Exhibit 99.1
Inhaled Liposomal Ciprofloxacin In Patients With Bronchiectasis And ChronicPseudomonas Aeruginosa Infection: Results From Two Parallel Phase III Trials(ORBIT-3 andORBIT-4)
C. Haworth1, A. Wanner2, J. Froehlich3, T. O’Neal3, A. Davis4, I. Gonda3, A. O’Donnell5
1Papworth Hospital NHS Foundation Trust - Cambridge/GB,2University of Miami School of Medicine - Miami, FL/US,3Aradigm Corporation - Hayward, CA/US,4Grifols - Research Triangle Park, NC/US,5Georgetown University - Washington, DC/US
Background
Chronic airway infection withPseudomonas aeruginosa(PA) in patients withnon-cystic fibrosis bronchiectasis (NCFBE) is associated with more frequent pulmonary exacerbations (PEs), hospital admissions, reduced quality of life and higher mortality than in patients without PA infection.ARD-3150 is an inhaled antibiotic containing liposome-encapsulated ciprofloxacin 150mg/3mL and free ciprofloxacin 60mg/3mL which resulted in compelling microbiological and clinical outcomes in a Phase II study(ORBIT-2) of NCFBE patientswith chronic PA infection.
Objectives
To evaluate the efficacy and safety of once dailyARD-3150 in 2 identical multi-national, randomized, double blind, placebo-controlled clinical trials(ORBIT-4, NCT02104245;ORBIT-3, NCT01515007).
Methods
582 patients with NCFBE, chronic infection with PA, and³2 PEs requiring treatment with antibiotics in the preceding year were enrolled inORBIT-4 (n=304) andORBIT-3 (n=278). NebulizedARD-3150 or placebo were administered once daily for six cycles of 28 days on treatment, separated by 28 days off treatment, for a total of 48 weeks. The key efficacy endpoints were the time to first protocol defined PE and the frequency of all and severe PEs (defined as requiring treatment with intravenous antibiotics and / or hospitalization).
Results
In both,ORBIT-4 andORBIT-3 treatment withARD-3150 compared to placebo was associated with an increase of >2 months in the median time to first PE. InORBIT-4 this result was statistically significant
in the log rank test with stratification for sex and prior PEs, while inORBIT-3 it was not.ORBIT-4 also showed a statistically significant reduction in the frequency of all protocol defined PEs (regardless of whether antibiotic treatment was given) and all severe PEs compared to placebo. InORBIT-3 the frequency of all and severe PEs was not statistically significantly reduced. Pooled analyses for PEs that required treatment with antibiotics resulted in statistically significant results for the prolongation of the median time to first PE of > 3 months and the reduction of the frequency of all and severe PEs. Pulmonary function tests (FEV1, FVC or DLCO) were not different between theARD-3150 and placebo groups in each study. The rates of treatment-emergent adverse events (TEAEs) and serious TEAEs were also similar in both treatment groups.
Conclusion
InORBIT-4, cyclical treatment withARD-3150 resulted in statistically significant prolongation of the time to first PE and reductions in the annual frequency of all and severe PEs in patients with NCFBE and chronic lung infections with PA.ORBIT-3 did not show significant results for the key PE endpoints. The safety profile betweenARD-3150 and placebo was similar.
Microbiological Results From Two Parallel, Randomized, Double-Blind, Placebo-Controlled Phase III Trials(ORBIT-4 andORBIT-3) Of The Inhaled AntibioticARD-3150 In Patients WithNon-Cystic Fibrosis Bronchiectasis And ChronicPseudomonas aeruginosa Infection
Juergen Froehlich1, Janice Dahms1, David Cipolla1, Donald VanDevanter2 and Igor Gonda1
1Aradigm Corporation - Hayward, CA/US,2Case Western Reserve University School of Medicine, Cleveland, OH/USA
Background
In a Phase II study(ORBIT-2), once-daily inhaledARD-3150 (liposome-encapsulated ciprofloxacin 150mg/3mL and free ciprofloxacin 60mg/3mL) showed promising clinical and microbiological responses, achieving the primary outcome of significant reduction in sputumP aeruginosa (PA) bacterial density in patients withnon-cystic fibrosis bronchiectasis (NCFBE) and chronic PA infection. In the 2 identical, multi-national, randomized, double blind, placebo-controlled, phase 3 trials (ORBIT-4, NCT02104245;ORBIT-3, NCT01515007) ofARD-3150 in patients with NCFBE, reduction in sputum PA bacterial density and ciprofloxacin susceptibility were key secondary endpoints. We report these microbiologic results from both trials.
Methods
Patients with NCFBE, chronic infection with PA, and³2 pulmonary exacerbations (PEs) requiring treatment with antibiotics in the preceding year, were enrolled in eitherORBIT-4 (n=304) orORBIT-3 (n=278). NebulizedARD-3150 or placebo was administered once-daily for six cycles of 28 days on treatment, separated by 28 days off treatment for a total of 48 weeks. In addition to the efficacy endpoints related to protocol-defined PEs, microbiological endpoints included reduction in colony forming units (CFU) in sputum PA density (log10 CFU/g) and ciprofloxacin minimum inhibitory concentration (MIC) changes from baseline. Individual log changes were analyzed using a general linear model procedure with treatment as factor and stratification factors of sex and previous number of PE as covariates.
Results
ARD-3150 significantly reduced mean (±SE) sputum PA density more than placebo on day 28 of the first dosing period by-1.80± 0.37 log10 and-1.87±0.38 CFU/g inORBIT-4 andORBIT-3, respectively (p<0.0001 for both). With the exception of cycle 3 inORBIT-3, significant reductions in sputum PA density compared with baseline (p<0.05) were observed at the end of every on-treatment period throughout both trials demonstrating a persistent antipseudomonal effect withARD-3150, but not with placebo. PA density increased returning to near baseline values during theoff-treatment periods. Reductions in PA sputum density withARD-3150 occurred regardless of susceptibility of PA isolates to ciprofloxacin at baseline or when PA isolates became more resistant (MIC>4 mcg/mL) on treatment. There was a greater tendency for increasing ciprofloxacin MICs withARD-3150 vs placebo during theon-treatment periods, and this increase subsided during theoff-treatment periods. A small number of patients exhibited the emergence of PA strains with ciprofloxacin MIC³64 mcg/mL; however, these were often transient.
Conclusion
Cyclical treatment with once-daily inhaledARD-3150 was associated with a significant reduction in sputum PA density, without attenuation of antibiotic activity, during each treatment cycle over the48-week trial.
Inhaled Liposomal Ciprofloxacin In Patients WithNon-Cystic Fibrosis Bronchiectasis (NCFBE) And ChronicPseudomonas Aeruginosa Infection: Pharmacokinetics Of Once-Daily InhaledARD-3150
Juergen Froehlich1, David Cipolla1, Anthony De Soyza2, Glynn Morrish3, Igor Gonda1
1Aradigm Corporation - Hayward, CA/US,2Newcastle University and Freeman Hospital Adult bronchiectasis service – Newcastle/UK,3Clinical Network Services, Toowong, QLD/Australia
Background
ARD-3150 is a combination of free (60mg/3mL) and liposome-encapsulated ciprofloxacin (150mg/3mL), providing immediate and slow release of ciprofloxacin to the respiratory tract and allowing once daily inhalation. In the double blindORBIT-3 trialARD-3150 was investigated in NCFBE patients with chronic lung infections withPseudomonas aeruginosa(PA) (NCT01515007). Treatment withARD-3150 or placebo consisted of 6 cycles of 28 days on/28 days off treatment, followed by a 28 day open label extension with once-dailyARD-3150 that included a PKsub-study.
Methods
Patients with NCFBE, documented chronic infection with PA, and³2 pulmonary exacerbations (PEs) requiring treatment with antibiotics in the preceding year, were enrolled (n=278) inORBIT-3. In the open label extension, nebulizedARD-3150 was administered once-daily for 28 days with intensive PK sampling in 16 patients. In these, blood was collectedpre-dose on Day 7, and at 15 min, 30 min, 1 h, 1.5 h, 2 h, 3 h, 4 h, 6 h and 8 h post-dose. Sputum samples were collectedpre-dose on Day 7, and15-30 min,1-1.5 h,2-2.5 h,3-3.5 h,4-4.5 h,6-6.5 h, and8-8.5 h post-dose. If possible,12-hour samples of sputum and plasma were collected at the study site or at the subject’s home. Additionally, sputum and blood samples were collectedpre-dose and 2 hours post-dose on Days 8 and 28. Plasma and sputum ciprofloxacin PK parameters were determined usingnon-compartmental analysis methods. Accumulation of ciprofloxacin in plasma and sputum was evaluated by the ratio of Day 8 and Day 28pre-dose and2-hour post-dose concentrations.
Results
There were 223 plasma and 205 sputum concentrations available for ciprofloxacin analysis. After inhalation ofARD-3150, there was an early peak of free ciprofloxacin both in sputum (median Tmax=0.8 h)
and plasma (median Tmax=1.4 h), followed by slow elimination. This profile represents the combined effect of immediate availability of free ciprofloxacin and slow release of the liposome-encapsulated ciprofloxacin fromARD-3150. Median sputum ciprofloxacin PK parameters were: Cmax= 1,530, mcg/g; Cmin= 70.25 mcg/g; and AUC0-24 = 11,570 (h*mcg/g). Median plasma ciprofloxacin PK parameters were: Cmax=180.0 ng/mL; Cmin=26.0 ng/mL; AUC0-24 = 1481 (h*ng/mL); and t1/2=9.3 h. Median sputum Cmaxwas 8,500 times greater than plasma Cmax. There was no systematic trend of further increasing sputum ciprofloxacin concentrations from day 8 to day 28, indicating that high steady state levels were sustained.
Conclusions
Treatment with once-daily inhaledARD-3150 is associated with high sputum ciprofloxacin concentrations throughout the 24 h dosing interval that are several orders of magnitude higher than plasma concentrations, are achieved early after initiation of treatment and remain above the minimum inhibitory concentration of typical PA strains during the28-dayon-treatment period. Systemic ciprofloxacin concentrations in plasma are at least an order of magnitude lower than plasma concentrations reported in the literature achieved with commonly used therapeutic doses of intravenously or orally administered ciprofloxacin.
