In vivo Effects of CCFD9260S Following Intravitreal Administration to Cynomolgus Monkeys

Abstract

Purpose : To characterize CCFD9260S, a recombinant, humanized monoclonal Fab on a PEG carrier directed against factor D, following intravitreal (ITV) administration to cynomolgus monkeys.

Methods : Male and female monkeys were randomly assigned to receive CCFD9260S at 0, 7.5 to 22 mg/eye/dose as single or repeated bilateral ITV once every 3 weeks for 9 weeks, 4 total doses. ITV of vehicle and 22 mg/eye were given as 2 × 50 μL injections 10 minutes apart. Ocular toxicity was assessed by clinical ophthalmic examinations, intraocular pressure (IOP), ocular fundus photography (OP), fluorescein angiography (FA), electroretinography (ERG), optical coherence tomography (OCT), and ocular anatomic pathology.

Results : Serum pharmacokintetics of repeat ITV CCFD9260S were not dose proportional. Further, systemic exposure was lower than expected but was affected by anti-drug antibody (ADA). No systemic toxicity was observed in either study. CCFD9260S sigle dose up to 20 mg/eye was well tolerated. Repeat dosing resulted in ocular inflammation at all dose levels after 2 weeks and tended to increase after the 2^nd dose. The incidence and severity of ocular inflammation lacked a dose-respone relationship. Inflammation included severe anterior and posterior uveitis resulting in a dosing holiday for several animals and an unscheduled euthanasia of a high dose animal. Systemic ADA correlated with the onset of inflammation. OP/FA findings also correlated with ocular inflammation, perivascular sheathing, hazy media, and/or optic nerve swelling at > 7.5 mg/eye. OCT-related transient and reversible findings in vehicle or high dose included hyper-reflective band, hypo-reflective line and retinal detachment. OCT findings at doses > 7.5 mg/eye included thickening of the retinal nerve fiber layer (RNFL) and white reflective spots in the vitreous. Drug-related microscopic findings included minimal-moderate mononuclear to mixed cell infiltrates in multiple intraocular tissues. CFD9260S had no effects on IOP or ERG.

Conclusions : Repeated ITV CCFD9260S resulted in the anterior and posterior uveitis at all dose levels. Systemic ADA was highly suggestive of an immune mediated response to CCFD9260S. In vivo findings of thickened RNFL and white reflective spots in the vitreous, perivascular sheathing as well as microscopic findings of minimal-moderate mononuclear to mixed cell infiltrates are consistent

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