A Semimechanistic Ocular Pharmacokinetic Model for ADVM-022 Gene Therapy Describing the Dose-Exposure Relationship in Monkeys and the Scaling to Human

Gene therapies are emerging as a new treatment modality. Due to their novelty, general pharmacological properties have yet to be established. For example, the translation from animal models to humans for first-in-human dose selection and the dose-exposure relationship remain poorly characterized. A mechanistic and quantitative framework would improve preclinical program design, enable more robust first-in-human dose predictions, and support more rigorous dose adjustments during clinical development. This study establishes a semimechanistic mathematical model for aflibercept expression and pharmacokinetics (PK) following intravitreal (IVT) ADVM-022 administration in monkeys and humans, drawing on the preclinical and clinical data presently available. ADVM-022 is an AAV2.7m8-based viral vector that delivers the gene encoding aflibercept, an antivascular endothelial growth factor (VEGF) fusion protein. It was developed as a gene therapy for treating wet age-related macular degeneration (wAMD) and is administered through a single IVT injection. The proposed model incorporates established ocular PK for intravitreally administered proteins, along with an expression component that links AAV dose to aflibercept production. Based on pooled PK data from monkey studies, the model suggests that transduction occurs not only in the retina but also in other ocular tissues bordering the vitreous, contributing to the observed intraocular aflibercept levels. Increasing doses within the lower range of preclinical studies (3 × 10¹⁰-2 × 10¹³ vg/eye) lead to increased transduction and expression, plateauing at upper limits of approximately 12.7 μg/day·cm³ for the retina, and 0.785 μg/day for extra-retinal tissues at higher doses. Assuming similar transduction efficiency between humans and monkeys, with adjustments for anatomical differences, the model provided predictions of ocular aflibercept concentrations that aligned with observations from the two dose groups in the phase 1 OPTIC clinical trial, supporting the utility of this approach.