Aradigm Corporation and the Woolcock Institute are collaborating to develop cutting-edge nanotechnologies that target the bacterial and fungal biofilms often present in patients with cystic fibrosis (CF), non-CF bronchiectasis (non-CF BE), and other chronic lung diseases.
The most prevalent pathogenic microorganisms found in CF and non-CF BE patients are Haemophilus influenzae, Pseudomonas aeruginosa, Streptococcus pneumoniae, Staphylococcus aureus, and Moraxella catarrhalis. These organisms can inhibit mucociliary clearance, destroy the epithelium that lines the respiratory tract, and produce bacterial and fungal biofilms (any group of microorganisms whose cells stick to each other and adhere to a surface), all of which promote persistent infection by blocking innate immune defenses and increasing antibiotic resistance.
“The adverse impact of bacterial and fungal biofilms in the medical field, including medical devices, organ transplantation and many severe infections with organisms such as Pseudomonas aeruginosa and non-tuberculous mycobacteria, is a significant problem,” Daniela Traini, a professor at Woolcock Institute and the Project Leader for this program, said in a press release.
“Biofilms are not only ubiquitous, they exhibit a recalcitrance to control. According to the United States National Institutes of Health, more than 60% of all microbial infections are caused by biofilms. While acute infections involving motile bacteria are generally treatable with antibiotics and antifungals, once a biofilm is established the infection is often untreatable,” Traini added.
The program, funded by a three-year grant from the Australian Research Councils Linkage Projects, will take place at the Woolcock Institute of Medical Research at the University of Sydney, in Australia, whose network of researchers and clinicians specialize in the causes, prevention, diagnosis and treatment of respiratory disease and sleep disorders.
Aradigm’s liposome formulations are nano-size liquid vesicles made out of lipids that encapsulate drugs, which are deposited directly into the respiratory tract and the drug slowly released, providing sustained and targeted delivery of the treatment with only a minimum effect on the rest of the body.
Aradigm recently reported the completion of the dosing of patients in its two Phase 3 clinical trials, ORBIT-3 (NCT01515007) and ORBIT-4 (NCT02104245), assessing Pulmaquin, its formulation of inhaled ciprofloxacin for the treatment of non-CF BE in patients with chronic infection by Pseudomonas aeruginosa bacteria. Both trials had similar protocols, with the exception of a pharmacokinetics sub-study that was conducted in only one of the clinical trials.
ORBIT-3 included 278 patients and ORBIT-4 included 304 patients, who received either Pulmaquin or a placebo for 48 weeks. Patients were treated every 28 days for six cycles, with 28 days off the treatment, which was followed by a 28-day open-label extension in which all patients were treated with Pulmaquin. The trials’ primary endpoint is the time for the first exacerbation, while reduced exacerbations and improvements in the quality of life are secondary endpoints.
Top-line data is expected to be released before the year’s end.
Pulmaquin combines liposome encapsulated and unencapsulated ciprofloxacin, an agent widely used to treat acute and chronic lung infections and with a broad spectrum of antibacterial activity.
The efficacy of the compound has previously been evaluated in preclinical safety studies, and in Phase 1 and 2 clinical trials. In the phase 2b ORBIT-2 study, treatment with Pulmaquin reduced the activity of the bacteria P. aeruginosa, as well as the time to first exacerbation in 42 adult patients with non-CF BE compared to placebo. No major adverse events related to treatment with Pulmaquin were observed.
Aradigm has been granted orphan drug designation by the U.S. Food and Drug Administration (FDA) for liposomal ciprofloxacin and ciprofloxacin for inhalation for non-CF BE. Pulmaquin has also been designated as a Qualified Infectious Disease Product (QIDP) by the FDA for the treatment of non-CF BE patients with chronic P. aeruginosa lung infections, which made the drug eligible for FDA’s Fast-Track designation, granted in 2014.