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Louis C Glazer, Jonathan G. Williams, Carmelina M Gordon, Pravin U Dugel, Mark Milton, Thomas Valencia, Ulf Klein, Sandrine Kretz, Kinfemichael Gedif, Cynthia L Grosskreutz, Parisa Zamiri; A first in human study of Intravitreal (IVT) CLG561 in Subjects with Advanced Age-Related Macular Degeneration (AMD). Invest. Ophthalmol. Vis. Sci. 2016;57(12):2672.
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© 2017 Association for Research in Vision and Ophthalmology.
The risk of developing AMD is strongly associated with polymorphisms in the complement alternative pathway. CLG561 is a fully human antibody Fab that neutralizes properdin, a positive regulator of alternative pathway activity. Inhibition of properdin prevents formation of early (C3a and C3b/iC3b) and late (C5a and C5b, and membrane attack complex) activation products. We conducted a multicenter, open label, single ascending dose study to assess the safety, tolerability, serum pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity of IVT CLG561 in patients with advanced AMD.
Thirty one patients received a single IVT dose of CLG561 (0.1 mg/50 μL (n=6), 0.5 mg/50 μL (n=6), 1.5 mg/50 μ (n=7), 5 mg/ 50 μL (n=6), and 10 mg/100 μL (n=6)). Safety assessments included clinical and laboratory evaluations, best corrected visual acuity (BCVA), intraocular pressure (IOP), dilated biomicroscopy, fundus photography, and fluorescein angiography. Serum PK (total CLG561), PD (total C5 and complement alternative pathway activity), and immunogenicity of CLG561 were also evaluated. Patients were followed for up to 84 days.
The mean age of the patients was 75.3 years. The majority of patients were female (61.3%) and Caucasian (96.8%), and had wet AMD (77.4%). No drug related systemic or ocular adverse events (AE) were observed. One patient in the 0.1 mg cohort experienced transient blindness due to a temporary rise in IOP and underwent ocular paracentesis, after which the IOP and BCVA returned to pre-injection values. Conjunctival hemorrhage was the most frequently reported ocular AE. After IVT injection, CLG561 slowly distributed from the eye into the systemic circulation. There was no clear time-dependent or dose-dependent change in serum concentrations of total properdin or serum complement activity (Wieslab assay). Anti-CLG561 antibodies were not detected.
Single IVT doses of CLG561 up to 10 mg were safe and well–tolerated. The serum concentrations of CLG561 were low and no inhibition of systemic complement activity was observed.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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