Aradigm says Pulmaquin 'safe,' 'well tolerated' in ORBIT-3, ORBIT-4 trials
Aradigm announced top-line results from its two Phase 3 clinical trials evaluating the safety and efficacy of Pulmaquin, the company's investigational proprietary formulation of once daily ciprofloxacin for inhalation, in patients with non-cystic fibrosis bronchiectasis with chronic lung infections with Pseudomonas aeruginosa. The ORBIT-3 and ORBIT-4 pivotal trials were identical in design except for a pharmacokinetics sub-study that was conducted in one of the trials. The primary endpoint in both ORBIT-3 and ORBIT-4 was an increase in the median time to first mild, moderate or severe pulmonary exacerbation. The key secondary efficacy endpoint in both trials was the frequency of PE's over the 48-week double-blind treatment period. In ORBIT-4 the median time to first mild, moderate or severe PE was 230 days in the Pulmaquin treatment group as compared to 163 days in the placebo group. This increase in the median time to first PE was statistically significant using non-stratified log-rank analysis. In the key secondary efficacy endpoint, there was a 37% reduction in the frequency of PE's over the 48-week treatment period in the Pulmaquin treatment group as compared to the placebo group. This result was statistically significant with a Hazard Ratio of Pulmaquin/placebo of 0.63 using non-stratified binomial regression. In ORBIT-3 the median time to first mild, moderate or severe PE was 221 days in the Pulmaquin treatment group as compared to 136 days in the placebo group. This increase in the median time to first PE was similar to ORBIT-4 but was not statistically significant using non-stratified log-rank analysis. In the key secondary efficacy endpoint, there was a 13% reduction in the frequency of PE's over the 48-week treatment period in the Pulmaquin treatment group as compared to the placebo group. This result was not statistically significant with a Hazard Ratio of Pulmaquin/placebo of 0.87 using non-stratified binomial regression. The analyses of combined data from both studies resulted in a statistically significant reduction in the number of PE's over the 48-week double-blind period, representing a 27% reduction in PE's over the period. When the additional analyses of combined data from both studies were conducted taking into account only PE's that were moderate or severe the median time to first PE in the Pulmaquin group was 302 days vs. placebo 198 days. There was also a statistically significant reduction in the number of moderate and severe PE's over the 48-week double-blind period using non-stratified analysis, representing a 33% reduction in PE's over the period. In each study, the treatment groups were stratified for gender, pre-trial frequency of exacerbations and smoking status. The Statistical Analysis Plan for the studies called for stratified analyses; however, since some strata were found to have no or very few subjects, both non-stratified and stratified analyses were conducted. The company believes that due to the limited number of subjects in some strata the non-stratified analyses are more appropriate as strata that are too small can produce highly unstable estimated treatment effects with potential outliers. Using the stratified analyses, the median time to first PE in ORBIT-3 was Pulmaquin: 221 days; placebo: 136 days; p=0.7681 and for ORBIT-4 was Pulmaquin: 230 days; placebo: 163 days; p=0.0885. Both studies demonstrated a statistically significant reduction in P. aeruginosa density at Day 28, the end of the first on-treatment period. For each study, the magnitude of this antibiotic effect remained persistent throughout all on-treatment periods. Pulmaquin was safe and well tolerated in both studies. There were no differences in the changes of lung function or symptoms of airway irritation between the Pulmaquin and placebo groups in the two studies. Overall, the incidence of all treatment emergent adverse events was similar between the Pulmaquin and placebo groups in both ORBIT-3 and ORBIT-4. In ORBIT-3 the rates of serious TEAEs were 30.6% with Pulmaquin and 25.3% with placebo while in ORBIT-4 the rates were 17.0% versus 28.6%. For each study, the randomization rate of Pulmaquin treated subjects to placebo was 2 to 1. There were 8 deaths in ORBIT-3 and 6 deaths in ORBIT-4; placebo: 4. None of the deaths was related to Pulmaquin or placebo. The most frequently observed treatment related TEAEs were of respiratory/thoracic/mediastinal nature and were reported in ORBIT-3 by 25.7% of subjects with Pulmaquin and in 21.1% of subjects with placebo, while the rates in ORBIT-4 were 16.5% with Pulmaquin versus 19.4% with placebo. After the completion of the 48-week double-blind period, both Pulmaquin and placebo treated patients were given the opportunity to receive Pulmaquin in a 28-day open label extension period. 89% of the patients who completed ORBIT-3 and 91% of the patients who completed ORBIT-4 enrolled in the extension period. The company also announced that it has received the final statistical analysis report from the two year inhalation carcinogenicity study in rats with Pulmaquin; there were no differences in the rate of observed tumors between the Pulmaquin and control groups. Aradigm has been granted orphan drug designation for Pulmaquin for non-CF BE in the U.S. In addition, FDA has designated Pulmaquin as a Qualified Infectious Disease Product. The QIDP designation is granted for treatment of non-CF BE patients with chronic lung infections with P. aeruginosa and made Pulmaquin eligible for Fast Track designation which was granted by the FDA in September 2014. Further data from the Phase 3 studies will be presented in future publications and medical meetings.