Ocular and Systemic Pharmacokinetics of a PEGylated-anti-Factor D Fab Multimer in Cynomolgous Monkeys

Abstract

Purpose : A relationship between hydrodynamic radius and vitreal half-life of proteins has been established in rabbits (Shatz et al 2016). The purpose of this study was to characterize the ocular and systemic pharmacokinetics (PK) of a PEGylated-anti-factor D Fab multimer in cynomolgous monkeys and compare it to that of an anti-factor D Fab.

Methods : Radio-iodinated PEGylated-Fab multimer was administered intravitreally at three dose levels to cynomolgous monkeys and vitreous, aqueous, retina, and serum samples were collected up to 28 days post-dose. A radio-iodinated Fab was also administered intravitreally in order to establish the fold extension in vitreal half-life. An intravenous arm was included in the study to characterize the systemic PK of the PEGylated-Fab multimer. An ocular PK model was fit to the cynomolgous monkey PK data and then used to make human predictions. Pharmacodynamic predictions of factor D were also completed based on the available literature data for factor D (Le et al 2015^a, Le et al 2015^b, Loyet et al 2012).

Results : The study was sufficiently powered to establish that there was a statistically significant difference in vitreal half-life between the anti-factor D Fab (2.57 days) and the PEGylated-anti-factor D Fab multimer (4.75 days). A vitreal half-life extension of ~2-fold was observed for the PEGylated-Fab multimer. The exposure of the PEGylated-Fab multimer was dose proportional in vitreous, aqueous, retina, and serum. Following IV administration, the PEGylated-anti-factor D Fab multimer displayed a biphasic concentration-time profile with a terminal half-life of 15 days. Based on the cynomolgous monkey PK and translating those parameters to human, the intravitreal dosing frequency in humans was predicted to be reduced 2-fold compared to that of a Fab in order to maintain similar target engagement over the extended dosing interval.

Conclusions : The observed ~2-fold extension in vitreal half-life for the PEGylated-Fab multimer in cynomolgous monkey was consistent with the expected half-life extension based on its hydrodynamic radius. Thus, this format would be expected to reduce the clinical intravitreal dosing frequency by 2-fold compared to that of a Fab.

Shatz et al Mol Pharmaceutics 2016; 13:2996–3003.; Le et al J Pharmacol Exp Ther 2015^a, 355:288-296., Le et al CPT Pharmacometrics Syst Pharmacol 2015^b, 4:595-604. Loyet et al IOVS 2012, 53(10):6628-6637.

This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.