Development of a Novel Calcium Channel Therapeutic for the Treatment of Asthma

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 NHLBI PA-21-259 项目摘要 严重哮喘是一种潜在的致命疾病，不能完全由抗炎小分子或 生物疗法。最近的证据表明，严重哮喘患者表现出实质性的呼吸道重塑 (AR)上皮细胞、杯状细胞和平滑肌细胞采用导致呼吸道的非典型表型 限制呼吸道组织增厚和纤维化、平滑肌肿块扩张(SMR)、粘液 积聚和呼吸道对刺激物的高反应性。这些组织重塑的变化对 标准护理抗炎(小分子或生物)或呼吸道舒张剂。SMR群众是 对支气管热成形术消融的反应和临床改善被记录下来，提示 降低SMR是控制重症哮喘的一种新手段。最近的研究表明，钙离子的释放被激活 Ca~(2+)(CRAC)通道是SMR的重要驱动因素，抑制CRAC可抑制SMR。威力龙 生物科学公司正在寻求一种新的方法来提供一种新的、强大的CRAC调节器开发候选者 局部到呼吸道，以获得最大的组织分布和控制SMR的效果。其他口服药， 全身活性CRAC阻滞剂通过抑制炎症介质在哮喘模型中显示疗效 这种疾病的危害。Vivreon将通过鼻腔给药超越这些早期的成功，实现最大限度的局部注射 传递到组织，以减少SMR和局部炎症。 CRAC途径通过激活NFAT和NF-B转录活性来调控许多基因。这些 CRAC通道的特性使其成为开发能够抑制SMR和 导致严重哮喘的炎症。Vivreon的实验性治疗在以下条件下显示出亚纳米分子效力 CRAC和良好的安全配置文件(无CYP抑制，可接受的偏离目标的活动配置文件，没有证据表明 心脏离子通道抑制)。在这个SBIR第一阶段项目中，我们将确认体外活性 抗气道平滑肌细胞和白细胞产生的促炎介质。在《目标2》中我们将 确认鼻腔给药后肺组织水平超过CRAC IC50值。我们 还将在本实验中监测血浆暴露，以评估全身活动的可能性 给药方案。在目标3中，我们将量化我们的CRAC调节器的疗效和剂量响应，通过 鼻腔途径(在目标2中得到证实)对SMR过程和平滑肌质量以及炎症的影响 过程，在哮喘模型中。成功完成这些目标将使该计划向前推进 进一步深入到支持IND的研究，如配方和吸入器给药优化，高级毒理学 在第二阶段SBIR资金和其他外部支持下，测试、化学放大和剂量范围发现。

Vivreon Biosciences, LLC 4940 Carroll Canyon Rd., Ste. 110 San Diego, CA 92121 milton@vivreonbiosciences.com NHLBI PA-21-259 Project Summary Severe asthma is a potentially lethal disease that is not fully controlled by anti-inflammatory small molecule or biologic therapies. Recent evidence indicates that severe asthma patients exhibit substantial airway remodeling (AR) where the epithelial, goblet and smooth muscle cells adopt atypical phenotypes that lead to airway restriction with airway tissue thickening and fibrosis, smooth muscle mass expansion (SMR), mucus accumulation and airway hyper reactivity to irritants. These tissue remodeling changes are not responsive to standard of care anti-inflammatory (small molecule or biologic) or airway relaxing agents. SMR masses are responsive to ablation by bronchial thermoplasty and clinical improvements are documented suggesting that reducing SMR is a novel means to control severe asthma. Recent studies indicate that the Ca2+ release-activated Ca2+ (CRAC) channel is a critical driver of SMR and that inhibition of CRAC could control SMR. Vivreon Biosciences is pursuing a novel approach to deliver a novel and potent CRAC modulator development candidate locally to the airways to obtain maximal tissue distribution and efficacy to control SMR. Other orally delivered, systemically active CRAC blockers showed efficacy in models of asthma by inhibiting the inflammatory mediators of the disease. Vivreon will surpass these early successes via intranasal delivery to achieve maximal local delivery to the tissue to reduce both SMR and local inflammation. The CRAC pathway regulates many genes through activation of NFAT and NF-B transcriptional activity. These attributes make the CRAC channel a suitable target for development of a drug that can suppress SMR and inflammation that drives severe asthma. Vivreon’s experimental therapeutic exhibits sub nanomolar potency at CRAC and a favorable safety profile (no CYP inhibition, acceptable off-target activity profile, no evidence of cardiac ion channel inhibition) upon oral dosing. In this SBIR Phase 1 project we will confirm in vitro activity against airway smooth muscle cell and leukocyte production of proinflammatory mediators. In Aim 2 we will confirm achievement of lung tissue levels that exceed CRAC IC50 values following intranasal administration. We will also monitor plasma exposure in this experiment to appreciate the potential for systemic activity with this dosing regimen. In Aim 3 we will quantify the efficacy and dose response of our CRAC modulator delivered by the intranasal route (confirmed in Aim 2) on the SMR process and smooth muscle mass, as well as inflammatory processes, in a model of asthma. Successful completion of these Aims will position the program to advance further into IND-enabling studies such as formulation and inhaler delivery optimization, advanced toxicology testing, chemistry scale up and dose-range finding with Phase II SBIR funding and other external support.