HBI-002 to Prevent Anthracycline-Related Cardiotoxicity

项目摘要 迫切需要开发预防癌症患者心脏毒性的方法， 用蒽环类药物治疗，蒽环类药物是治疗癌症的一类重要药物（例如阿霉素）。 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的主要临床问题， 也限制了剂量和使用。超过四分之一的接受阿霉素治疗的患者发生显著的心脏病， 发病率，这种影响已被证明是剂量依赖性的。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 心脏毒性预防，包括保护心肌细胞免于细胞死亡， 心血管健康 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研究CO潜在获益的临床研究中， 然而，预期iCO和CORMS不是药学上可接受的和可行的治疗选择 由于使用iCO时，存在压缩CO气瓶的意外暴露风险，以及 难以控制剂量，以及CORM、载体分子毒理学、稳定性和CO释放 这些特点已被证明是发展的重大障碍。建议的目标 该项目是研究HBI-002，一种新型口服CO药物产品，开发该产品是为了使CO的使用能够 预防使用蒽环类药物的心脏毒性。 CO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批准用于人类 试验. HBI-002包含含有精确量的不结合于药物的CO的口服制剂。 载体分子（即不是CORM），并有效地从胃肠道吸收。临床前体内 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 开发步骤是证明HBI-002在临床相关动物模型中有效， 使用蒽环类药物的心脏毒性，如其他形式的CO所显示的那样， 潜在作用机制。本文在大量文献的基础上， 心脏毒性，我们将在本项目中测试的中心假设是：HBI-002将减弱阿霉素- 通过刺激线粒体生物合成诱导心脏毒性。

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.