 24 week double-blind, placebo-controlled study, 2. An open label extension following the first study. In study 1, the following adverse effects occurred more frequently in 2 or more patients receiving eteplirsen compared to placebo: Balance disorder (38%), vomiting (38%), contact dermatitis (25%). These percentages represent crude frequencies due to the small sample of patients studied; therefore, they may not be representative of the general population. All patients in study 1 continued to participate in study 2. The following adverse effects occurred at a rate ≥10% among the 88 patients receiving ≥30 mg/kg/week of eteplirsen for up to 208 weeks in study 2: vomiting, contusion, excoriation, arthralgia, rash, pain at catheter site, and upper respiratory tract infections. These adverse events also occurred more frequently in patients in study 2 compared to patients in study 1 on the same dose of eteplirsen. Facial flushing, transient erythema, and elevated temperature have been reported to occur on the days of eteplirsen infusion.

Affected organisms

Not Available

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: Not Available

Products

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Brand Name Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End
Unlock Additional Data
Exondys 51	Injection	50 mg/1mL	Intravenous	Sarepta Therapeutics, Inc.	2016-09-19	Not applicable
Exondys 51	Injection	50 mg/1mL	Intravenous	Sarepta Therapeutics, Inc.	2016-09-19	Not applicable

Additional Data Available

Application Number

Available for Purchase

A unique ID assigned by the FDA when a product is submitted for approval by the labeller.

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Product Code

Available for Purchase

A governmentally-recognized ID which uniquely identifies the product within its regulatory market.

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Chemical Identifiers

UNII: AIW6036FAS
CAS number: 1173755-55-9

References

General References

Miceli MC, Nelson SF: The case for eteplirsen: Paving the way for precision medicine. Mol Genet Metab. 2016 Jun;118(2):70-1. doi: 10.1016/j.ymgme.2016.04.001. Epub 2016 Apr 14. [PubMed:27102846]
Kole R, Krieg AM: Exon skipping therapy for Duchenne muscular dystrophy. Adv Drug Deliv Rev. 2015 Jun 29;87:104-7. doi: 10.1016/j.addr.2015.05.008. Epub 2015 May 14. [PubMed:25980936]
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. [PubMed:23907995]

External Links

KEGG Drug: D09900
PubChem Substance: 347910319
RxNav: 1810569
ChEMBL: CHEMBL2108278
RxList: RxList Drug Page
Drugs.com: Drugs.com Drug Page
Wikipedia: Eteplirsen

FDA label

Download (197 KB)

Clinical Trials

Clinical Trials

Phase	Status	Purpose	Conditions	Count
3	Completed	Treatment	Duchenne's Muscular Dystrophy (DMD)	1
3	Recruiting	Treatment	Muscular Dystrophy, Duchenne	1
2	Active Not Recruiting	Treatment	Duchenne's Muscular Dystrophy (DMD)	1
2	Completed	Treatment	Duchenne's Muscular Dystrophy (DMD)	3
2	Completed	Treatment	Muscular Dystrophy, Duchenne	1
2	Enrolling by Invitation	Treatment	Duchenne's Muscular Dystrophy (DMD)	2
1, 2	Completed	Treatment	Duchenne's 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)
Unlock Additional Data
US9018368	No	2015-04-28	2025-06-28
US9416361	No	2016-08-16	2021-05-04
US9506058	No	2016-11-29	2034-03-14
US8486907	No	2013-07-16	2025-06-28
US9243245	No	2016-01-26	2028-10-27
US10364431	No	2019-07-30	2034-03-14
US10337003	No	2019-07-02	2034-03-14
USRE47751	No	2019-12-03	2025-06-28
USRE47769	No	2019-12-17	2025-06-28
US10533174	No	2001-05-04	2021-05-04
US10781451	No	2005-06-28	2025-06-28

Additional Data Available

Filed On

Available for Purchase

The date on which a patent was filed with the relevant government.

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Properties

State: Solid
Experimental Properties: Not Available

Targets

Details1. DMD-001 gene (exon 51 target site)

Kind

Nucleotide

Organism

Humans

Pharmacological action

Yes

Actions

Binding

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. [PubMed:23907995]