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

Vivreon Biosciences，LLC 4940卡罗尔峡谷路，Ste. 110 San Diego，CA 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，严重的哮喘患者表现出大量的气道重塑 (AR)其中上皮细胞、杯状细胞和平滑肌细胞采用非典型表型， 限制与气道组织增厚和纤维化，平滑肌质量扩张（SMR），粘液 积聚和气道对刺激物的高反应性。这些组织重塑的变化对 标准治疗抗炎剂（小分子或生物制剂）或气道松弛剂。SMR质量是 记录了支气管热成形术对消融的反应和临床改善，表明 降低SMR是控制严重哮喘的新方法。最近的研究表明，钙释放激活 Ca 2+（CRAC）通道是SMR的关键驱动因子，抑制CRAC通道可以控制SMR。比夫雷翁 Biosciences正在寻求一种新的方法来提供一种新的有效的CRAC调节剂开发候选药物 局部至气道，以获得最大的组织分布和控制SMR的功效。其他口服给药， 全身活性CRAC阻断剂通过抑制炎症介质在哮喘模型中显示出有效性 疾病。Vivreon将通过鼻内递送超越这些早期的成功， 递送至组织以减少SMR和局部炎症。 CRAC途径通过激活NFAT和NF-κ B B转录活性调节许多基因。这些 这些特性使得CRAC通道成为开发能够抑制SMR的药物的合适靶点， 导致严重哮喘的炎症。Vivreon的实验性治疗剂显示出亚纳摩尔的效力， CRAC和有利的安全性特征（无药物抑制，可接受的脱靶活性特征，无证据表明 心脏离子通道抑制）。在本SBIR 1期项目中，我们将确认体外活性 抑制气道平滑肌细胞和白细胞产生促炎介质。在目标2中， 证实鼻内给药后达到超过CRAC IC 50值的肺组织水平。我们 还将监测本实验中的血浆暴露，以了解其全身活性的潜力。 给药方案。在目标3中，我们将量化我们的CRAC调节剂的功效和剂量反应， 鼻内途径（在目的2中确认）对SMR过程和平滑肌质量以及炎症的影响 在哮喘的模型中。这些目标的成功完成将使该计划得以推进 进一步开展IND赋能研究，如制剂和吸入器给药优化、高级毒理学 在第二阶段SBIR资金和其他外部支持下进行测试、化学放大和剂量范围探索。

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.