HBI-002 to Treat Ulcerative Colitis

项目摘要 迫切需要开发新的方法来治疗患有溃疡性结肠炎的患者。 结肠炎（UC），估计影响美国约一百万成年人，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、促进组织修复和限制病原性细菌感染。 迄今为止，吸入的CO气体（iCO）和与载体分子结合的CO（CORM）已经成为治疗的模式。 在大多数动物和所有临床研究中，然而，iCO和CORMS预计不会 是药学上可接受的和可行的慢性治疗选择，因为iCO具有意外的风险， 暴露于压缩CO气瓶以及难以控制剂量， CORM、载体分子毒理学、稳定性和CO释放特性已被证明是一种有效的方法。 发展的巨大障碍。本项目的目的是研究HBI-002，一种新的口服给药途径， 或直肠给药的CO药物产品，其被开发用于在UC中长期使用CO。 CO的安全性和耐受性已在五项成功的I期临床研究中得到证实， 通过明确的临床前数据集，FDA批准了人体试验。HBI-002包含 含有不与载体分子结合的精确量的CO的口服制剂（即，不是CORM） 并从胃肠道有效吸收。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 开发步骤是证明HBI-002在临床相关UC动物模型中有效， 已显示与其他形式的CO，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，我们将在本项目中检验的中心假设是：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小鼠模型。

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.