HBI-002 to Treat Ulcerative Colitis

HBI-002 治疗溃疡性结肠炎

• 批准号: 10006911
• 负责人: Edward Gomperts
• 金额: $ 21.91万
• 依托单位: HILLHURST BIOPHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-16 至 2021-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10006911
• 关键词: Adrenal Cortex Hormones; Adult; Aminosalicylate; Animal Model; Animals; Award; Bacteria; Bacterial Infections; Biological Availability; Canis familiaris; Carbon Monoxide; Characteristics; Chronic; Clinical; Clinical Research; Clinical Trials; Clostridium difficile; Colitis; Colon; Data; Data Set; Development; Disease; Disease Progression; Disease remission; Dose; Escherichia coli; Experimental Animal Model; Experimental Models; Formulation; Gases; Gastrointestinal tract structure; Genes; Goals; Heightened Cancer Risk; Hemoglobin; Hemoglobin concentration result; Human; Immune Tolerance; Immune response; Immunomodulators; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inhalation; Inhalation Exposure; Integrins; Kinetics; Large Intestine; Link; Liquid substance; Literature; Malignant Neoplasms; Mesalamine; Methods; Modality; Modeling; Morbidity - disease rate; Mus; New Agents; Oral; Pathogenicity; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Phase I Clinical Trials; Phase II Clinical Trials; Phenotype; Population; Population Study; Preparation; Rattus; Rectal Administration; Regimen; Reporting; Research; Research Personnel; Research Support; Risk; Safety; Seasons; Sickle Cell Anemia; Small Business Innovation Research Grant; Sulfasalazine; TNF gene; Testing; Therapeutic; Therapeutic Index; Tissues; Toxic effect; Toxicology; Ulcerative Colitis; United States; base; cigarette smoke; cigarette smoking; clinically relevant; experience; gastrointestinal; gut microbiota; healing; human subject; improved; improved outcome; in vivo; infection risk; inhibitor/antagonist; innovation; mortality; mouse model; novel; novel strategies; novel therapeutics; pharmacokinetics and pharmacodynamics; pre-clinical; preclinical efficacy; preclinical study; rectal; research clinical testing; side effect; small molecule; therapeutic development; tissue repair; volunteer

PROJECT SUMMARY There is an urgent need for the development of new approaches to treat patients suffering from Ulcerative Colitis (UC), which is estimated to impact approximately one million adults in the United States, leading to morbidity, heightened risk of cancer, and mortality. In multiple preclinical studies, we and others have defined the therapeutic potential of low-dose exogenous carbon monoxide (CO) in UC, including in simultaneously reducing inflammation, promoting tissue repair, and limiting pathogenic bacterial infection. To date, inhaled CO gas (iCO) and CO bound to carrier molecules (CORMs) have been the modalities of choice in the majority of animal and in all the clinical studies. However, iCO and CORMS are not expected to be pharmaceutically acceptable and viable chronic therapeutic options due to, with iCO, the risk of inadvertent exposure from the presence of compressed CO cylinders as well as difficulties in controlling dosing and, with CORMs, carrier molecule toxicology, stability, and CO release characteristics that have proven to be a substantial barrier to development. The objective of the proposed project is to investigate HBI-002, a novel oral or rectally administered CO drug product that was developed to enable the chronic use of CO in UC. The safety and tolerability of CO has been demonstrated in five successful Phase 1 clinical studies supported by well-defined preclinical data sets that led to approval by the FDA for human testing. HBI-002 comprises an oral formulation containing precise amounts of CO that are not bound to a carrier molecule (i.e. not a CORM) and efficiently absorbed from the gastrointestinal tract. Preclinical in vivo pharmacokinetic and pharmacodynamic studies demonstrated proof-of-concept feasibility, tolerability, and bioavailability. The next step in development is to demonstrate that HBI-002 is effective in clinically relevant animal models of UC as has been shown with other forms of CO and to better understand the potential mechanism(s) of action. Based upon the substantial literature of CO in IBD, our central hypothesis that will be tested in this project is: HBI-002 will modulate the immune response to regulate inflammation, improve survival, and promote healing in UC mouse models.

项目概要 迫切需要开发新方法来治疗患有溃疡的患者 结肠炎 (UC)，估计影响美国约 100 万成年人，导致 发病率、癌症风险增加和死亡率。在多项临床前研究中，我们和其他人已经定义了 低剂量外源性一氧化碳 (CO) 在 UC 中的治疗潜力，包括同时 减少炎症，促进组织修复，并限制病原菌感染。 迄今为止，吸入 CO 气体 (iCO) 和与载体分子结合的 CO (CORM) 已成为 大多数动物和所有临床研究中的选择。然而，iCO 和 CORMS 预计不会 是药学上可接受且可行的慢性治疗选择，因为使用 iCO 时，存在无意的风险 暴露于压缩二氧化碳气瓶的存在以及控制剂量的困难以及 CORM、载体分子毒理学、稳定性和 CO 释放特性已被证明是 严重阻碍发展。该项目的目标是研究 HBI-002，一种新型口服药物 或直肠给药的 CO 药物产品，该产品是为了在 UC 中长期使用 CO 而开发的。 CO 的安全性和耐受性已在五项成功的 1 期临床研究中得到证实 通过明确的临床前数据集，该数据集导致 FDA 批准进行人体测试。 HBI-002 包括一个 含有精确量的 CO 且未与载体分子结合的口服制剂（即不是 CORM） 并能有效地从胃肠道吸收。临床前体内药代动力学和 药效学研究证明了概念验证的可行性、耐受性和生物利用度。下一个 开发步骤是证明 HBI-002 在 UC 临床相关动物模型中有效，因为 已与其他形式的 CO 一起显示，并更好地了解潜在的作用机制。基于 根据 IBD 中 CO 的大量文献，我们将在本项目中测试的中心假设是：HBI-002 将调节免疫反应以调节炎症、提高生存率并促进愈合 UC 鼠标模型。