HBI-002 for Cystic Fibrosis

PROJECT SUMMARY There is an urgent need for the development of new approaches to treat patients suffering from cystic fibrosis (CF). CF results in a poor quality of life and a median life expectancy in the U.S. of only ~46 years of age, despite a number of available drugs. In CF, persisting chronic lung infections with severe acute pulmonary exacerbations and non-resolving airway hyper-inflammation driven by lung neutrophilia result in tissue damage and the irreversible decline of lung function. We have recently demonstrated the therapeutic potential of low dose exogenous carbon monoxide (CO) in preclinical CF models, by reducing inflammation without compromising immune function. 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 clinical studies, and the safety and tolerability of low dose CO has been demonstrated in 22 successful Phase 1 and 2 clinical studies, including in patients with pulmonary conditions such as ARDS and COPD. However, iCO and CORMS are not expected to be pharmaceutically acceptable and viable therapeutic options in CF patients due to, for iCO, the risk of accidental inhalation exposure from the presence of compressed CO gas cylinders and imprecise dosing, especially in CF patients that have limited and variable respiratory function, and, for CORMs, problematic release kinetics and toxicological concerns with carrier molecules. The objective of the proposed project is to investigate HBI-002, a novel oral low dose CO drug product that enables the use of low dose CO in CF. HBI-002 is an oral liquid drug product containing CO. Dosing and follow up in a Phase 1 clinical study under IND in healthy adult subjects with HBI-002 have been completed demonstrating safety and appropriate pharmacokinetics as measured by Cmax, though final data analysis is ongoing. The next step in development is to demonstrate that HBI-002 is effective in clinically relevant animal models of CF 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 chronic inflammatory conditions and our findings in CF models, our central hypothesis that will be tested in this project is: HBI-002 will reduce neutrophilic pathological inflammation in the CF lung without compromising the immune response to infection in experimental mouse models of CF.