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Pravin U Dugel; A Phase I single ascending dose study of an intravitreal (IVT) anti-C5 monoclonal antibody (LFG316) in patients with advanced age related macular degeneration (AMD). Invest. Ophthalmol. Vis. Sci. 2014;55(13):1954.
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© ARVO (1962-2015); The Authors (2016-present)
Multicenter, open label, single ascending dose study to assess the safety, tolerability, maximum tolerated dose, immunogenicity and serum pharmacokinetics and pharmacodynamics of intravitreal LFG316 in patients with advanced AMD. LFG316 is a monoclonal antibody that binds to a complement protein (C5) and inhibits the activation of C5. AMD is strongly associated with polymorphisms in complement factors H, B, and C3. In vitro and in the blood of patients, the risk alleles appear to over-activate the complement cascade and activated complement factors are noted in drusen. C5 is an essential node upstream of the Membrane Attack Complex (C5b-9) and C5a. We hypothesize that inhibition of C5 activation by LFG316 will slow or arrest AMD progression and thereby preserve vision.
LFG316 was administered as a single intravitreal dose of 0.15, 0.5, 1.5, or 5 mg in a volume of 50 µl to patients (6 per cohort) with advanced AMD. Safety assessments included clinical and laboratory evaluations, best corrected visual acuity, intraocular pressure measurement, color fundus photography, and fluorescein angiography. Serum pharmacokinetics (total LFG316), pharmacodynamics (total C5 and alternative complement pathway activity) and immunogenicity of LFG316 were also evaluated.
The overall mean age of the 24 enrolled patients was 78.7 years. No clinically significant systemic or ocular adverse events (AE) were observed. Conjunctival hemorrhage was the most frequently reported ocular AE. There was no evidence of a change in serum total C5 concentrations or the activity of the serum alternative complement pathway after the administration of any IVT dose of LFG316. The intravitreal administration of LFG316 did not lead to the generation of anti-LFG316 antibodies.
Single intravitreal doses of LFG316, up to 5 mg, were safe and well-tolerated across all treatment groups. No drug related systemic or ocular adverse events were noted. Conjunctival hemorrhage was the most frequently reported ocular AE likely due to the intravitreal injection procedure. Serum concentrations of LFG316 were low and did not inhibit the alternative complement pathway. LFG316 is currently being evaluated in Phase II clinical trials.
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