Identification

Name
Eteplirsen
Accession Number
DB06014
Type
Biotech
Groups
Approved, Investigational
Biologic Classification
Gene Therapies
Antisense oligonucleotides
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]

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
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Exondys 51Injection50 mg/1mLIntravenousSarepta Therapeutics, Inc.2016-09-19Not applicableUs
Exondys 51Injection50 mg/1mLIntravenousSarepta Therapeutics, Inc.2016-09-19Not applicableUs
Categories
UNII
AIW6036FAS
CAS number
1173755-55-9

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
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)

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

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
Not Available
Food Interactions
Not Available

References

General References
  1. 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]
  2. 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]
  3. 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
ChEMBL
CHEMBL2108278
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Eteplirsen
FDA label
Download (197 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1, 2CompletedTreatmentDuchenne's Muscular Dystrophy (DMD)2
2Active Not RecruitingTreatmentDuchenne's Muscular Dystrophy (DMD)2
2CompletedTreatmentDuchenne's Muscular Dystrophy (DMD)1
2CompletedTreatmentMuscular Dystrophy, Duchenne1
2RecruitingTreatmentDuchenne's Muscular Dystrophy (DMD)1
3Active Not RecruitingTreatmentDuchenne's Muscular Dystrophy (DMD)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
InjectionIntravenous50 mg/1mL
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US9018368No2015-04-282025-06-28Us
US9416361No2016-08-162021-05-04Us
US9506058No2016-11-292034-03-14Us
US8486907No2013-07-162025-06-28Us
US9243245No2016-01-262028-10-27Us

Properties

State
Solid
Experimental Properties
Not Available

Taxonomy

Classification
Not classified

Targets

Kind
Nucleotide
Organism
Human
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. [PubMed:23907995]

Drug created on November 18, 2007 11:29 / Updated on November 02, 2018 06:13