Ixoberogene soroparvovec (Ixo-vec) for the treatment of neovascular age-related macular degeneration: Nonclinical data in support of human equivalent dose of 6E10 vg/eye and staggered bilateral dosing

Abstract

Purpose : Ixo-vec is a gene therapy designed to produce robust, durable levels of aflibercept for the treatment of neovascular age-related macular degeneration (nAMD). In a Phase 1 clinical trial in nAMD, a single intravitreal (IVT) injection of Ixo-vec at 6E11 and 2E11 vg/eye resulted in therapeutic levels of aflibercept in patients through three years. Nonclinical studies described here evaluated whether a lower dose of Ixo-vec can provide robust ocular aflibercept levels, and whether AAV-induced adaptive immunity (neutralizing antibodies) after first dose could have an impact on fellow eye treatment.

Methods : Nonhuman primates (NHPs) were administered IVT Ixo-vec at either 3E10 or 1E11 vg/eye (n=4/group), or vehicle (n=2/group) (human equivalent dose, HED of 6E10 vg/eye and 2E11 vg/eye). Vitreous and aqueous samples were collected for aflibercept quantification on days 30, 60 and 98 post dose. Tolerability assessed by ophthalmic examinations, ERG, OCT and tonometry. No immunosuppression was used throughout the study. An additional study evaluated tolerability and aflibercept levels in NHPs following staggered bilateral administration of Ixo-vec with a 2-month dosing interval between eyes.

Results : Ixo-vec administered at both doses resulted in therapeutic aflibercept levels with mean peak levels comparable with levels observed in previous studies utilizing higher doses of Ixo-vec. Ixo-vec was well tolerated. Slight to mild dose-dependent intraocular inflammation (IOI) and microscopic findings of minimal mononuclear cell infiltrations were observed. Staggered bilateral administration of Ixo-vec did not exacerbate IOI in the second eye. Although trending toward lower aflibercept compared to the first eyes, levels in second eyes were within the predicted therapeutic range found across multiple NHP studies, despite NAbs detected in serum after the first dose.

Conclusions : Ixo-vec at doses as low as 3E10 vg/eye (HED 6E10 vg/eye) provided robust, durable levels of aflibercept within targeted therapeutic range, similar to higher doses with minimal IOI. IOI was evidenced by mononuclear cell infiltrates. Staggered bilateral administration resulted in levels of aflibercept expected within the therapeutic range without exacerbation in IOI suggesting the feasibility of dosing patients bilaterally with Ixo-vec.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.