Vivreon Biosciences, LLC 4940 Carroll Canyon Rd., Ste. 110 San Diego, CA 92121 milton@vivreonbiosciences.com NIAMS PA-20-260 Project Summary Osteoarthritis (OA) is a progressive arthritic condition and the most common form of painful and disabling arthritis, affecting over 10% of adults over 60 years of age. Destruction of joint cartilage and bone occurs with significant chronic inflammation of the synovium tissue that normally nourishes and supports the joint. There is no available Disease Modifying Osteoarthritis Drug (DMOAD), and the need is great. Joint destructive synovitis is driven largely by inflammatory and destructive innate immune cell responses to signals from damaged tissues and senescent joint cells. An ideal therapeutic to control synovitis and modify OA progression would be safe and able to reduce damaging macrophage overactivity in the synovium while maintaining the repair activities of beneficial macrophage activation. The Ca2+ Release Activated Ca2+ Channel (CRAC), the topic of this SBIR Phase I project, is supported as a drug target by genetic evidence of a causative role for CRAC pathway components and by upregulation of the CRAC channel protein in OA tissues. The CRAC channel is activated by multiple proinflammatory receptors on macrophages, and signaling events downstream of CRAC activation drive a multiplicity of biochemical and gene expression events driven by NF-B and NFAT promoters typical of chronic inflammation. Vivreon Biosciences seeks to control synovitis and reduce OA-associated morbidity by advancing a lead CRAC blocker compound, VV8321, into the drug development pipeline. We propose that VV8321 exhibits properties that make it suitable for intra-articular injection and the likelihood of a prolonged retention in the joint to provide sustained inhibition of synovial macrophage inflammation. In this project we will further characterize VV8321 to advance it into a full drug development program appropriate for external funding support. In Aim 1 we will perform in vitro assays to characterize VV8321 ADME behaviors, cytochrome P450 enzyme family liabilities (CYP mRNA induction), cytotoxicity screening, cardiovascular hERG channel liability and genotoxic liabilities (Ames test). Aim 1 will also investigate the joint and plasma pharmacokinetic behavior of VV8321 upon intra-articular injection into rat knees. In Aim 2 VV8321 efficacy will be tested in two rat models of OA – a destabilization of the medial meniscus model and a chemical induction model (monosodium iodoacetate injection into the knee joint). Successful completion of the program will position Vivreon to advance VV8321 into a full drug development program with sufficient documentation to attract additional Phase II and external funding support.