Long-acting potential of suprachoroidally delivered BCX4161, a selective plasma kallikrein inhibitor, for diabetic macular edema

Abstract

Purpose : BCX4161 is a potent and selective inhibitor of human plasma kallikrein activity. Elevated plasma kallikrein (PKal) levels have been reported in the vitreous humor of patients with diabetic macular edema (DME). Inhibition of PKal activity can be an effective therapeutic strategy for the treatment of DME. Suprachoroidal delivery of BCX4161 suspension may result in sustained and safe therapeutic drug levels in the retina-choroid. Hence, the purpose of this study was to assess ocular pharmacokinetics (PK), durability and tolerability of suprachoroidally delivered BCX4161 in rabbits.

Methods : A single bilateral suprachoroidal injection (100 µL) of BCX4161 suspension was administered to male Dutch-Belted (DB) pigmented rabbits (N=2-3 rabbits/ timepoint) at a dosage of 0.5 mg/eye. Ocular tissues (RPE-choroid-sclera (RCS), retina, vitreous humor, aqueous humor), and blood were collected, at pre-determined timepoints for up to 12 weeks, and analyzed for drug content. An 8-mm biopsy punch was used to collect the central retina and the central RCS around the optic nerve. Ocular tolerability was assessed via in-life clinical observations including slit-lamp and indirect ophthalmoscopy.

Results : Suprachoroidally delivered BCX4161 was generally well tolerated in rabbits. No overt signs of toxicity were observed in rabbits during this 12-week study. Sustained and high exposure of BCX4161 was observed in the RCS and the retina throughout the study duration. Mean retina concentrations reached a maximum value (C_max) of 75 µg/gm (peripheral retina) and 13 µg/gm (central retina) at 24 hours postdose (T_max). On day 84 (the last timepoint), mean BCX4161 levels in the central retina (30 µg/gm) and the peripheral retina (21 µg/gm) were 1-2 orders of magnitude higher than the in-vitro IC99 (100 nM) levels. The dose depot (RCS) had 1 to 2 orders of magnitude higher mean concentration than the retina, and the retina had 1 to 2 orders of magnitude higher mean concentration than the vitreous humor. Low levels of BCX4161 were observed in some samples of aqueous humor and plasma.

Conclusions : Suprachoroidally delivered BCX4161 suspension provided sustained and targeted delivery of BCX4161 to the chorioretina, has the potential to be a safe, effective and long-acting therapy for the treatment of DME, and warrants further studies.

This is a 2021 ARVO Annual Meeting abstract.