Exon Skipping EXONDYS 51 (eteplirsen) for Treatment of Duchenne Muscular Dystrophy

EXONDYS 51 (eteplirsen) injection, for intravenous use

Eteplirsen is an antisense oligonucleotide of the phosphorodiamidate morpholino oligomer (PMO) subclass. PMOs are synthetic molecules in which the five-membered ribofuranosyl rings found in natural DNA and RNA are replaced by a six-membered morpholino ring. Each morpholino ring is linked through an uncharged phosphorodiamidate moiety rather than the negatively charged phosphate linkage that is present in natural DNA and RNA. Each phosphorodiamidate morpholino subunit contains one of the heterocyclic bases found in DNA (adenine, cytosine, guanine, or thymine). Eteplirsen contains 30 linked subunits. The molecular formula of eteplirsen is C364H569N177O122P30 and the molecular weight is 10305.7 daltons.

Mechanism of Action
 Eteplirsen is designed to bind to exon 51 of dystrophin pre-mRNA, resulting in exclusion of this exon during mRNA processing in patients with genetic mutations that are amenable to exon 51 skipping. Exon skipping is intended to allow for production of an internally truncated dystrophin protein.

All EXONDYS 51-treated patients evaluated (n=36) were found to produce messenger ribonucleic acid (mRNA) for a truncated dystrophin protein by reverse transcription polymerase chain reaction.

Following single or multiple intravenous infusions of EXONDYS 51 in male pediatric DMD patients, plasma concentration-time profiles of eteplirsen were generally similar and showed multi-phasic decline. The majority of drug elimination occurred within 24 hours. Approximate dose-proportionality and linearity in PK properties were observed following multiple-dose studies (0.5 mg/kg/week [0.017 times the recommended dosage] to 50 mg/kg/week [1.7 times the recommended dosage]). There was no significant drug accumulation following weekly dosing across this dose range. The inter-subject variability for eteplirsen Cmax and AUC range from 20 to 55%. Following single or multiple intravenous infusions of EXONDYS 51, 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). 

 In vitro investigation suggested that plasma protein binding of eteplirsen in human ranges between 6 to 17%. The mean apparent volume of distribution (Vss) of eteplirsen was 600 mL/kg following weekly intravenous infusion of EXONDYS 51 at 30 mg/kg. Twenty-four hours after the end of the infusion, mean concentrations of eteplirsen were 0.07% of Cmax. Accumulation of eteplirsen during once weekly dosing has not been observed.

The total clearance of eteplirsen was 339 mL/hr/kg following 12 weeks of therapy with 30 mg/kg/week. 

Eteplirsen did not appear to be metabolized by hepatic microsomes of any species tested, including humans. 

Renal clearance of eteplirsen accounts for approximately two-thirds of the administered dose within 24 hours of intravenous administration. Elimination half-life (t1/2) of eteplirsen was 3 to 4 hours 

Initial U.S. Approval: 2016

EXONDYS 51 is an antisense oligonucleotide 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 EXONDYS 51. A clinical benefit of EXONDYS 51 has not been established. Continued approval for this indication may be contingent upon verification of a clinical benefit in confirmatory trials. 

30 milligrams per kilogram of body weight once weekly.
Administer as an intravenous infusion over 35 to 60 minutes 
Dilution required prior to administration

100 mg/2 mL (50 mg/mL) in single-dose vial 
500 mg/10 mL (50 mg/mL) in single-dose vial 


The most common adverse reactions (incidence ≥35% and higher than placebo) were balance disorder and vomiting

Reference: FDA Package Insert

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