New drug VS-110 for treating inflammatory bowel diseases

治疗炎症性肠病新药VS-110

基本信息

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
项目类别：
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&apos 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

项目摘要

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，UC 和 UC 的患病率在过去 50 年中已增加至 120-200/100,000 人。 CD 的发病率为 50-200/100,000 人，20-30 岁的人群中 UC 和 CD 的发病率最高。目前治疗 UC 和 CD 的药物尚未显示出一致的效果，尤其是长期维持治疗，需要新的药物来治疗 UC 和 CD 并预防复发。 (VDR) 一旦被其内源性激素骨化三醇 (1,25(OH) 2D3) 激活，就会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 轴在炎症通路中发挥着重要作用。调节与 IBD 相关的许多炎症因子尽管 VDRM 对心血管、中枢神经系统、免疫和肾脏系统有益的数据令人鼓舞，但目前 VDRM 主要用于治疗慢性肾脏病和继发性甲状旁腺功能亢进症。其原因之一是目前 VDRM 的治疗窗口较窄，为 1-4 倍，这是通过比较疗效所需的剂量与所测试的高钙血症剂量来确定的。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 在 Vidasym 的有效剂量范围内应该具有很少或没有高钙毒性。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 的治疗窗超过 50 倍，并且在有效剂量范围内未检测到高钙血症毒性。对 IBD 的治疗具有有效的治疗效果具体目标 1：使用实验性结肠炎模型评估 VS-110 在阻止结肠炎发展方面的治疗效果。目标 2：阐明 VS-110 治疗作用背后的抗结肠炎机制。一旦这项 I 期研究完成，这些数据将使 VS-110 进入包括 VS-110 合成量表在内的 II 期 IND 支持研究。 -up、工艺开发以及药代动力学、代谢、安全性和毒理学的 II 期研究的完成将使 VS-110 进入人体临床试验，以开发 VS-110。每日一次口服胶囊（0.2 - 5 ¿目前用于治疗 IBD 的胃肠道抗炎药物如美沙拉嗪（Asacol、Lialda、Pentasa）和布地奈德 2011 年全球年销售额为 29 亿美元。假设 VS-110 占 20%进军IBD市场，预计年销售额约为5.8亿美元。