Director, Quantitative Clinical Pharmacology Sarepta Therapeutics, Inc. Collierville, Tennessee, United States
Background: Eteplirsen, golodirsen, and casimersen are phosphorodiamidate morpholino oligomers (PMOs) for the treatment of Duchenne muscular dystrophy (DMD) in patients with mutations amenable to 51, 53, and 45 exon skipping, respectively. Nonclinical studies have shown comparable drug metabolism and pharmacokinetic properties. Here, clinical pharmacology characteristics are compared. Methods: Drug disposition data from patients with DMD and healthy volunteers were used in the comparative analysis, including 6 eteplirsen, 3 golodirsen, and 3 casimersen studies. Noncompartmental analysis of plasma concentration and urine excretion profiles was performed; individual PK exposure parameters were summarized by age and dose group for each PMO. In vitro assays were performed to support specific clinical pharmacology evaluations. Results: In healthy volunteers, radiolabeled absorption, distribution, metabolism, and excretion studies showed complete recovery (≥99.2%) in urine for all PMOs over the 9-day period post drug administration. No metabolites from PMOs were identified in plasma or urine, suggesting no in vivo metabolism. Overall, the DDI liability of all 3 PMOs is low. In patients with DMD, the PMOs exhibited dose-proportional PK across studied doses (2–30mg/kg). Plasma concentration profiles and exposures were generally consistent across PMOs at the therapeutic 30 mg/kg dose. Eteplirsen 30 mg/kg plasma exposures were similar across the age range (6 mo–adolescent). tQT prolongation evaluation is ongoing; preliminary findings support low likelihood of tQT liability. Conclusion: Data from healthy volunteers and patients with DMD show clinical pharmacology properties are consistent across PMOs, suggesting drug class effect.
