New drug VS-110 for treating inflammatory bowel diseases

描述(申请人提供)：炎症性肠病(IBD)涉及所有或部分消化道的慢性炎症。症状可能包括腹痛、严重腹泻和营养不良。IBD主要包括溃疡性结肠炎(UC)和克罗恩病(CD)。在西方，在过去的50年里，UC的患病率增加到120-200/100,000人，CD的患病率增加到50-200/100,000人。UC和CD的发病率在20-30岁的人群中最高。因此，IBD会影响人在生命中最健康和最有生产力的年龄段，导致患者、卫生保健系统和社会的长期成本。目前治疗UC和CD的药物效果并不一致，尤其是对慢性维持治疗。需要新的药物来治疗UC和CD并防止复发。维生素D受体(VDR)一旦被其内源性激素骨化三醇(1，25(OH)2D3)激活，就在炎症途径中调节信号通路。临床前和临床研究也表明，维生素D-VDR轴在调节多种炎性因子参与IBD中起着重要作用。尽管有关VDRM对心血管、中枢神经系统、免疫和肾脏系统的益处的数据令人鼓舞，但目前VDRM主要用于治疗慢性肾脏疾病中的继发性甲状旁腺功能亢进，并在较小程度上用于治疗骨质疏松症和牛皮癣。其中一个原因是由于目前VDRM的治疗窗口很窄，通过比较疗效所需的剂量和高钙毒性来确定其治疗范围为1-4倍。因此，目前市场上的VDRM需要频繁的剂量滴定和血清钙监测，这给临床管理带来了相当大的挑战。理想的VDRM应该在有效剂量范围内具有很小的或没有高钙毒性。Vidasym采取了一种独特的药物发现/开发方法来发现与现有VDRM高度不同的新型VDRM。Vidasym的VS-110的治疗窗口是&gt；50倍，在有效剂量范围内没有检测到高钙毒性。我们推测VS-110对IBD有很强的治疗效果。具体目的1：用实验性结肠炎模型评价VS-110阻断结肠炎发展的疗效。具体目的2：阐明VS-110抗结肠炎的作用机制。一旦这项第一阶段的研究完成，这些数据将使VS-110进入第二阶段的IND使能研究，包括VS-110的合成放大、工艺开发和药代动力学、代谢、安全性和毒理学。第二阶段研究的完成将使VS-110进入人体临床试验。Vidasym计划将VS-110开发成一种口服胶囊，每天一次(0.2-5g/天)，用于治疗IBD。目前，治疗胃肠道炎症疾病的药物，如美沙拉明(Asacol，Lialda，Pentasa)和布地奈德，2011年在全球实现了29亿美元的年销售额。假设VS-110在IBD市场有20%的渗透率，预计年销售额将达到5.8亿美元。

DESCRIPTION (provided by applicant): Inflammatory bowel diseases (IBD) involve chronic inflammation of all or part of the digestive tract. Symptoms may include abdominal pain, severe diarrhea and malnutrition. IBD primarily includes ulcerative colitis (UC) and Crohn's disease (CD). In the West, the prevalence has increased in the past 50 years to 120-200/100,000 persons for UC and 50-200/100,000 persons for CD. Incidence rates for both UC and CD are highest among individuals who are 20-30 years old. Thus, IBD affects individuals in the most healthy and productive years of life, resulting in long-term cost to the patient, health-care syste and society. Current drugs for treating UC and CD have not shown consistent effects, especially for chronic maintenance therapy. New agents are needed to treat UC and CD and prevent relapse. Vitamin D receptor (VDR), once activated by its endogenous hormone calcitriol (1,25(OH) 2D3), modulates signaling pathways in the inflammation pathway. Pre-clinical and clinical studies have also shown that the vitamin D-VDR axis plays an important role in regulating many inflammatory factors involved in IBD. Despite encouraging data on VDRM's benefits for the cardiovascular, CNS, immune, and renal systems, currently VDRMs are mainly indicated for managing secondary hyperparathyroidism in chronic kidney disease, and to a lesser degree used to treat osteoporosis and psoriasis. One of the reasons for this is due to the narrow therapeutic window of current VDRMs in the 1-4-fold range as determined by comparing doses required for efficacy vs. the hypercalcemic toxicity. Consequently, current on-market VDRMs require frequent dose titration and serum calcium monitoring, which causes considerable challenges in clinical management. An ideal VDRM should be with little or no hypercalcemic toxicity in the efficacious dose range. Vidasym has taken a unique drug discovery/development approach to discover novel VDRMs that are highly differentiated from existing VDRMs. Vidasym's VS-110 has a therapeutic window of >50-fold with no detectable hypercalcemic toxicity in the efficacious dose range. We hypothesize that VS-110 has potent therapeutic efficacy for the treatment of IBD. Specific Aim 1: To assess the therapeutic efficacy of VS-110 in blocking the development of colitis using experimental colitis models. Specific Aim 2: To elucidate the anti-colitic mechanism underlying the therapeutic effects of VS-110. Once this phase I study is completed, the data will allow the advancement of VS-110 into Phase II IND-enabling studies including VS-110 synthesis scale-up, process development and pharmacokinetics, metabolism, safety and toxicology. The completion of Phase II studies will allow VS-110 to enter human clinical trials. Vidasym plans to develop VS-110 into an oral, once daily capsule (0.2 - 5 ¿g/day) for treating IBD. Currently drugs for anti-inflammatory diseases in the GI tract such as mesalamine (Asacol, Lialda, Pentasa) and budesonide achieved US$2.9 billion in annual worldwide sales in 2011. Assuming VS- 110 has a 20% penetration into the IBD market, the estimated annual sales will be ~US$0.58 billion.