Background: Delandistrogene moxeparvovec is an rAAVrh74 vector-based gene transfer therapy that delivers a transgene encoding an engineered, functional form of dystrophin shown to stabilize or slow disease progression in Duchenne muscular dystrophy (DMD); it is approved in the US and other selected countries.
Objectives: To characterize vector genome pharmacokinetics (PK) and the relationship between serum vector exposure and clinical safety biomarkers in patients (pts) with DMD.
Methods: Serum and excreta were obtained from pts treated with a single intravenous delandistrogene moxeparvovec administration (1.33×10¹⁴ vg/kg) in ENDEAVOR (NCT04626674), a phase 1b, multi-cohort trial; cohorts 1 (ambulatory; aged ≥4–<8 y), 2 (ambulatory; aged ≥8–<18 y), and 3 (non-ambulatory; all ages) were included (N=32). Vector exposure was quantified by digital droplet polymerase chain reaction. Serum and excreta vector exposure-time data were characterized by population PK modeling; serum vector exposure metrics by simulation of individual population PK model parameters were obtained by empirical Bayes estimates. Relationships between clinical safety biomarkers (baseline; weeks 1-12) and serum vector metrics and dose (total capsid, total vector genome) were evaluated.
Results: Vector exposure-time profiles and serum and excreta PK were consistent across all pts and demonstrated a biphasic disposition (a rapid distribution phase, then a slow terminal elimination phase). Estimated vector genome elimination half-life was ≈12 h in serum (most of the drug is expected to be cleared from serum by 1 week post dose) and 40 h in urine, 55 h in feces, and 60 h in saliva. PK parameters were consistent across all cohorts. No apparent relationship was identified between exposures and dosage and clinical safety biomarkers of liver injury (gamma-glutamyl transferase, glutamate dehydrogenase), cardiac injury (troponin-I), and immune system response (C3, C4, CH50, platelet count).
Conclusions: Delandistrogene moxeparvovec vector genome undergoes rapid distribution and widely distributes into target muscle tissue before elimination in urine and feces. Serum and excreta PK characteristics were consistent across a broad DMD population (aged 4–20 y) regardless of ambulatory status and support the existing dosing regimen. Clinical safety biomarker findings continue to support the favorable safety profile and weight-based dosing of delandistrogene moxeparvovec.