HBI-002 to Prevent Anthracycline-Related Cardiotoxicity

项目总结 迫切需要开发预防癌症患者心脏毒性的方法 使用治疗癌症的一类重要药物--蒽环类药物(如阿霉素)。 与蒽环类药物治疗相关的心脏毒性是一个严重影响患者护理和 还限制了剂量和用法。在接受阿霉素治疗的患者中，超过四分之一的患者出现明显的心脏病 发病率，而且这种影响已被证明是剂量依赖的。在多项临床前研究中，我们和其他人 已经确定了低剂量外源性一氧化碳(CO)在蒽环类药物中的治疗潜力 预防心脏毒性，包括保护心肌细胞不受细胞死亡的影响，并保持整体 心血管健康。 到目前为止，吸入的CO气体(ICO)和与载体分子(球茎)结合的CO一直是 在大多数动物和为研究一氧化碳的潜在益处而进行的所有临床研究中都有选择。 然而，预计ICO和球茎不是药学上可接受和可行的治疗选择。 由于ICO存在因存在压缩的CO钢瓶而意外暴露的风险 难以控制剂量和球茎载体分子毒理学、稳定性和CO释放 已被证明是发展的重大障碍的特征。建议的目标是 项目是研究HBI-002，一种新的口服一氧化碳药物产品，开发出来使一氧化碳的使用能够 预防使用蒽环类药物对心脏的毒性。 一氧化碳的安全性和耐受性已在18项成功的1期和2期临床研究中得到证实 在由明确定义的临床前数据集支持的其他适应症中，这些数据集导致FDA批准人类 测试。HBI-002包含一种口服配方，含有精确数量的CO，不与 载体分子(即不是球茎)，从胃肠道有效吸收。临床前体内试验 药代动力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 开发的一步是证明HBI-002在临床相关的动物模型中是有效的。 与其他形式的一氧化碳一样，使用蒽环类药物对心脏的毒性也已被证明，并更好地了解 潜在的作用机制(S)。基于大量文献中一氧化碳在预防蒽环类药物中的作用 心脏毒性，我们将在这个项目中检验的中心假设是：HBI-002将减弱阿霉素- 通过刺激线粒体生物发生而诱导心脏毒性。

PROJECT SUMMARY There is an urgent need for the development of approaches to prevent cardiotoxicity in cancer patients being treated with anthracyclines, an important class of drugs in the treatment of cancer (e.g. doxorubicin). Anthracycline treatment-related cardiotoxicity is a major clinical problem that severely impacts patient care and also limits dose and usage. More than a quarter of patients who receive doxorubicin develop significant cardiac morbidity, and this effect has been shown to be dose dependent. In multiple preclinical studies, we and others have defined the therapeutic potential of low-dose exogenous carbon monoxide (CO) in anthracycline cardiotoxicity prevention, including protecting the cardiomyocyte from cell death and maintaining overall cardiovascular health. 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 carried out to study the potential benefit of CO. However, iCO and CORMS are not expected to be pharmaceutically acceptable and viable 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 CO drug product that was developed to enable the use of CO to prevent cardiotoxicity from anthracycline use. The safety and tolerability of CO has been demonstrated in eighteen successful Phase 1 and 2 clinical studies in other indications 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 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 cardiotoxicity from anthracycline use 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 preventing anthracycline cardiotoxicity, our central hypothesis that will be tested in this project is: HBI-002 will attenuate Doxorubicin- induced cardiotoxicity through stimulation of mitochondrial biogenesis.