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Andy Whitlock, Laura Belen, Matt J Chapin, Paul J Gomes, Matt Birrell, Anjali Pandey, David Hollander; Preclinical Assessment of the Syk Inhibitor PRT2761 for Allergic Conjunctivitis. Invest. Ophthalmol. Vis. Sci. 2018;59(9):5568.
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© ARVO (1962-2015); The Authors (2016-present)
To evaluate the efficacy of a new therapeutic, the highly selective Syk kinase inhibitor PRT2761, in a murine model of allergic conjunctivitis. Allergic conjunctivitis is a disease of chronic B cell receptor (BCR) stimulation, isotype class-switching to IgE plasma cells, and IgE crosslinking of FcεR1 leading to basophil and mast cell degranulation. PRT2761 inhibits BCR and FcεR1 signaling and functional responses in human whole blood assays with IC50s ranging from 0.1 – 0.5 µM.
Animals were sensitized with subcutaneously injected short ragweed allergen (day 1, day 11), and underwent conjunctival allergen challenge (CAC) on day 18 with short ragweed allergen. Following challenge, mice were randomized into treatment groups (n=8) and given topical test compounds: PRT vehicle, 0.1% PRT2761, 1% PRT2761, 1% prednisolone, or saline QID for 2 days, and TID for an additional 4 days during allergen challenges.. Challenges were conducted twice daily, on day 21 thru 24. Responses to allergen challenge were evaluated after challenges 1, 4, 6 and 8.
PRT2761 (1%) significantly reduced mean change in hyperemia (pre- versus post-CAC) compared to saline on 4 of 4 test days; PRT2761 (0.1%) significantly reduced the mean change in hyperemia compared to saline on 2 of 4 test days. The positive control prednisolone (1.0%) also elicited a significant decrease in the mean change in hyperemia on 2 of 4 test days. A statistically significant reduction in overall mean hyperemia was observed with 1% PRT2761 on 3 of 4 test days. No significant changes were seen for ocular discharge, lid swelling, or squinting.
PRT2761 shows efficacy in relief of allergic conjunctivitis similar to that of prednisolone in this murine model of the disease. Results suggest that the Syk inhibitor PRT2761 could provide an alternative to existing therapeutic modalities such as anti-histamines or corticosteroids.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
Change in mean hyperemia scores, post-Conjunctival Allergen Challenge.
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