HBI-002 to Prevent Anthracycline-Related Cardiotoxicity

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.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.