PII-075 - MODEL-BASED EVALUATION OF DELANDISTROGENE MOXEPARVOVEC ADENO-ASSOCIATED VIRUS PHARMACOKINETICS AND SAFETY IMPLICATIONS

L. East¹, S. Mason¹, E. Darton¹, D. Griffin¹, O. Rogers¹, X. Zhang¹, S. Lewis¹, M. Derks², L. Rodino-Klapac¹; ¹Sarepta Therapeutics, Inc., Cambridge, MA, USA, ²Roche Pharma Research and Early Development, Roche Products Ltd, Welwyn Garden City, England, United Kingdom.

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 select countries. We characterized 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 IV delandistrogene moxeparvovec administration (1.33×1014 vg/kg) in ENDEAVOR (NCT04626674), a Phase 1b, multi-cohort trial; Cohorts 1 (ambulatory; aged ≥4– < 8 yrs), 2 (ambulatory; aged ≥8– < 18 yrs), and 3 (non-ambulatory; all ages) were included (N=32). Vector exposure was quantified by ddPCR. 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 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 bi-phasic disposition (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 (Table). No apparent relationship was identified between exposures and dosage and clinical safety biomarkers of liver injury (GGT, GLDH), cardiac injury (troponin-I) and immune system response (C3, C4, CH50, platelet count).

Conclusion: 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 yrs) 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.