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ARD-3150 Pulmaquin and ARD-3100 Lipoquin

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Scientific Publications

Inhaled Ciprofloxacin for the Management of Infections in Non-Cystic Fibrosis Bronchiectasis (BE) Patients

BE is a chronic “orphan” condition characterized by abnormal dilatation of the bronchi and bronchioles associated with chronic infection. The patient’s lung function is often irreversibly reduced compared to that found in healthy individuals. BE is frequently observed in patients with cystic fibrosis (CF). However, it is a condition that affects over 110,000 people without CF in the United States and many more in other countries, and results from a cycle of inflammation, recurrent infection, and bronchial wall damage. Many of these patients are non-smokers and the origin of their BE is unknown. There is currently no drug specifically approved for the treatment of BE in the U.S. The poor quality of life and untimely death in BE patients is associated with chronic respiratory infections with Pseudomonas aeruginosa.

We have been testing two formulations of inhaled ciprofloxacin (Pulmaquin and Lipoquin) that differ in the proportion of rapidly available and slow release ciprofloxacin. Pulmaquin (also called Dual Release Ciprofloxacin for Inhalation – DRCFI or ARD-3150) uses the slow release liposomal formulation (Lipoquin, also called Ciprofloxacin for Inhalation – CFI or ARD-3100) mixed with a small amount of ciprofloxacin dissolved in an aqueous medium. We tested once daily inhaled Pulmaquin in the ORBIT-2 (Once-daily Respiratory Bronchiectasis Inhalation Treatment) 168 day, multicenter, international Phase 2b clinical trial in 42 adult patients with non-cystic fibrosis bronchiectasis. Statistical significance was achieved in the primary endpoint - the mean change in Pseudomonas aeruginosa density in sputum (CFU) from baseline to day 28: there was a significant mean reduction of 4.2 log10 units in the Pulmaquin group, reflecting an almost sixteen-thousand fold decrease in bacterial load, versus a very small mean decrease of 0.1 log10 units in the placebo group (p=0.004). Secondary endpoint analysis showed that 17 subjects in the placebo group required supplemental antibiotics for respiratory-related infections versus 8 subjects in the Pulmaquin group (p=0.05). The Kaplan-Meier analysis showed that the median time to first pulmonary exacerbation in the per protocol evaluation increased from 58 days in the placebo group to 134 days in the active treatment group and was statistically significant (p<0.05, log rank test). Pulmaquin was well tolerated and there were no significant decreases in lung function, as measured by FEV1 (forced expiratory volume in one second), at 28 days in either group. Overall, the incidence and severity of adverse events were similar in both the placebo and treatment groups; however, Pulmaquin had a superior pulmonary safety profile reflected in the number and severity of pulmonary adverse events. The reduction from baseline in Pseudomonas aeruginosa CFUs with Pulmaquin was rapid and persistent throughout the treatment cycles as exemplified by the statistically significant reductions of the mean log CFU values in the Pulmaquin group versus the placebo at day 14 and day 28 during the first treatment cycle, as well as at the end of the second and third cycles of treatment (days 84 and 140, respectively).

Another Phase 2b study in BE patients - ORBIT-1 - was conducted with once daily inhaled Lipoquin. The primary endpoint was the mean change in Pseudomonas aeruginosa CFUs from baseline to day 28: there was a significant mean reduction (p<0.001) of 2.942 log10 CFUs in the 3mL Lipoquin group and a significant mean reduction (p< 0.001) of 3.842 log10 CFUs in the 2mL Lipoquin group compared to placebos. Pooled placebo groups had a mean reduction of log10 CFUs of 0.437. There was no statistically significant difference between the 2 mL and 3 mL Lipoquin doses. Lipoquin was well-tolerated and no bronchodilator treatment was mandated before inhaled study treatments. There were no statistically significant differences between the active and placebo groups in the number of patients experiencing at least one respiratory treatment-emergent adverse event. The incidence of serious adverse events (SAEs) was low and none of them were treatment related.

After we completed the analysis of all preclinical and clinical data from the two different formulations of inhaled ciprofloxacin (Lipoquin and Pulmaquin), we determined that Pulmaquin showed superior performance. Therefore, Pulmaquin is taken into Phase 3 clinical trials in BE.

Lipoquin (ARD-3100) — Inhaled Ciprofloxacin for the Management of Infections in Cystic Fibrosis (CF) Patients

CF is an “orphan” genetic disease that causes thick, sticky mucus to form in the lungs, pancreas and other organs. In the lungs, the mucus tends to block the airways, causing lung damage and making these patients highly susceptible to lung infections. According to the Cystic Fibrosis Foundation, CF affects roughly 30,000 children and adults in the United States and roughly 70,000 children and adults worldwide. Recent reports suggest that there may be over 100,000 largely undiagnosed CF patients in India. According to the American Lung Association, the direct medical care costs for an individual with CF in the U.S. are currently estimated to be in excess of $40,000 per year. Chronic respiratory infections, especially with Pseudomonas aeruginosa, are the key cause of poor quality of life and untimely death of CF patients.

Currently, there are two inhaled antibiotics (not containing ciprofloxacin) approved for the chronic management of respiratory infections in CF; one of them is given twice a day and the other one three times a day. We think that once a day dosing of our inhaled long acting ciprofloxacin could be a welcome reduction in the burden of therapy for this patient population. Furthermore, some patients may benefit from rotating two or more inhaled antibiotics so that they maintain some form of inhaled antibiotic therapy all the time. As ciprofloxacin is an antibiotic of a different class, with a different mechanism of action to the two currently approved inhaled antibiotics, its use could maximize the control of respiratory infections in CF patients and avoid the side effects associated with the use of the other antibiotics.

We conducted a multi-center 14-day treatment Phase 2a trial in CF patients to investigate safety, efficacy and pharmacokinetics of once daily inhaled Lipoquin. The Pseudomonas aeruginosa colony forming units (CFU), an objective measure of the reduction in pulmonary bacterial load, decreased by a mean 1.43 log over the 14-day treatment period (p<0.0001). Pulmonary function testing as measured by the forced expiratory volume in one second (FEV1) showed a significant mean increase of 6.86% from baseline after 14 days of treatment (p=0.04). The study drug was well tolerated, and there were no serious adverse events reported during the trial.

ARD-1100 — Liposomal Ciprofloxacin for Biodefense Purposes (inhaled tularemia, pneumonic plague, Q-fever)

UK scientists from the Health Protection Agency (HPA) and Defence Science and Technology Laboratory (Dstl) reported the successful testing of our inhaled liposomal ciprofloxacin against Coxiella burnetii in a mouse model of this virulent infection. This work was conducted as part of the collaborative consortium that we formed with HPA, Dstl and Aradigm to evaluate the efficacy of our inhaled liposomal ciprofloxacin against high threat microbial agents. Coxiella burnetii is a Gram-negative intracellular bacterium and the causative agent of the disease Q fever. C. burnetii is endemic worldwide, infects a wide variety of animals and humans and has a low infectious dose by the inhalational route. Clinical presentation in humans may lead to an acute infection with flu-like symptoms, or a chronic life-threatening disease. A recent epidemic of Q fever in humans took place in the Netherlands in 2009, with 2,357 reported cases and 6 deaths.

The scientists from the UK Defence Science and Technology Laboratory (Dstl) also reported in a preliminary study that they have demonstrated that a single dose of Aradigm’s liposomal ciprofloxacin formulation Lipoquin administered 24 hours after exposure to a lethal dose of the bacterium Yersinia pestis provided full protection in this murine model of pneumonic plague. In comparison, a single dose of oral ciprofloxacin administered 24 hours post-exposure provided no protection. The Dstl team had previously demonstrated that a single dose of our inhaled liposomal ciprofloxacin protects animals against lethal doses of inhaled tularemia infection – another microbial threat.

Scientific Publications
Cipolla D. et al. Development of Liposomal Ciprofloxacin to Treat Lung Infections. Pharmaceutics. 2016. 8(1): 6. | Supplementary Material

Cipolla D. et al. Formation of Drug Nanocrystals under Nanoconfinement Afforded by Liposomes. RSC Advances. 2016. 6: 6223-6233.


Cipolla D. et al. Emerging Opportunities for Inhaled Antimicrobial Therapy. J Antimicro. 2015. 1(1): 104.


Cipolla D. et al. Aerosol Performance and Stability of Liposomes Containing Ciprofloxacin Nanocrystals. J Aer Med Pulm Drug Del. 2015. 28(6): 411-422.


Cipolla D. et al. Comment on: Inhaled antimicrobial therapy-Barriers to effective treatment. Adv. Drug Deliv. Rev. 2015. 85: e6-e7.


Norville IH. et al. Efficacy of liposome-encapsulated ciprofloxacin in a murine model of Q fever. Antimicrob Agents Chemother. 2014. 58: 5510-5518.


Cipolla D. et al. Aerosol Performance and Long Term Stability of Surfactant-Associated Liposomal Ciprofloxacin Formulations with Modified Encapsulation and Release Properties. AAPS PharmSciTech. 2014. 15(5): 1218-1227.


Hamblin KA. et al. The Potential of Liposome-Encapsulated Ciprofloxacin as a Tularemia Therapy. Front Cell Infect Microbiol. 2014. 4: 79

 

Cipolla D et al. Modifying the Release Properties of Liposomes toward Personalized Medicine. J. Pharm Sci. 2014. 103(6): 1851-1862.


Darweesh RS. And Sakagami M. In Vitro Inhibitory Activities of Liposomal Ciprofloxacin Against Lipopolysaccharide (LPS)-Induced IL-8 Release from the Calu-3 Cells. RDD 2014. Dalby R.N. et al. (eds). 2014. 747-750.


Cipolla D. et al. Development and Characterization of an In Vitro Release Assay for Liposomal Ciprofloxacin for Inhalation. J. Pharm. Sci. 2014. 103(1): 314-327.

 

Hamblin KA. Et al. Liposome encapsulation of ciprofloxacin improves protection against highly virulent Francisella tularensis strain Schu S4. Antimicrob Agents Chemother. 2014. 58: 3053-3059.


Cipolla D et al. Liposomal Formulations for Inhalation. Ther Delivery. 2013. 4(8): 1047-1072.


Ong HX. et al. In vitro and ex vivo methods predict the enhanced lung residence time of liposomal ciprofloxacin formulations for nebulisation. Eur J Pharm Biopharm. 2013. 86(1): 83-89.


Cipolla D. et al. Liposomal Ciprofloxacin for Inhalation Retains Integrity Following Nebulization. RDD Europe 2013. Dalby R.N. et al. (eds). 2013. 237-242.


Serisier DJ. Et al. Inhaled, Dual-Release Liposomal Ciprofloxacin in Non-Cystic Fibrosis Bronchiectasis (ORBIT-2) – a Randomised, Double-Blind, Placebo-Controlled Trial. Thorax. 2013. 68(9): 812-817.


Ong HX. etal. Liposomal Nanoparticles Control the Uptake of Ciprofloxacin Across Respiratory Epithelia. Pharm Res. 2012. 29(12): 3335-3346.


Ong HX. et al. Inhaled Liposomal Ciprofloxacin Nanoparticles Control the Release of Antibiotic at the Bronchial Epithelia. RDD 2012. Dalby R.N. et al. (eds). 2012. 851-854.


Cipolla D et al. Liposomes, niosomes and proniosomes - a critical update of their (commercial) development as inhaled products. RDD Europe 2011. Dalby R.N. et al. (eds). 2011. 41-54.


Cipolla D. Et al. Inhaled Liposomal Ciprofloxacin: In Vitro Properties and Aerosol Performance. RDD 2010. Dalby R.N. et al. (eds). 2010. 409-414.


Bruinenberg P. et al. Inhaled liposomal ciprofloxacin: Once a day management of respiratory infections. RDD 2010. Dalby R.N. et al. (eds). 2010. 73-82.


Blanchard, J. Pulmonary Drug Delivery as a First Response to Bioterrorism. RDD X. Dalby R.N. et al. (eds). 2006. 73-82.


Yim D. et al. The development of inhaled liposome-encapsulated ciprofloxacin to treat cystic fibrosis. RDD X. Dalby R.N. et al. (eds). 2006. 425-428.

Educational Links
For more information on cystic fibrosis, visit the following web sites:
Cystic Fibrosis Foundation
MedlinePlus
Cystic Fibrosis | A Support Community

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