Vivreon Biosciences, LLC NCI Phase 2 SBIR Submission 1R43CA224454-02 Project Summary Vivreon Biosciences is pleased to apply for NCI’s Phase 2 SBIR. Vivreon Biosciences is an innovative life sciences company that is developing a novel small molecule, Ca2+ channel inhibitor, VV2003, to improve outcomes in persons undergoing checkpoint inhibitor immunotherapy. Checkpoint inhibitors have improved overall survival in numerous cancers, but enterocolitis has emerged as the most frequent dose-limiting toxicity associated with these therapies. Checkpoint inhibitor induced colitis is currently treated with immunosuppressive therapy, which blunts the tumor-killing potential of the checkpoint inhibitor immunotherapy. VV2003 is an oral candidate therapeutic designed to selectively and safely block checkpoint inhibitor-induced enterocolitis without systemic immunosuppression side effects. Vivreon seeks NCI funding to bridge the gap between discovery and development. This grant aims to further validate VV2003 as a safe and effective candidate therapeutic by answering key questions regarding VV2003 pharmacokinetics and efficacy prior to advancing VV2003 into full Investigational New Drug (IND)-enabling studies and into first in human clinical evaluation. Upon successful completion of the program, our preclinical candidate will be the first to specifically inhibit Ca2+ release-activated Ca2+ (CRAC) channels for immunosuppression targeted specifically to sites of enterocolitis. Leukocyte CRAC channels facilitate Ca2+ influx, a process that is upstream of numerous enterocolitis disease-causing processes including leukocyte proliferation and inflammatory cytokine secretion. VV2003 has low systemic bioavailability and remains in the gut lumen following oral administration. This permits VV2003 to achieve colon-restricted immunosuppression, avoiding unwanted systemic side effects. We have developed several strategies to confirm that VV2003 can be used in combination with multiple checkpoint inhibitor immunotherapies, including in vitro and in vivo checkpoint inhibitor immunotherapy efficacy assays. The final aim for this proposal is characterization and testing of the first CRAC channel inhibitor to address enterocolitis associated with checkpoint immunotherapy.