Novel Small Molecule Macrophage Inhibitors for the Treatment of Retinal Diseases

PROJECT SUMMARY ABSTRACT Persistent disease activity PDA in spite of anti vascular endothelial growth factor VEGF therapy remains a significant clinical unmet need for patients with neovascular age related macular degeneration NVAMD The purpose of this STTR Phase I grant application is to develop novel therapies that will be effective for the treatment of PDA associated with NVAMD The current proposal represents a collaboration between Eyedesis Biosciences LLC a spinout biotechnology company focused on retinal diseases and a Collaborative Team of investigators from Eye Pharmacology and Medicinal Chemistry at Duke University School of Medicine This team has established that the primary cause of PDA in the clinic is neovascular remodeling NVR and that NVR appears to be mediated by blood derived macrophages in experimental models of NVAMD The Pharmacology Team has identified calcium calmodulin dependent protein kinase kinase CaMKK as a key regulatory kinase that amplifies macrophage effector function A collaborative effort of Eye and Pharmacology has demonstrated that both genetic deletion and local pharmacologic inhibition of CaMKK prevents the development of NVR in experimental NVAMD The Medicinal Chemistry team has designed and initiated the synthesis of novel small molecule inhibitors of CaMKK for the treatment of NVAMD and other retinal diseases with macrophage mediated pathobiology Funded by an internal Duke Translational Research Institute seed fund grant this Collaborative Team of investigators has performed critical work to establish CaMKK as a potential therapeutic target for NVAMD and a viable drug development initiative with Duke owned novel intellectual property IP Eyedesis Biosciences was founded to formalize this initiative as a commercial drug development program following IP outlicense The proposed STTR Phase I project will attempt to achieve four key milestones Novel small molecules are potent inhibitors of macrophage CaMKK and effector function in vitro These small molecules are more selective for CaMKK than STO with less off target activity The small molecules are well tolerated when injected around the eye i e subconjunctivally and Subconjunctival ocular administration of these compounds is effective in preventing NVR The key deliverable will be the identification of at least one small molecule that meets these goals Successful realization of the Phase I milestones will justify additional development in Phase II including nomination of lead candidate s for intravitreal therapy clinical formulation for intravitreal injection of candidate drugs performance of IND enabling studies i e GLP toxicology and PK for injectable therapies PROJECT NARRATIVE RELEVANCE The goal of this innovation project is to develop a new class of drugs to treat inflammatory causes of retinal diseases especially the severe form of neovascular or wet macular degeneration which remains a significant cause of vision loss This new class of drugs will attempt to target inflammatory cells in the eye that appear to cause the severe form of wet macular degeneration This project represents a collaboration between scientists at Duke University School of Medicine and Eyedesis Biosciences a recently formed drug development company who will work together to develop new effective treatments for those patients with severe wet macular degeneration who remain at risk for vision loss in spite of currently available treatments