Safety and pharmacokinetic profile of eteplirsen, SRP-4045, and SRP-4053, three phosphorodiamidate morpholino oligomers (PMOs) for the treatment of patients with Duchenne muscular dystrophy (DMD)

Eteplirsen, SRP-4045 and SRP-4053 are three PMOs developed as treatments for DMD. DMD is mostly caused by mutations in the dystrophin gene that lead to a reading frame shift and premature translation termination. PMOs promote exon skipping during splicing of dystrophin pre-mRNA, restoring the reading frame and translation of internally truncated, but functional dystrophin protein. Eteplirsen, SRP-4045, and SRP-4053 are intended to treat patients with mutations amenable to skipping exon 51, 45 and 53, respectively. IND enabling preclinical studies have been completed for eteplirsen, SRP-4045, and SRP-4053. In vitro metabolism data and PK profiles in animals were similar for all three PMOs. No adverse responses were detected in safety pharmacology studies in non-human primates (NHPs). Genotoxicity studies were negative. NHPs given 12 weekly IV doses up to 320 mg/kg showed no significant sequence-specific toxicities. A clinical study of eteplirsen with doses of 30 and 50 mg/kg/wk reported no clinically significant treatment-related adverse events through 120 weeks of treatment. A few cases of transient, mild urine protein elevation resolved without intervention or drug interruption and one femur fracture was determined to be treatment-unrelated. There were no hospitalizations, discontinuations, or clinically significant treatment-related changes for lab parameters, including liver enzymes, kidney function, coagulation, or platelet counts. Plasma Cmax and AUC increased proportionally with dose, and half-life was approximately 3 h with no plasma accumulation observed. The consistent preclinical profiles and lack of 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.