VGB-R04

VGB-R04, an investigational gene therapy employs an engineered AAV8 capsid-based vector to deliver a liver-specific expression cassette encoding the high-activity FIX Padua variant (R338L) of human coagulation factor IX for Hemophilia B. The pharmacodynamics, Pharmacokinetic, immunogenicity and safety of VGB-R04 needs to be evaluated for non-clinical research.

The pharmacodynamics, Pharmacokinetic, immunogenicity and safety study of VGB-R04 via intravenous injection in mice and cynomolgus monkeys were conducted to support an investigational new drug (IND) application. The endpoints included pharmacodynamic biomarkers, in-life measurements. Anti-AAV8 neutralizing antibodies and anti-hFIX Padua protein antibody test, viral shedding, and tissue bio-distribution were analyzed.

The peak concentration was noted one hour after injection, subsequently exhibiting a distinct decline over time. The elimination rate of target genes in mouse blood exceeded that in cynomolgus monkeys. The concentration in liver tissues was indicating distinct liver tissue tropism. The elimination rate of target genes in mouse liver exceeded that in cynomolgus monkeys. The plasma concentration of hFIX Padua protein exhibited a dose-dependent elevation in mice. Cynomolgus monkeys exhibited significant elevation in plasma concentrations of hFIX Padua protein at 4 × 10¹³ vg/kg. Anti-AAV8 neutralizing antibodies can be detected in both species, but no antibodies against anti-hFIX Padua were seen in mice. The NOAEL were 8 × 10¹² vg/kg in mice and 4 × 10¹³ vg/kg in monkeys.

The studies demonstrated the pharmacodynamic advantages, pharmacokinetic profile with target distribution and potential safety of VGB-R04 in mice and cynomolgus monkeys after a single administration. The results support the gene therapy for future clinical studies.