Single ocular injection of a sustained-release anti -VEGF delivers 6 months pharmacokinetics and efficacy in a primate laser CNV model

Abstract

A potent anti-vascular endothelial growth factor (VEGF) biologic and a compatible delivery system were co-evaluated for protection against wet age-related macular degeneration (AMD) over a 6month period following a single intravitreal (IVT) injection. The anti-VEGF molecule is dimeric, containing two different anti-VEGF domain antibodies (dAb) attached to a human IgG1 Fc region: a dual dAb. The delivery system is based on microparticles of PolyActive™ hydrogel co-polymer. The molecule was evaluated both in vitro for potency against VEGF and in ocular VEGF-driven efficacy modelsin vivo. The dual dAb is highly potent, showing a lower IC50 than aflibercept in VEGF receptor binding assays (RBAs) and retaining activity upon release from microparticles over 12 months in vitro. Microparticles released functional dual dAb in rabbit and primate eyes over 6 months at sufficient levels to protect Cynomolgus against laser-induced grade IV choroidal neovascularisation (CNV). This demonstrates proof of concept for delivery of an anti-VEGF molecule within a sustained-release system, showing protection in a pre-clinical primate model of wet AMD over 6 months. Polymer breakdown and movement of microparticles in the eye may limit development of particle-based approaches for sustained release after IVT injection.

Comparative Study of In Situ Loaded Antibody and PEG‐Fab NIPAAM Gels

“…While IVT injections are the best way to administer a reproducible dose of an antibody to the back of the eye, clinical practice is hampered by the need for IVT injections of these medicines every 1–2 months. To better treat chronic blinding conditions, there is a need to develop ocular formulations that could maintain a therapeutic dose of a medicine in the vitreous cavity for longer periods of time …”

“…Particles which are prone to aggregation or larger than 300 nm in the vitreous can scatter light to interfere with vision . Particle migration to the front of the eye results in release of drug that simply clears from the eye with aqueous outflow. An additional risk is particulates blocking the aqueous outflow.…”

Long‐term therapeutic effect in nonhuman primate eye from a single injection of anti‐VEGF controlled release hydrogel

“…34 However, controlled release devices that are well tolerated in rabbits may still elicit inflammation and other incompatibility problems in primates. 16 To address this question, the hydrogel encapsulating bevacizumab was injected to monkey eyes intravitreally to evaluate short-term and long-term biocompatibility. The retinal function was tracked by electroretinography (ERG).…”

“…18,23 The aqueous elimination half-life calculated assuming first order elimination was 3.5 days, which is similar to the value calculated by Miyake et al (2.8 days). 16 The in vitro release kinetics and the in vivo rabbit eye pharmacokinetics of the present hydrogel has been described previously. The hydrogel was able to release bevacizumab at therapeutically relevant level for at least half year in vivo in rabbits eyes.…”

“…(a) the time for protein release is not long enough; (b) the depot fails to preserve the protein activity; (c) the delivery vehicles are not compatible with ocular tissues. [16][17][18][19][20] The lack of an animal model to evaluate the prolong therapeutic duration of these formulations brings an additional barrier to the translation of these devices to clinical use. 18 Previously, we developed an injectable hydrogel composed of hyaluronic acid grafted with vinylsulfone (HA-VS) and dextran grafted with thiol (Dex-SH).…”