Aradigm reported positive results from the ORBIT-3 (NCT01515007 ) and ORBIT-4 (NCT02104245) Phase 3 clinical trials assessing Pulmaquin for the treatment of non-cystic fibrosis bronchiectasis (non-CF BE) in patients with chronic lung infection by Pseudomonas aeruginosa bacteria.
The pivotal clinical trials ORBIT-3 and ORBIT-4 had a similar design, with the exception of a pharmacokinetics (drug properties) sub-study that was conducted in one of the trials.
ORBIT-3 included 278 patients and ORBIT-4 had 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, followed by a 28-day open-label extension study in which patients were treated with Pulmaquin.
The trials’ primary endpoint was the time for the first exacerbation, while frequency of pulmonary exacerbation over the 48-week period served as the secondary endpoint in both studies.
Aradigm reported that in ORBIT-4, the median time to the first pulmonary exacerbation was 230 days in the group of patients receiving Pulmaquin compared to 163 days in the placebo-treated patients, a result that was statistically significant. Over the 48-week treatment period, the frequency of pulmonary exacerbations was reduced by 37 percent in patients treated with Pulmaquin versus placebo-treated patients. This result was also considered statistically significant.
In ORBIT-3, the median time to first pulmonary exacerbation was 221 days in the patients taking Pulmaquin compared to 136 days in the placebo-treated patients. However, this was not considered statistically significant. Over the 48-week treatment period, the frequency of pulmonary exacerbations was reduced by 13 percent in patients treated with Pulmaquin versus placebo-treated patients — again, not statistically significant.
When the data of the two studies was combined, researchers found that Pulmaquin treatment resulted in a statistically significant reduction of 27 percent in the number of pulmonary exacerbations over the entire study period compared to a placebo.
Also, the combined data (referring only to moderate and severe pulmonary exacerbations) showed that the median time to the first pulmonary exacerbation in patients treated with Pulmaquin was 302 days compared to 198 days in placebo-treated patients. Over the 48-week treatment period, there was a statistically significant reduction of 33 percent in the number of moderate to severe pulmonary exacerbations in Pulmaquin-treated patients versus a placebo.
Researchers also found a statistically significant reduction in P. aeruginosa density at day 28 in both studies, and the degree of the antibiotic effect of Pulmaquin was persistent during on-treatment periods.
In both studies, Pulmaquin was safe and well tolerated. There were no differences in changes of lung function or symptoms of airway irritation between Pulmaquin and placebo groups. The most commonly reported treatment-related adverse events were of respiratory, thoracic, or mediastinal nature.
“Patients with non-cystic fibrosis BE chronically infected with P. aeruginosa have a particularly severe form of this disease,” Anne O’Donnell, MD, principal investigator for the North American segment of the ORBIT-3 and ORBIT-4 trials, said in a press release.
“It is exciting to see that after many setbacks in the development of inhaled antibiotics to treat these patients we are finally seeing results with good safety and efficacy,” said O’Donnell, professor of medicine and chief of the Division of Pulmonary, Critical Care and Sleep Medicine at Georgetown University Medical Center.
“Chronic lung infections with P. aeruginosa are a growing global healthcare problem for patients with lung diseases like non-cystic fibrosis BE and COPD,” said Charles Haworth, MD, principal investigator for the Phase 3 studies for ex-North American regions.
“In cystic fibrosis patients we have had success in treating chronic lung infections with inhaled antibiotics, and I am very pleased that Pulmaquin is demonstrating a reduction of pulmonary exacerbations in non-cystic fibrosis BE,” added Haworth, director at the Cambridge Centre for Lung Infection, Papworth Hospital, Cambridge, England.
Aradigm also reported that in its two-year inhalation carcinogenicity study of Pulmaquin, there were no statistically significant differences in the rate of observed tumors between Pulmaquin-treated mice and control groups.
“We are delighted that once daily inhaled Pulmaquin is demonstrating a compelling reduction of pulmonary exacerbations and persistent antibiotic activity against P. aeruginosa infections, together with a good tolerability and safety profile in our Phase 3 clinical trials, as well as no carcinogenicity in animal studies,” said Dr. Juergen Froehlich, MD, Aradigm’s chief medical officer.
“We will review the next steps towards an application for approval of Pulmaquin in the U.S. at an upcoming meeting scheduled with FDA and are planning to engage soon in discussions of these results with the EMA as well,” he said.
Pulmaquin has been granted Orphan Drug status for non-CF BE in the U.S., and has also been designated a Qualified Infectious Disease Product (QIDP) by the U.S. Food and Drug Administration (FDA) for the treatment of non-CF BE patients with chronic P. aeruginosa lung infections, which qualified the drug for FDA Fast Track designation, granted in 2014.