EXONDYS 51 (Eteplirsen) intravenous injection

Sarepta Therapeutics, Inc. Cambridge, MA, USA

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INDICATION: Treatment of Duchenne muscular dystrophy (DMD) in patients who have a confirmed mutation of the DMD gene that is amenable to exon 51 skipping. Approved under accelerated approval based on an increase in dystrophin in skeletal muscle observed in some patients treated with EXONDYS 51

Mechanism of Action Binds to exon 51 of dystrophin pre-mRNA (messenger ribonucleic acid), 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.
Pharmacodynamics (PD) All EXONDYS 51 treated patients evaluated (n=36) were found to produce mRNA for a truncated dystrophin protein by reverse transcription polymerase chain reaction.

 In Study 2, the average dystrophin protein level in muscle tissue after 180 weeks of treatment with EXONDYS 51 was 0.93% of normal (i.e., 0.93% of the dystrophin level in healthy subjects). Because of insufficient information on dystrophin protein levels before treatment with EXONDYS 51 in Study 1, it is not possible to estimate dystrophin production in response to EXONDYS 51 in Study 1.

 In Study 3, the average dystrophin protein level was 0.16% of normal before treatment and 0.44% of normal after 48 weeks of treatment with EXONDYS 51. The median increase in truncated dystrophin in Study 3 was 0.1%.           

Pharmacokinetics (PK) Single or multiple intravenous infusions lead to the peak plasma concentrations (Cmax) of eteplirsen occurring 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).

Following single or multiple intravenous infusions 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 Cmax and AUC range from 20 to 55%, respectively.

Plasma protein binding (in vitro) in human ranges between 6 to 17%. The mean apparent volume of distribution (Vss)  was 600 mL/kg following weekly intravenous infusion of EXONDYS 51 at 30 mg/kg.

 Total clearance is 339 mL/hr/kg following 12 weeks of therapy with 30 mg/kg/week. Renal clearance accounts for approximately two-thirds of the administered dose within 24 hours of intravenous administration.

 Elimination half-life (t1/2) is 3 to 4 hours. 

PK-PD Analysis Not reported.
Population PK Not reported.
 Specific Populations  Effect of age (65 years or older), sex, race or renal/hepatic Impairment was not reported.
 Drug Interactions  In vitro studies showed that eteplirsen did not significantly inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A4/5. Eteplirsen did not induce CYP2B6 or CYP3A4, and induction of CYP1A2 was substantially less than the prototypical inducer, omeprazole. Eteplirsen was not a substrate nor did it have any major inhibitory potential for any of the key human transporters tested (OAT1, OAT3, OCT1, OCT2, OATP1B1, OATP1B3, P-gp, BCRP, MRP2 and BSEP). Based on in vitro data on plasma protein binding, CYP or drug transporter interactions, and microsomal metabolism, eteplirsen is expected to have a low potential for drug-drug interactions in humans.
 Source   http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/206488lbl.pdf







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