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

Vivreon生物科学有限责任公司 圣卡罗尔峡谷路4940号110 加州圣地亚哥，邮编92121 邮箱：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，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。关节软骨和骨骼的破坏发生在 通常滋养和支持关节的滑膜组织的严重慢性炎症。的确有 目前尚无治疗骨关节炎的药物(DMOAD)，需求量很大。关节破坏性滑膜炎 很大程度上是由炎症性和破坏性的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。一种理想的治疗方法来控制滑膜炎和改善骨性关节炎的进展将是安全和 能够减少滑膜中破坏性的巨噬细胞过度活动，同时保持 有利于巨噬细胞的激活。钙离子释放激活钙通道(CRAC)，这是本SBIR的主题 第一阶段项目，CRAC途径致病作用的遗传证据支持作为药物靶点 并通过上调骨关节炎组织中CRAC通道蛋白的表达。CRAC通道通过以下方式激活 巨噬细胞上的多个促炎受体，以及CRAC激活驱动下游的信号事件 由NF-B和NFAT启动子驱动的多种生化和基因表达事件 发炎。 Vivreon生物科学公司寻求通过推进领先的CRAC来控制滑膜炎和减少与OA相关的发病率 阻滞剂化合物VV8321进入药物开发流程。我们认为VV8321具有一些特性 这使得它适合关节内注射，并有可能在关节内长期滞留，以提供 持续抑制滑膜巨噬细胞炎症。在本项目中，我们将进一步描述VV8321以 将其推进到适合外部资金支持的全面药物开发计划中。在目标1中，我们将表演 体外测定VV8321的ADME行为、细胞色素P450酶家族功能(CYP mRNA 诱导)、细胞毒性筛选、心血管HERG通道易感性和遗传毒性易感性(Ames试验)。目标 1还将研究VV8321在关节内注射时的关节和血浆药代动力学行为 老鼠的膝盖。在AIM 2中，VV8321的疗效将在两种OA大鼠模型上进行测试-内侧不稳定性 半月板模型和化学诱导模型(膝关节注射碘乙酸单钠)。 该计划的成功完成将使Vivreon公司将VV8321推进到全面的药物开发中 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.