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Eric Furfine, Kathy Collins, David Escobar, Christian Li, Patricia Lowden, Allyson Masci, Jesse Milling, Kelly Tenneson, Gary Wolfe, Joseph Kovalchin; Preclinical Development of EBI-005: a Potent Interleukin-1 (IL-1) Receptor-1 (R1) Blocker for Topical Ocular Administration was Safe in GLP Toxicology Studies and Active in a Mouse Model of Dry Eye Disease (DED). Invest. Ophthalmol. Vis. Sci. 2013;54(15):4320.
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Herein we describe the results of non-clinical IND-enabling studies of a stable formulation of EBI-005, a novel, potent, protein IL-1R1 inhibitor optimized to treat ocular surface inflammatory disorders. Multiple lines of evidence indicate that topical IL-1R1 blockade is therapeutically active in reducing signs and symptoms of DED, including a Phase 2 clinical study using a prototype IL-1R1 blocker. EBI-005 is more effective than cyclosporine, the current standard of care, in a mouse model of DED.
GLP studies in mice and rabbits assessed the topical ocular and systemic toxicology of EBI-005. Animals were treated with EBI-005 four times daily for six weeks (plus a two-week recovery phase) by topical ocular administration or once daily subcutaneously. Toxicokinetics and immunogenicity were assessed. Separately, EBI-005, twice daily, was compared to positive and negative control molecules in a mouse model of DED that induced signs of the disease using a low humidity chamber.
EBI-005 was well-tolerated in mouse and rabbit GLP toxicology studies where maximum tolerated doses were not reached. Ocular toxicity in rabbits was limited to minor irritation and redness of the conjunctiva that was associated with minor ocular mononuclear cell infiltrations. Mice treated with EBI-005 had no treatment-related ocular findings. Drug-related effects from subcutaneous administration were limited minor findings at the injection site. Systemic drug concentrations after ocular administration were low or undetectable in mice and rabbits. Ocular concentrations were not detectable by 12 hours after the last administration in rabbits. Despite the appearance of anti-drug antibodies, systemic active drug levels did not decrease in the majority of animals treated subcutaneously. In a mouse model of DED, EBI-005 was more effective than the prototype IL-1R1 blocker, anakinra, and a control for non-specific protein load, mouse serum albumin. EBI-005 was active at doses as low as 0.1 mg/mL and maximally active at 10 mg/mL.
EBI-005 was well-tolerated in mouse and rabbit toxicology studies and highly effective in a mouse model of DED. These results support the start of an ongoing six-week study designed to assess the safety and biological activity of EBI-005 in patients with DED.
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