SBIR-STTR Award

Direct to Phase II

Lung infections by non-tuberculous mycobacteria (NTM) Mycobacterium avium and Mycobacterium abscessus are increasing in incidence. Diseases caused by both Mycobacteria are common in patients with chronic lung conditions, e.g., cystic fibrosis (CF), non-CF bronchiectasis and emphysema. The current clinical paradigm is to treat patients with M. avium or M. abscessus lung infections with combination therapy given orally or IV. Unfortunately, these therapies often fail, or patients do not tolerate them due to side-effects. Thus, there is a need to develop new anti-mycobacterial therapies with better efficacy and improved safety and tolerability. The overall objective of this project is to test if three novel preparations designed for maximum efficacy and tolerability in the lung (Ciprofloxacin for Inhalation, CFI, Lipoquin®; Dual Release Ciprofloxacin for Inhalation, DRCFI, Linhaliq; and a recently invented ciprofloxacin nanocrystal liposome formulation), provide effective NTM therapy alone and/or in combination with other antimycobacterial agents using in vitro and in vivo models of M. avium and M. abscessus lung infection. All three formulations are comprised of ciprofloxacin encapsulated in liposomes, which provide sustained slow release of the ciprofloxacin in the lung from the liposome, allowing for once-daily dosing. The DRCFI formulation is a mixture of CFI and free ciprofloxacin. The rationale for developing DRCFI is to combine the advantages of an initial transient high concentration of free ciprofloxacin to increase maximum levels in the lung from the free ciprofloxacin component of DRCFI, followed by the slow release of ciprofloxacin from CFI (liposomal component). The nanocrystals release drug more slowly than the others. Aradigm has demonstrated other important advantages of these formulations: avid ingestion by macrophages leading to effective killing of intracellular NTM infections, and the ability to kill NTM even within biofilms formed by these organisms in the lung. The specific aims are: 1) for M avium complex infection, test efficacy of: a) CFI/DRCFI/nanocrystals in combination with standard therapies clarithromycin/ethambutol and amikacin in macrophage/biofilm test systems; b) aerosolized CFI/DRCFI/nanocrystals in combination with systemic clarithromycin/ethambutol and amikacin for lung infection in mice; c) impact of emergence of antibiotic resistance on efficacy; 2) for M abscessus infection, test efficacy of: a) CFI/DRCFI/nanocrystals in combination with standard of therapy linezolid/imipenem in macrophage/biofilm test systems; b) aerosolized CFI/DRCFI/nanocrystals in combination with standard therapies systemic linezolid/imipenem; and c) impact of emergence of antibiotic resistance on efficacy. If an efficacious treatment with CFI or DRCFI (alone or in combination with other drugs) is identified, clinical trials will start in patients with M. avium or M. abscessus lung infection, including those with HIV/AIDS. Aradigm has sufficient safety data in humans and animals to support long-term clinical trials in patients with CFI/DRCFI as well as sufficient cGMP manufacturing in place to support large-scale clinical trials.

Public Health Relevance Statement:
Project Narrative Lung infections by Mycobacterium avium and Mycobacterium abscessus are increasing in incidence (3). M. avium-Mycobacterium intracellulare has become a common complication in patients with chronic lung disease, e.g., emphysema, cystic fibrosis (CF) or bronchiectasis (4,5). Mycobacterium abscessus is associated with infection in patients with CF or follows M. avium infection in patients with chronic pulmonary conditions. Unfortunately, therapies for these infections often fail or are not tolerated, and the infections further compromise these patients' health. Also, a large percentage of the patients develop infections that are resistant to the available antibiotics, presumably because of inadequate concentrations at the sites of infection. There is thus a need to develop new anti-mycobacterial therapies for both diseases. The objective of this project is to test the efficacy of three new liposomal formulations of ciprofloxacin, developed specifically for inhalation, to overcome the problems of systemic therapy in combination with other antimycobacterial agents, using in vitro and in vivo models of M. avium and M. abscessus lung infection.

Project Terms:
Adverse effects; aerosolized; AIDS/HIV problem; Amikacin; Animals; Antibiotic Resistance; Antibiotics; Antimycobacterial Agents; Bacteria; base; Benchmarking; Biological Assay; Breathing; Bronchiectasis; Chronic; Chronic lung disease; Ciprofloxacin; Clarithromycin; Clinical; clinical efficacy; Clinical Research; Clinical Trials; Colony-forming units; Combined Antibiotics; Combined Modality Therapy; commercial application; Complex; Complication; Cyclic GMP; Cystic Fibrosis; cystic fibrosis patients; Data; design; Disease; Dose; efficacy testing; efficacy trial; Encapsulated; Ethambutol; experimental study; FDA approved; Formulation; Funding; Future; Genus Mycobacterium; Health; Human; Imipenem; improved; In Vitro; in vivo; in vivo Model; Incidence; Infection; Ingestion; intraperitoneal; Killings; Linezolid; Liposomes; liquid formulation; Lung; macrophage; Microbial Biofilms; Modeling; mouse model; Mus; mycobacterial; Mycobacterium avium; Mycobacterium avium-intracellulare Infection; Mycobacterium Infections; Mycobacterium intracellulare; nanocrystal; Nebulizer; non-tuberculosis mycobacteria; novel; Oral; Organism; Patients; Pharmaceutical Preparations; Phase; phase 1 study; Predisposition; Preparation; Program Development; Pseudomonas aeruginosa; Pulmonary Emphysema; Research; Research Infrastructure; Resistance; resistant strain; Safety; Saline; Site; System; Systemic Therapy; Testing; Time