Predevelopment of VV8321, a Novel CRAC Channel Therapeutic for the Treatment of Osteoarthritis

Vivreon Biosciences，LLC 4940卡罗尔峡谷路，Ste. 110 San Diego，CA milton@vivreonbiosciences.com NIAMS PA-20-260 项目摘要 骨关节炎（OA）是一种进行性关节炎病症，并且是疼痛和致残的最常见形式。 关节炎，影响超过10%的60岁以上的成年人。关节软骨和骨的破坏发生在 滑膜组织的严重慢性炎症，通常覆盖和支撑关节。有 没有可用的疾病修饰骨关节炎药物（DMOAD），并且需求很大。关节破坏性滑膜炎 很大程度上是由炎症和破坏性先天免疫细胞对受损组织信号的反应驱动的 和衰老的关节细胞。一种控制滑膜炎和改变OA进展的理想治疗方法将是安全的， 能够减少滑膜中的破坏性巨噬细胞过度活动，同时维持 有益的巨噬细胞激活。Ca 2+释放激活的Ca 2+通道（CRAC），本SBIR的主题 I期项目，通过CRAC途径致病作用的遗传证据支持其作为药物靶标 通过上调OA组织中的CRAC通道蛋白，CRAC通道通过以下方式激活 巨噬细胞上的多种促炎受体，以及CRAC激活驱动下游的信号传导事件 由NF-κ B B和NFAT启动子驱动的多种生物化学和基因表达事件， 炎症 Vivreon Biosciences寻求通过推进领先的CRAC来控制滑膜炎并降低OA相关的发病率 阻断剂化合物VV 8321进入药物开发管道。我们提出，VV 8321表现出的性质， 这使得它适合于关节内注射，并可能在关节中长期保留， 持续抑制滑膜巨噬细胞炎症。在本项目中，我们将进一步表征VV 8321， 将其推进到适合外部资金支持的完整药物开发计划中。在目标1中， 体外测定以表征VV 8321 ADME行为、细胞色素P450酶家族责任（CYP 450 mRNA 诱导）、细胞毒性筛选、心血管hERG通道倾向性和遗传毒性倾向性（艾姆斯试验）。目的 1还将研究VV 8321在关节内注射到受试者中后的关节和血浆药代动力学行为。 老鼠膝盖在目标2中，将在两种OA大鼠模型中测试VV 8321的功效--一种中膜的不稳定， 半月板模型和化学诱导模型（将碘乙酸盐注射到膝关节中）。 该项目的成功完成将使Vivreon能够将VV 8321推进到全面的药物开发阶段。 该计划有足够的文件，以吸引额外的第二阶段和外部资金支持。

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.