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

Vivreon Biosciences，LLC 4940卡罗尔峡谷路，Ste. 110 San Diego，CA 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道疾病，发病率高达5，000分之一 个体病理性炎症发生在结肠和直肠的内层， 常驻白细胞对肠道中正常耐受的细菌和其他促炎物质的反应。 这导致潜在的危及生命的溃疡性病变和生活质量的显著破坏。目前 表明小分子和生物药物并非对所有患者有效，或者许多患者 随着时间的推移，对治疗无反应，需要额外的治疗选择。一个有前途和新颖的 控制UC的治疗方法是将抗炎药物的作用限制在肠道的内层 其中局部炎症反应是最极端的，从而同时限制全身性抗- 药物的炎症副作用。一种具有这种肠道限制特性的口服药物 类似于应用于皮肤以控制皮肤的自身免疫炎症的局部药剂。白细胞Ca2 + 释放激活的Ca2+（CRAC）通道对肠单核细胞和T细胞（肠单核细胞和T细胞的主要细胞驱动因子）起作用。 UC）并且由针对外源抗原的白细胞受体触发。CRAC途径调节许多前- 通过激活NFAT和NF-κ B B的转录活性，这些细胞中的炎性基因被激活。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标。 Vivreon的小分子先导CRAC通道阻滞剂VV 8220表现出与肠道一致的物理特性 受限制的口服候选药物，包括口服给药后的强效和有限的全身暴露。这里 我们建议对VV 8220进行进一步的开发前研究，以表征并确认其适用性， 一种用于治疗UC的肠道限制性口服候选药物。在目标1（ADME/DMPK研究）中，我们将评估其直接 对细胞色素P450家族（CYP）酶活性和mRNA表达的影响， 体外hERG通道阻断试验、通过艾姆斯试验的遗传毒性潜力及其体内药代动力学。 在目标2中，我们将在两种小鼠模型中评估其疗效。第一个是DSS模型， 肠屏障和随后的菌群驱动的UC。第二种涉及炎性幼稚细胞的过继转移。 T细胞移植到缺乏抑制性Treg细胞的受体小鼠中，这些细胞通常控制肠道炎症反应 （免疫性T细胞模型）。两个模型结果将通过疾病活动指数、组织病理学和 通过测量肠固有层中UC炎症生物标志物髓过氧化物酶（MPO）。成功 这些目标的完成将使VV 8220计划能够推进到国家自主研发的研究，如高级 毒理学试验、化学放大和剂量范围研究，采用II期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.