Predevelopment of VV8220, a Gut-selective CRAC Channel Therapeutic for Ulcerative Colitis

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 NIAID PA-21-259 项目摘要 溃疡性结肠炎(UC)是最常见的炎症性肠病，每5000人中就有一人受到影响 个人。病理性炎症发生在结肠和直肠的内层，原因是不适当的 常驻白细胞对肠道内正常耐受细菌和其他促炎物质的反应。 这会导致潜在的危及生命的溃烂病变和严重的生活质量中断。目前 指示的小分子和生物药物并不是对所有患者都有效，或者许多患者变得 随着时间的推移，对治疗没有反应，需要额外的治疗选择。一部前景看好的小说 控制UC的治疗方法是将抗炎药物的作用限制在肠道内层 局部炎症反应最极端的地方，从而同时限制全身抗炎 药物的炎症性副作用。一种具有这种肠道限制特性的口服药物将会起作用 类似于外用药物应用于皮肤，以控制皮肤的自身免疫性炎症。白细胞内的钙离子 释放激活的钙离子(CRAC)通道作用于肠道单核细胞和T细胞(主要的细胞驱动因子 UC)，并由外来抗原的白细胞受体触发。CRAC途径调节许多前-受体。 炎症基因通过激活NFAT和NF-B转录活性在这些细胞中发挥作用。这些属性 使CRAC通道成为开发肠道限制性小分子药物的合适靶点。 Vivreon的小分子先导CRAC通道阻滞剂VV8220显示出与肠道一致的物理特性 受限制的口服候选药物，包括强大的效力和有限的全身给药剂量。这里 我们建议对VV8220进行进一步的开发前研究，以表征和确认其适用性 一种治疗UC的肠道限制性口服药物候选。在目标1(ADME/DMPK研究)中，我们将评估其直接 细胞色素P450家族(CYP)酶活性和mRNA表达的影响及其心血管易感性 体外HERG通道阻断试验，其通过Ames试验的遗传毒性潜力，以及其体内药代动力学。 在目标2中，我们将在两个小鼠模型上评估其疗效。首先是DSS模型，涉及到对 肠道屏障和随后的菌群驱动的UC。第二个涉及炎症性幼稚的收养转移 T细胞进入缺乏抑制性Treg细胞的受体小鼠，Treg细胞通常控制肠道炎症反应 (采用T细胞模型)。这两个模型的结果将通过疾病活动指数、组织病理学和 通过测定肠道固有层中UC炎性生物标志物髓过氧化物酶(MPO)的含量。成功 完成这些目标将使VV8220计划进入支持IND的研究，如高级 毒理学测试、化学放大和剂量范围发现与第二阶段SBIR和外部资金。

Vivreon Biosciences, LLC 4940 Carroll Canyon Rd., Ste. 110 San Diego, CA 92121 milton@vivreonbiosciences.com NIAID PA-21-259 Project Summary Ulcerative colitis (UC) is the most common form of inflammatory bowel disease affecting up to one in 5,000 individuals. The pathologic inflammation occurs in the inner lining of the colon and rectum due to an inappropriate response of resident leukocytes to normally tolerated bacteria and other pro-inflammatory material in the gut. This results in potentially life-threatening ulcerative lesions and significant disruption to quality of life. Currently indicated small molecule and biologic drugs are not effective in all patients, or many patients become unresponsive to therapies over time, and additional treatment options are needed. One promising and novel therapeutic approach to controlling UC is to restrict anti-inflammatory drug action to the inner lining of the gut where the local inflammatory response is most extreme, thereby simultaneously limiting systemic anti- inflammatory side effects of the drug. An orally available drug with such gut-restricted properties would be acting similarly to topical agents applied to the skin to control autoimmune inflammation of the skin. The leukocyte Ca2+ release activated Ca2+ (CRAC) channel is operative on gut monocytes and T cells (primary cellular drivers of UC) and is triggered by leukocyte receptors for foreign antigens. The CRAC pathway regulates many pro- inflammatory genes in these cells through activation of NFAT and NF-B transcriptional activity. These attributes make the CRAC channel a suitable target for development of a gut-restricted small molecule drug. Vivreon's small molecule lead CRAC channel blocker, VV8220, exhibits physical properties consistent with a gut restricted oral drug candidate, including strong potency and limited systemic exposure upon oral dosing. Here we propose to perform further predevelopment studies with VV8220 to characterize and confirm its suitability as a gut-restricted oral drug candidate for treatment of UC. In Aim 1 (ADME/DMPK studies) we will assess its direct effects on cytochrome P450 family (CYP) enzyme activities and mRNA expression, its cardiovascular liability via an in vitro hERG channel blockade test, its genotoxic potential via an Ames test, and its in vivo pharmacokinetics. In Aim 2 we will evaluate its efficacy in two mouse models. First is the DSS model involving disruption of the intestinal barrier and consequent flora-driven UC. The second involves adoptive transfer of inflammatory naïve T cells into recipient mice lacking suppressive Treg cells that normally control a gut inflammatory response (Adoptive T cell model). The two model results will be assessed by a Disease Activity Index, histopathology and by measurement of the UC inflammatory biomarker myeloperoxidase (MPO) in gut lamina propria. Successful completion of these Aims will position the VV8220 program to advance into IND-enabling studies like advanced toxicology testing, chemistry scale up and dose-range finding with Phase II SBIR and external funding.