Modifications of Sunitinib-Loaded GB-102 Microparticles that Lengthen Drug Release: 9-Months Ocular Tolerability and PK in Rabbit Following IVT Dosing

Abstract

Purpose : To evaluate the ocular tolerability and pharmacokinetics (PK) of a new longer-lasting formulation of GB-102, a novel microparticle (MP) formulation of the potent dual VEGFR/PDGFR inhibitor sunitinib malate (SM).

Methods : We previously reported SM-containing, biodegradable MP (GB-102) that provide pharmacologically active levels of sunitinib in retina/RPE-choroid for 6 months following a single intravitreal (IVT) injection. SM is an FDA-approved, anti-cancer drug. A new formulation of GB-102 that releases SM continuously for at least 220 days in vitro has been characterized for drug loading, particle size and in vitro release kinetics. Drug-containing (1 mg SM) or placebo (drug-free) MPs were injected (0.05 mL) into the vitreous of pigmented rabbits using a 27G needle. Slit-lamp and fundus examinations were performed 10 days after dosing and monthly thereafter for up to 8 months. Ocular and plasma levels of sunitinib were assessed for the first 6 months of this ongoing 9-month study.

Results : Similar to the original GB-102 MP formulation, the new MP formulation coalesced in the inferior vitreous into a depot that remained outside the visual axis. There were no clinically significant, test article-related findings for the first 8 months post-dose. Sunitinib levels in retina/RPE-choroid were 100- to 10,000-fold higher than its receptor K_i at 3- and 6-months post-dose, whereas systemic levels remained at least 10-fold below its K_i.

Conclusions : Results to date indicate that IVT injection of the new GB-102 formulation is well-tolerated and able to maintain pharmacologically active levels in retina/RPE-choroid for at least 6-months post-dose. The original GB-102 formulation releases drug for 2-3 months and is able to maintain active levels of sunitinib in retina/RPE-choroid for 5-6 months after one injection. The additional 3-4 months’ exposure is likely due to reversible melanin-binding properties of sunitinib. Thus a single IVT injection of the new GB-102 MP may be able to retain active drug levels in retina/RPE-choroid up to 12 months and potentially enable once-per-year treatment for neovascular age-related macular degeneration.

This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.