Ocular Pharmacokinetics and Safety of Suprachoroidal A01017, Small Molecule Complement Inhibitor, Injectable Suspension in Rabbits

Abstract

Purpose : Complement alternative pathway (AP) activation has been implicated via genetic association in dry age-related macular degeneration (AMD). Inhibition of complement components using therapeutics delivered systemically or via intermittent intravitreal injection has yielded varying clinical trial success. Alternative delivery methods could yield more sustained high levels of inhibition and consequently improved clinical benefits. Given the bioavailability and durability potential of suprachoroidal (SC) small molecule suspensions, this preclinical study assessed the safety and pharmacokinetics (PK) of SC A01017, a highly potent complement factor D inhibitor that blocks AP activity.

Methods : A single bilateral suprachoroidal injection (100 µL) of A01017 suspension was administered to male Dutch-Belted (DB) pigmented rabbits (N=2-3 rabbits/timepoint) to assess toxicity and PK. Toxicity was assessed at 0 (vehicle control), 0.03, 0.1, 0.3, and 1 mg/eye based on mortality, clinical observations, ophthalmic observations, intraocular pressure measurement, electroretinography, and pathology. Ocular PK was assessed at 0.03, 0.1, 0.3 mg/eye. Retinal pigment epithelium-choroid-sclera (RCS), neural retina, vitreous, aqueous humor and blood collected on days 15, 29, 43, 57, 71, and 92 were analyzed for drug content via LC-MS-MS.

Results : SC A01017 was well tolerated in DB rabbits. Minimal, non-adverse drug-related toxicity was observed in this study. Sustained high exposure of A01017 was observed in RCS and retina throughout the 92-day study at all three doses. Elimination of A01017 from RCS was roughly first-order, with an estimated half-life (T_1/2) of 66, 66, and 76 days at 0.03, 0.1, and 0.3 mg/eye level, respectively. Mean RCS levels on day 92 (C_last) were 13400, 81500, and 409000 ng/mL at dose levels 0.03, 0.1, and 0.3 mg/eye, respectively, that are 3-5 orders of magnitude higher than the in-vitro (AP hemolysis assay) IC₉₀ value. Mean retina levels (AUC_0-92) were 76.8, 606, and 5040 day*μg/mL for dose level 0.03, 0.1, and 0.3 mg/eye, respectively. Low or no quantifiable A01017 was detected in vitreous, aqueous humor or plasma.

Conclusions : SC delivery of A01017 suspension provided well tolerated, sustained high drug levels in the posterior segment in rabbits, and merits further studies in the development of long-acting small molecule complement inhibitors for dry AMD.

This is a 2020 ARVO Annual Meeting abstract.