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

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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

Indication Type	Indication	Combined Product Details	Approval Level	Age Group	Patient Characteristics	Dose Form
Management of	Duchenne muscular dystrophy		••••••••••••		••••••••• •••••••• •• •••• •• ••••••••	•••••••••

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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)	binding	Humans

Absorption

Following single or multiple intravenous infusions, the peak plasma concentrations (C_max) 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 C_max 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

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
Exondys 51	Injection	50 mg/1mL	Intravenous	Sarepta Therapeutics, Inc.	2016-09-19	Not applicable

Categories

ATC Codes

M09AX06 — Eteplirsen

• M09AX — Other drugs for disorders of the musculo-skeletal system
• M09A — OTHER DRUGS FOR DISORDERS OF THE MUSCULO-SKELETAL SYSTEM
• M09 — OTHER DRUGS FOR DISORDERS OF THE MUSCULO-SKELETAL SYSTEM
• M — MUSCULO-SKELETAL SYSTEM

Drug Categories

• Antisense Oligonucleotides
• Morpholines
• Musculo-Skeletal System
• Nucleic Acids, Nucleotides, and Nucleosides
• Nucleotides
• Oligonucleotides
• Oxazines
• Polynucleotides

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]

External Links

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

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
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	2020-01-14	2021-05-04
US10781451	No	2020-09-22	2025-06-28
USRE48468	No	2021-03-16	2028-10-27

Properties

State

Solid

Experimental Properties

Not Available

Targets

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

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]

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Drug created at November 18, 2007 18:29 / Updated at February 01, 2022 02:38