New drug VS-110 for treating inflammatory bowel diseases

治疗炎症性肠病新药VS-110

• 批准号: 8586283
• 负责人: Yan Chun LI
• 金额: $ 29.92万
• 依托单位: VIDASYM, INC.
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-15 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8586283
• 关键词: 2 year old; Abdominal Pain; Address; Admission activity; Adverse effects; Affect; Animal Model; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Apoptosis; Attenuated; Budesonide; Calcitriol; Calcium; Cardiovascular system; Chronic; Chronic Kidney Failure; Clinical Management; Clinical Research; Clinical Trials; Colitis; Colon; Crohn' s disease; Data; Development; Diarrhea; Disease; Dose; Drug Kinetics; Epithelial; Epithelial Cells; Exhibits; Gastrointestinal tract structure; Glycols; Goals; Health; Healthcare; Healthcare Systems; Hormones; Hospitals; Human; Immune; Incidence; Individual; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Kidney; Knowledge; Lead; Life; MYLK gene; Maintenance; Maintenance Therapy; Malnutrition; Marketing; Medical; Mesalamine; Metabolism; Modeling; Molecular; Monitor; NF-kappa B; New Agents; Octanes; Oral; Osteoporosis; Outcome; Pain; Pathway interactions; Patients; Penetration; Persons; Pharmaceutical Preparations; Phase; Physicians; Play; Prevalence; Process; Production; Psoriasis; Receptor Signaling; Relapse; Research Personnel; Resuscitation; Role; Safety; Sales; Savings; Secondary Hyperparathyroidism; Serum; Signal Pathway; Small Business Technology Transfer Research; Societies; Sodium Dextran Sulfate; Study Section; Sulfonic Acids; Symptoms; System; Therapeutic; Therapeutic Effect; Therapeutic Index; Tight Junctions; Titrations; Toxic effect; Toxicology; Treatment Efficacy; Trinitrobenzenes; Ulcerative Colitis; Visit; Vitamin D; Vitamin D3 Receptor; base; capsule; commercial application; cost; cytokine; drug discovery; novel; phase 1 study; phase 2 study; pre-clinical; prevent; public health relevance; scale up; technological innovation

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.

描述（由申请人提供）：炎症性肠病（IBD）涉及全部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和CD的患病率分别上升到120-200/10万人和50-200/10万人。UC和CD的发病率在20-30岁的人群中最高。因此，IBD影响的个体处于生命中最健康和最有生产力的年龄，对患者、卫生保健系统和社会造成长期成本。目前治疗UC和CD的药物尚未显示出一致的效果，特别是慢性维持治疗。需要新的药物来治疗UC和CD并防止复发。维生素D受体（VDR）一旦被内源性激素骨化三醇（1,25(OH) 2D3）激活，就可以调节炎症通路中的信号通路。临床前和临床研究也表明，维生素D-VDR轴在调节IBD中涉及的许多炎症因子中起重要作用。尽管VDRM对心血管、中枢神经系统、免疫和肾脏系统的益处令人鼓舞，但目前VDRM主要用于治疗慢性肾脏疾病的继发性甲状旁腺功能亢进，并且在较小程度上用于治疗骨质疏松症和牛皮癣。造成这种情况的原因之一是由于目前VDRMs的治疗窗口在1-4倍范围内狭窄，这是通过比较疗效所需剂量与高钙血症毒性确定的。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应在有效剂量范围内很少或没有高钙血症毒性。Vidasym采用独特的药物发现/开发方法来发现与现有vdrm高度不同的新型vdrm。Vidasym的VS-110具有50倍的治疗窗，在有效剂量范围内无可检测到的高钙血症毒性。我们假设VS-110在治疗IBD方面具有强大的疗效。目的1：利用实验性结肠炎模型，评价VS-110阻断结肠炎发展的治疗效果。特异性目的2：阐明VS-110治疗结肠炎的作用机制。一旦I期研究完成，这些数据将允许VS-110进入II期ind研究，包括VS-110合成放大、工艺开发和药代动力学、代谢、安全性和毒理学。II期研究的完成将允许VS-110进入人体临床试验。Vidasym计划将VS-110开发成一种口服、每日一次的胶囊（0.2 - 5克/天），用于治疗IBD。目前，用于胃肠道抗炎疾病的药物，如美沙拉胺（Asacol, Lialda, Pentasa）和布地奈德，2011年全球年销售额达到29亿美元。假设VS- 110在IBD市场的渗透率为20%，预计年销售额将达到约5.8亿美元。