Pharmacokinetics and target engagement of intravitreal administration of ANX007, an anti-C1q antibody fragment, in nonhuman primates

Abstract

Purpose : C1q and the classical complement cascade, key regulators of synaptic pruning in neuronal development, are aberrantly activated in neurodegenerative ophthalmic diseases, including geographic atrophy and glaucoma. ANX007 is a novel fragment antibody that specifically recognizes the substrate-binding head groups of C1q and functionally inhibits the classical complement cascade. Nonclinical studies were completed to assess ANX007 biodistribution and C1q target engagement in the eye and serum following intravitreal (IVT) administration in cynomolgus monkeys.

Methods : Three studies were completed. In a single dose study, animals received 1 or 5 mg/eye IVT (n=2/group/timepoint), and serum, vitreous, and non-perfused tissue samples were collected through Day 30 post-dose. In combined analyses of two repeat-dose studies, animals received two monthly IVT doses of 0, 1, 2.5, or 5 mg/eye on Days 1 and 29 (n=2-6/group/timepoint), and terminal serum, aqueous, and vitreous were collected on Day 44 or 59 in each study. In 0 and 5 mg/eye groups, animals were perfused, and retina, choroid and optic nerve samples were collected on Day 44 or 59. Free ANX007 and free C1q were measured using specific and sensitive ELISA-based assays.

Results : All doses were well-tolerated. Vitreous ANX007 levels were measurable up to 30 days following a single or repeat doses of ANX007 at all dose levels studied. The ANX007 half-life in the vitreous was 3 days. Aqueous and vitreous levels were highly correlated, and aqueous levels were 4-fold lower than in the vitreous. In perfused tissue following two monthly 5 mg/eye doses, ANX007 levels were measurable 30 days post-last dose in the retina and choroid, and through 15 days in the optic nerve samples, confirming the diffusion of drug to the back of the eye. Presence of free drug was associated with a complete reduction of free C1q in fluids and perfused tissues.

Conclusions : Following IVT administration, ANX007 distributes to relevant sites of neurodegenerative ophthalmic disease within the retina, with clear evidence of C1q target engagement. Engagement of C1q in the aqueous humor reflects inhibition in the vitreous and retinal tissue, and is hypothesized to be sufficient to mitigate classical complement activation in neurodegenerative ophthalmic disease. This data supports further clinical evaluation of ANX007 for the treatment of such diseases.

This is a 2021 ARVO Annual Meeting abstract.