Novel Small Molecule Anti-Inflammatory Eye Drops for Ocular Graft Versus Host Disease

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SUMMARY Ocular graft versus host disease (OGVHD) is a severe ocular surface inflammatory disease (OSID), occurring in patients undergoing allogenic hematopoietic stem cell transplantation (HSCT). OGVHD is characterized by dry eye, meibomian gland dysfunction, conjunctival scarring, lid margin scarring, keratopathy, and corneal ulceration, causing significant ocular morbidity and vision loss for affected patients. Presently, there are no effective disease-modifying therapies for OGVHD. The purpose of this SBIR Phase II grant application is to develop novel and effective therapies for the treatment of OGVHD and potentially other OSIDs. The current proposal from Pulsar Life Sciences is focused on developing calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2)-targeted therapies for ocular diseases. Our preliminary studies and the results from a Phase 1 STTR to Eyedesis Biosciences (parent company) demonstrate that murine OGVHD is associated with conjunctival infiltration by T cells and MФ, two cell types in which CaMKK2 has been previously shown to be a regulator of inflammatory cell function; topical application of the tool compound SMIC, STO-609, significantly reduced murine OGVHD severity in vivo; and many compounds from a proprietary library of novel SMICs invented by Eyedesis inhibited CaMKK2 activity in vitro. These findings support the hypothesis that novel inhibitors of CaMKK2 can be developed to treat OGVHD. Eyedesis has successfully completed Phase 1 aims to demonstrate that many novel SMICs were potent inhibitors of CaMKK2 in vitro, most novel SMICs were well tolerated when applied topically to the eye, and two novel SMICs administered topically were efficacious in treating murine OGVHD. In this follow-on Phase 2 SBIR application, Pulsar will complete lead optimization and IND-enabling studies required for our filing of an IND application. Aim 1 will finalize lead optimization and select the lead candidate, Aim 2 will perform the technical transfer to contract GMP drug manufacturer and contract GMP drug formulation, establish CMC properties, and characterize formulation stability, and Aim 3 will perform IND-enabling pharmacology and toxicology studies. The end deliverable will be to submit an IND application to the FDA and perform the first-in-human clinical studies with this topical eyedrop for OGVHD.