SBIR-STTR Award

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.

Public Health Relevance Statement:
PROJECT NARRATIVE This proposal is intended to support research evaluating whether HBI-002, an oral carbon monoxide therapeutic, can improve outcomes in animal models of anthracycline-associated cardiotoxicity. If successful, the project will provide proof-of-concept for further development of HBI-002 in anthracycline-induced cardiotoxicity as a promising therapeutic to improve outcomes in this long-standing, irreversible, and life- threatening problem with no effective solution.

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

There is an urgent need for the development of approaches to prevent cardiotoxicity in cancer patients beingtreated 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 andalso limits dose and usage. More than a quarter of patients who receive doxorubicin develop significant cardiacmorbidity, and this effect has been shown to be dose dependent. In multiple preclinical studies, we and othershave defined the therapeutic potential of low-dose exogenous carbon monoxide (CO) in anthracyclinecardiotoxicity prevention, including protecting the cardiomyocyte from cell death and maintaining overallcardiovascular health.To date, inhaled CO gas (iCO) and CO bound to carrier molecules (CORMs) have been the modalities ofchoice 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 optionsdue to, with iCO, the risk of inadvertent exposure from the presence of compressed CO cylinders as well asdifficulties in controlling dosing and, with CORMs, carrier molecule toxicology, stability, and CO releasecharacteristics that have proven to be a substantial barrier to development. The objective of the proposedproject is to investigate HBI-002, a novel oral CO drug product that was developed to enable the use of CO toprevent cardiotoxicity from anthracycline use.The safety and tolerability of CO has been demonstrated in eighteen successful Phase 1 and 2 clinical studiesin other indications supported by well-defined preclinical data sets that led to approval by the FDA for humantesting. HBI-002 comprises an oral formulation containing precise amounts of CO that are not bound to acarrier molecule (i.e. not a CORM) and efficiently absorbed from the gastrointestinal tract. Preclinical in vivopharmacokinetic studies demonstrated proof-of-concept feasibility, tolerability, and bioavailability. The nextstep in development is to demonstrate that HBI-002 is effective in clinically relevant animal models ofcardiotoxicity from anthracycline use as has been shown with other forms of CO and to better understand thepotential mechanism(s) of action. Based upon the substantial literature of CO in preventing anthracyclinecardiotoxicity, our central hypothesis that will be tested in this project is: HBI-002 will attenuate Doxorubicin-induced cardiotoxicity through stimulation of mitochondrial biogenesis.

Public Health Relevance Statement:
PROJECT NARRATIVE This proposal is intended to support research evaluating whether HBI-002, an oral carbon monoxide therapeutic, can improve outcomes in animal models of anthracycline-associated cardiotoxicity. If successful, the project will provide proof-of-concept for further development of HBI-002 in anthracycline-induced cardiotoxicity as a promising therapeutic to improve outcomes in this long-standing, irreversible, and life- threatening problem with no effective solution.

Project Terms:
<14-Hydroxydaunomycin>