First Author: C.Semba USA
Co Author(s): W. Peterson M. Yang J. Cleland
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IVT injections of agents (aflibercept, bevacizumab, ranibizumab) to block vascular endothelial growth factor (VEGF) have revolutionized management of wet AMD. However, frequent IVT injections have increased the treatment burden for patients and practitioners. An unmet need exists for long-acting agents to reduce IVT injections. GB-102 is a depot formulation of sunitinib, a receptor tyrosine kinase inhibitor that targets multiple pathways associated with neovascularization, vascular permeability, and cellular proliferation including VEGFR-1, -2, -3 and PDGF-α, -β. The purpose was to characterize the ocular and systemic PK of GB-102 up to 7 months (M) after a single IVT injection in vivo.
Preclinical research and development prior to initiation of a multicentre Phase 1 / 2 clinical study.
Biodegradable microparticles containing sunitinib (GB-102) were engineered from polylactide-co-glycolide; (PLGA) for extended drug release. The microparticles are approximately 25 μm in diameter and designed to be injected through a 27 g needle, coalesce into a single aggregated depot when exposed to vitreous at 37° C, and fully resorb in 3 to 4 M. A prior study evaluating dosing of IVT GB-102 microparticles in a C57BL/6 murine laser injury model of choroidal neovascularization (CNV) demonstrated sustained suppression of CNV for GB-102 (0.01 mg sunitinib) through 9 weeks versus control. GB-102 containing 1 mg sunitinib was dosed as a single IVT injection (50 μL) using a 27 gauge needle inserted through the inferior pars plana in pigmented New Zealand rabbits. Slit-lamp and fundus examination were conducted at each monthly visit (baseline, M1-7). Total sunitinib levels were quantified by LC/MS/MS (liquid chromatography (LC); mass spectrometry (MS)) in the vitreous, retina, RPE-choroid (RPE/C), and plasma (level of quantitation 0.1 ng/ml) at M1-7.
Sunitinib levels in the RPE/C were approximately >1000-fold above the inhibitory constant (Ki) for VEGFR-1, -2, -3 and PDGFR- α, -β inhibition at all time points through 7M. In contrast, plasma levels of sunitinib remained >50-fold below the Ki throughout the 7M post-dose. Injected GB-102 coalesced in the vitreous as an immobile, implant-like aggregate that remained outside the visual axis. The implants were fully resorbed by 4M. Based upon the tissue concentration of sunitinib in the RPE/C layer, inhibitory concentrations of drug can be sustained for at least 7M with a single IVT injection of GB-102.
GB-102 is a novel depot formulation of sunitinib intended for intravitreal administration. PK evaluation in vivo demonstrates that inhibitory concentrations of sunitinib in the RPE/C to suppress all VEGF and PDGF receptors can be maintained through 7 months with a single IVT injection. The evidence supports the potential for a twice-yearly treatment for the management of wet AMD. Multicentre clinical studies are planned in patients with wet AMD.