Aerosol Delivery of CPZEN-45 for Treatment of Nontuberculous Mycobacterial (NTMs) Infections
Abstract
Non-tuberculous mycobacteria (NTM) are environmental bacteria found commonly in soil, water, and biofilms, the slimy substance found on water-solid interfaces. Chronic lung disease is the most frequent disorder caused by NTM; moreover, NTM lung infections not uncommonly complicate individuals with chronic obstructive pulmonary disease (COPD, aka emphysema) and cause significant deterioration in lung function. Lung disease due to NTM – most often due to Mycobacterium avium complex (MAC) – is a silent and emerging epidemic in the U.S. and many parts of the world. In recent years, the prevalence of NTM lung disease in the U.S. increased by 8.2% per year. Indeed, the number of NTM lung disease (NTM-LD) cases has now far surpassed that for tuberculosis in the U.S. In military and Veteran hospitals, the number of NTM cases is significant and appears to be increasing, reflecting what is seen in the general population but also due to the high prevalence of COPD risk factor in the U.S. Veteran population. NTM-LD is often treated for at least 18-24 months with at least three and sometimes four or more drug regimen. Despite this intense regimen – reflecting the high resistance of NTM to available antibiotics – the long-term cure rate is at best ~50% as the relapse rate is high. Thus, new antibiotics are urgently needed. Members of our research team have discovered a new chemical entity, CPZEN-45, which has been shown to have a novel mechanism of action. It is considered highly promising because it has been shown: (i) to directly kill many pathogenic species of NTM (both drug-sensitive and drug-resistant), (ii) to have efficacy in laboratory animals experimentally infected with NTM, (iii) to possess an acceptable toxicity profile, and (iv) to be able to be delivered directly to the lungs as a dry powder. Before CPZEN-45 can be studied in patients with NTM-LD, we must do further preclinical work by making sure we can produce sufficient quantities of high-quality CPZEN-45 as well as supply large amounts of the compound to do further testing in animals to further ensure efficacy and safety. The ultimate goal of this project is to improve the clinical outcome for patients with NTM lung disease. We envision three areas that could benefit from accomplishing this project: (i) showing feasibility and capability of producing enough CPZEN-45 for experimental work, also laying the groundwork for future clinical trials in patients; (ii) development of a drug efficacy study in a chronic model of NTM infection in experimental animals as NTM-LD in people is a chronic infection; and (iii) further investigation of CPZEN-45 given by inhalation with the ultimate long-range goal of improving efficacy as a result of high local concentration of the antibiotic, limiting toxicity and reducing costs because less amount of the antibiotic need to be given systemically, and improving adherence as the long-range goal is to have the patient self-administer CPZEN-45 by a convenient hand-held dry-powder inhaler. Based on these goals, we believe that this project is timely and aligns well with two of the Fiscal Year 2017 Peer Reviewed Medical Research Program Topic Areas as well as areas of emphasis: “Respiratory Health” and “Antimicrobial Resistance.”
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810765
Entities
People
- Gail Cassell
Organizations
- Infectious Disease Research Institute
- United States Army