PP09.5 – 2350: Pharmacokinetic evaluation of eteplirsen, SRP-4045, and SRP-4053; Three phosphorodiamidate morpholino oligomers (PMOs) for the treatment of patients with Duchenne muscular dystrophy (DMD)

Abstract

Background DMD is a rare, X-linked recessive, degenerative neuromuscular disorder caused by mutations in the dystrophin gene. The most prevalent mutations result in a reading frame shift and premature translation termination, resulting in a lack of dystrophin, a protein that plays a key structural role in muscle fiber function. Exon-skipping PMOs direct alternative splicing of the dystrophin pre-mRNA to restore the mRNA reading frame and enable translation of an internally truncated yet functional dystrophin protein. Eteplirsen, an investigational exon-skipping PMO, has been dosed at up to 50 mg/kg/wk for over 3 years in a clinical study with no reported clinically significant treatment-related adverse events. Preclinical analysis enables comparison of the pharmacokinetic properties of eteplirsen, SRP-4045, and SRP-4053, three PMOs with specific sequences developed to treat patients with mutations amenable to skipping exon 51, 45 and 53, respectively. Methods Studies conducted to evaluate the in vitro pharmacokinetic properties of eteplirsen, SRP-4045 and SRP-4053 included analysis of plasma protein binding and metabolic stability in hepatic microsomes of mice, rats, monkeys, and humans. Induction and inhibition of cytochrome P450 isoenzymes were also assessed. Results Pharmacokinetic profiles for the three PMOs were similar across species. All three compounds showed comparable Cmax, AUC, and clearance, and displayed similar dose proportionality across the three doses examined (5, 40, and 320 mg/kg). Each exhibited low protein binding in all species, no evidence of in vitro metabolism by hepatic microsomes, no extensive inhibition of the major drug metabolizing cytochrome P450 isoenzymes CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP3A4/5, and no induction of CYP1A2, CYP2B6, or CYP3A4 at biologically relevant concentrations. Conclusions The consistent preclinical profiles and lack of any significant, sequence-specific toxicities for eteplirsen, SRP-4045, and SRP-4053 demonstrate PMOs to be a well-tolerated therapeutic class, with potential applications in a wide variety of disease indications.