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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 ("PE"). 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 (p=0.0462) 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 (p=0.0007) with a
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 (p=0.8488) 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
(p=0.3125) with a
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 (Hazard Ratio Pulmaquin/placebo: 0.73; p=0.0015), 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 (i.e., those that required interventions with antibiotics or hospitalization) the median time to first PE in the Pulmaquin group was 302 days vs. placebo 198 days (p=0.0217). There was also a statistically significant reduction in the number of moderate and severe PE's over the 48-week double-blind period (Hazard Ratio Pulmaquin/placebo: 0.67; p=0.0002) 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 (ORBIT-3: p= < 0.0001; ORBIT-4: p= < 0.0001). 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 (FEV1 % predicted and FVC % predicted) or symptoms of airway irritation between the Pulmaquin and placebo groups in the two studies. Overall, the incidence of all treatment emergent adverse events ("TEAE") was similar between the Pulmaquin and placebo groups in both ORBIT-3 (Pulmaquin: 89.6%; placebo: 91.6%) and ORBIT-4 (Pulmaquin: 86.4%; placebo: 96.9%). 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 (Pulmaquin: 5 (2.7%); placebo: 3 (3.2%)) and 6 deaths in ORBIT-4 (Pulmaquin: 2 (1.0%); placebo: 4 (4.1%)). 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. Eighty-nine percent of the patients who completed ORBIT-3 and 91% percent of the patients who completed ORBIT-4 enrolled in the extension period.
"Patients with non-cystic fibrosis BE chronically infected with P.
aeruginosa have a particularly severe form of this disease. 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 Dr. Anne O'Donnell, MD, Professor of
Medicine and Chief,
"Chronic lung infections with P. aeruginosa are a growing global
health care problem for patients with lung diseases like non-cystic
fibrosis BE and COPD. 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," said Dr.
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.
"We sincerely thank all of the patients and investigators who
participated in these studies for their commitment. 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. We will review the next steps
towards an application for approval of Pulmaquin in the
Further data from the Phase 3 studies will be presented in future publications and medical meetings.
Investor Conference Call Information
A replay of the call will also be available through the
Pulmaquin is a dual release formulation composed of a mixture of liposome encapsulated and unencapsulated ciprofloxacin. Ciprofloxacin, available in oral and intravenous formulations, is a widely prescribed antibiotic. It is used to treat acute lung infections and is often preferred because of its broad-spectrum antibacterial activity against various bacteria, such as P. aeruginosa. Pulmaquin was evaluated in two Phase 3 studies to determine its safety and effectiveness as a once-a-day inhaled formulation for the chronic treatment of patients with non-CF BE who have chronic lung infections with P. aeruginosa.
Following Phase 2a development of the liposomal portion of Pulmaquin
(Lipoquin®) and Phase 1 development of Pulmaquin, the Phase 2b study
ORBIT-2 with Pulmaquin was a 24-week multicenter, randomized,
double-blind, placebo-controlled trial in 42 adult non-CF BE subjects.
This study demonstrated a significant reduction in P. aeruginosa
sputum density (p=0.002) and an increase in time to first exacerbation
in the per protocol population (p=0.046) and the mITT (p=0.057)
populations in the Pulmaquin treated subjects compared to placebo.
Overall, the incidence of all treatment emergent adverse events was
similar between groups. The most frequently reported treatment related
adverse events (reported by ≥ 3 patients in either treatment group)
included product taste abnormal and nausea in the Pulmaquin group and
wheezing in the placebo group.
The Phase 3 clinical program for Pulmaquin in non-CF BE consisted of two worldwide, double-blind, placebo-controlled pivotal trials (ORBIT-3 and ORBIT-4) that are identical in design except for a pharmacokinetics sub-study that was conducted in one of the trials. Each trial enrolled patients (278 in ORBIT-3 and 304 in ORBIT-4) into a 48-week double-blind period consisting of 6 cycles of 28 days on treatment with Pulmaquin or placebo plus 28 days off treatment, followed by a 28 day open label extension in which all participants received Pulmaquin (total treatment duration, including the double-blind period, of approximately one year). The superiority of Pulmaquin vs. placebo during the double-blind period was evaluated in terms of the time to first PE (primary endpoint), while key secondary endpoints included the reduction in the number of PE's and improvements in quality of life measures. Lung function was monitored as a safety indicator.
About Non-Cystic Fibrosis Bronchiectasis
Non-CF BE is a severe, chronic and rare disease characterized by
abnormal dilatation of the bronchi and bronchioles, frequently
associated with chronic lung infections. It is often a consequence of a
vicious cycle of inflammation, recurrent lung infections, and bronchial
wall damage. Non-CF BE represents an unmet medical need with high
morbidity and mortality that affects more than 150,000 people in the
More information about
Except for the historical information contained herein, this news
release contains forward-looking statements that involve risk and
uncertainties, including those related to the analyses of the results
from the ORBIT-3 and ORBIT-4 clinical trials and the interpretation of
those results by regulators, the ability of the Company to file for
approval of Pulmaquin based on those results and the ability to continue
successful product development of our potential product candidates,
including Pulmaquin, as well as the other risks detailed from time to
time in the Company's filings with the
Chief Financial Officer
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