HBI-002 to Prevent Anthracycline-Related Cardiotoxicity

HBI-002 可预防蒽环类药物相关的心脏毒性

基本信息

批准号：
10459735
负责人：
Edward Gomperts
金额：
$ 1.69万
依托单位：
HILLHURST BIOPHARMACEUTICALS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-15 至 2023-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10459735
关键词：
Animal Model Animals Anthracycline Attenuated Award Biogenesis Biological Availability Breast Breast Cancer Model Breast Cancer Patient Cancer Model Cancer Patient Canis familiaris Carbon Monoxide Cardiac Cardiac Myocytes Cardiology Cardiotoxicity Cell Death Characteristics Clinical Clinical Research Data Data Set Development Dexrazoxane Dose Doxorubicin Drug Kinetics Effectiveness Exposure to Formulation Gases Gastrointestinal tract structure Goals Hematologic Neoplasms Hemoglobin Hemoglobin concentration result Human Inhalation Inhalation Exposure Injury Investigational Drugs Iron Chelation Kinetics Life Literature Lung Lung Adenocarcinoma Malignant Neoplasms Malignant neoplasm of lung Mitochondria Modality Modeling Morbidity - disease rate Mus Myocardium Oral Oral Administration Ovarian Oxidative Stress Patient Care Patients Pharmaceutical Preparations Pharmacologic Substance Phase Phase I Clinical Trials Phase II Clinical Trials Preparation Prevention Rattus Reporting Research Research Personnel Research Support Risk Safety Seasons Sickle Cell Anemia Small Business Innovation Research Grant Solid Neoplasm Testing Therapeutic Therapeutic Index Toxic effect Toxicology Tumor Burden Wild Type Mouse advanced breast cancer base cancer therapy cardioprotection cardiovascular health clinical development clinically relevant effective therapy experience healthy volunteer improved improved outcome in vivo mouse model novel novel therapeutics potential biomarker pre-clinical preclinical study prevent therapeutic development triple-negative invasive breast carcinoma

项目摘要

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.

项目摘要迫切需要开发用于预防癌症患者心脏毒性的方法用蒽环类药物治疗，这是癌症治疗（例如阿霉素）的重要药物。蒽环治疗相关的心脏毒性是一个主要临床问题，严重影响患者护理和还限制剂量和用法。接受阿霉素的患者中有四分之一以上会发展出明显的心脏发病率，这种作用已被证明是剂量依赖性的。在多个临床前研究中，我们和其他人已经定义了低剂量外源性碳一氧化碳（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受细胞死亡的侵害并保持整体心血管健康。迄今在大多数动物和所有临床研究中的选择，以研究CO的潜在益处。但是，ICO和CORM不预计是可以接受且可行的治疗选择由于ICO，有压缩的CO圆柱体存在无意暴露的风险控制剂量和CORMS的困难，载体分子毒理学，稳定性和CO释放被证明是发展障碍的特征。提议的目标项目将研究HBI-002，这是一种新型的口服CO药物，旨在使CO能够使用CO 防止使用蒽环类药物的心脏毒性。在十八阶段和2期临床研究中已证明了CO的安全性和耐受性在其他指示的指示下，定义明确的临床前数据集导致了FDA的批准测试。 HBI-002包括一个口服配方，其中包含与A结合的精确量的CO 载体分子（即不是CORM），并从胃肠道有效吸收。体内临床前药代动力学研究表明概念证明的可行性，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有效正如其他形式的CO所显示的那样，蒽环类使用的心脏毒性，以更好地了解动作的潜在机制。基于CO的大量文献预防蒽环类心脏毒性，我们将在该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引起的心脏毒性。