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Eric S Furfine, Yuri Matsumoto, Joseph Kovalchin, Paul Wu, Blanca Lain, Shaun Coate, Mike Schmidt; Optimized Intravitreal IL-6 Antagonist for the Treatment of Diabetic Macular Edema and Uveitis. Invest. Ophthalmol. Vis. Sci. 201657(12):.
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© ARVO (1962-2015); The Authors (2016-present)
IL-6 is a pleiotropic cytokine with established roles in inflammation and angiogenesis. Vitreal IL-6 levels are significantly elevated in patients with diabetic macular edema (DME) and uveitis. IL-6 blockade reduces retinal leukostasis and angiogenesis in animal models. In humans, systemic IL-6 blockade can lower VEGF levels in rheumatoid arthritis patients and reduces cystoid macular edema in patients with uveitis. Eleven Biotherapeutics has optimized EBI-031, a human IL-6 blocking antibody with a high potency, to have a long intravitreal (IVT) retention time and rapid systemic clearance ideal for IVT treatment of DME, uveitis, and other ocular inflammatory diseases. EBI-031 binds and blocks signaling of human and nonhuman primate IL-6 and the IL-6/sIL-6Rα complex in cellular assays ~1,000 fold more potently than tocilizumab. This study characterizes the IVT pharmacokinetics and tolerability of EBI-031 in nonhuman primates.
Cynomolgus and African green monkeys were injected IVT monthly for 2 months with EBI-031 0.25 to 2.5 mg/eye bilaterally. IVT pharmacokinetics were modeled from systemic drug levels after IVT administration. IV PK parameters were determined from a 50 mg dose. Drug levels and anti-drug antibody response were measured by ELISA. Tolerability and safety were assessed by fundus photography.
IVT administration of EBI-031 2.5 mg/eye bilaterally resulted in a modeled IVT half-life of approximately 5 days and a systemic half-life of approximately one day. Cynomolgus monkeys developed an anti-drug antibody response by two weeks compared to African green monkeys in which antibodies were undetectable over the first month. The drug was well tolerated and the retinas were healthy in both species.
The five day IVT half-life of EBI-031 was approximately twice what is reported for afilbercept and ranibizumab in monkey studies and corroborated what was observed in a previous rabbit study. The minimal immune response to the drug, the potency of binding IL-6 and the long half-life make African Greens the best species for IND-enabling toxicology work. In addition, the long IVT half-life and potency of IL-6 blockade suggest IL-6 signaling could be substantially blocked for 3 or more months in patients with uveitis or DME after a single IVT injection of EBI-031. The drug was well tolerated in both species irrespective of an anti-drug antibody response.
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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