(Liposomal Ciprofloxacin)

Development of a new way to treat chronic debilitating and life-threatening respiratory infections in cystic fibrosis.

This product candidate is currently in Phase 2 programs for respiratory infections associated cystic fibrosis and bronchiectasis. Ciprofloxacin has been approved by the FDA as an anti-infective agent and is widely used for the treatment of a variety of bacterial infections. Today ciprofloxacin is delivered by oral or intravenous administration. We believe that delivering this potent antibiotic directly to the lung may improve its safety and efficacy in the treatment of pulmonary infections. We believe that our novel sustained release formulation of ciprofloxacin may be able to maintain therapeutic concentrations of the antibiotic within infected lung tissues, while reducing systemic exposure and the resulting side effects seen with currently marketed ciprofloxacin products. To achieve this sustained release, we employ liposomes, which are lipid-based nanoparticles dispersed in water that encapsulate the drug during storage and release the drug slowly upon contact with fluid covering the airways and the lung. In an animal experiment, ciprofloxacin delivered to the lung of mice appeared to be rapidly absorbed into the bloodstream, with no drug detectable four hours after administration. In contrast, the liposomal formulation of ciprofloxacin produced significantly higher levels of ciprofloxacin in the lung at all time points and was still detectable at 12 hours. We also believe that for certain respiratory disease indications it may be possible that a liposomal formulation enables better interaction of the drug with the disease target, leading to improved effectiveness over other therapies. We have at present three target indications that share much of the laboratory and production development efforts, as well as a common safety data base.

ARD-3100 and ARD-3150 - Liposomal Ciprofloxacin for the Treatment of Infections in Cystic Fibrosis and Non-CF Bronchiectasis Patients

We have two proprietary liposomal ciprofloxacin programs for the treatment and control of respiratory infections associated with chronic diseases - one common to patients with cystic fibrosis, or CF, and the other for infections associated with non-cystic fibrosis bronchiectasis.

CF is a 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. According to the American Lung Association, the direct medical care costs for an individual with CF are currently estimated to be in excess of $40,000 per year.

The inhalation route affords direct administration of the drug to the infected part of the lung, maximizing the dose to the affected site and minimizing the wasteful exposure to the rest of the body where it could cause side effects. Therefore, treatment of CF-related lung infections by direct administration of antibiotics to the lung may improve both the safety and efficacy of treatment compared to systemic administration by other routes, as well as improving patient convenience as compared to injections. Oral and injectable forms of ciprofloxacin are approved for the treatment of Pseudomonas aeruginosa, a lung infection to which CF patients are vulnerable. Currently, there is only one inhalation antibiotic approved for the treatment of this infection, which is administered twice a day. We believe that local lung delivery via inhalation of ciprofloxacin in a sustained release formulation could provide a convenient, effective and safe treatment of the debilitating and often life-threatening lung infections that afflict patients with CF. In particular, an important consideration in the development of new treatments for this disease is the reduction of the burden of therapy for the patients, their relatives and healthcare providers. Our goal is to develop a convenient, once-a-day inhalation product in order to reduce the amount of time and effort associated with administration of the therapy.

Our liposomal ciprofloxacin CF program represents the first program in which we intend to retain full ownership and development rights for the United States. We believe we have the preclinical development, clinical and regulatory expertise to advance this product through development in the most efficient manner. We intend to commercialize this program in the United States on our own.

We are also developing inhaled liposomal ciprofloxacin for pulmonary infections associated with non-CF bronchiectasis - a chronic pulmonary disease with symptoms similar to cystic fibrosis affecting over 100,000 patients in the United States. This is an orphan drug disease with an unmet medical need; there is currently no approved drug treatment in the USA for this indication.

Development

We have received orphan drug designations from the FDA for this product for the management of CF, and for the treatment of respiratory infections associated with non-CF bronchiectasis. As a designated orphan drug, liposomal ciprofloxacin is eligible for tax credits based upon its clinical development costs, as well as assistance from the FDA to coordinate study design. The designation also provides the opportunity to obtain market exclusivity for seven years from the date of New Drug Application, or NDA, approval.

We initiated preclinical studies for liposomal ciprofloxacin in 2006 and we also continued to work on new innovative formulations for this product with the view to maximize the safety, efficacy and convenience to patients. In October 2007, we completed a Phase 1 clinical trial in 20 healthy volunteers in Australia. This was a safety, tolerability and pharmacokinetic study that included single dose escalation followed by dosing for one week. Administration of the liposomal formulation by inhalation was well tolerated and no serious adverse reactions were reported. The pharmacokinetic profile obtained by measurement of blood levels of ciprofloxacin following the inhalation of the liposomal formulation was consistent with the profile from sustained release of ciprofloxacin; the blood levels of ciprofloxacin were much lower than those that would be observed following administration of therapeutic doses of ciprofloxacin by injection or via the gastrointestinal tract. We believe that this is a desirable pharmacokinetic profile likely to result in reduction of the incidence and severity of systemic side effects of ciprofloxacin and to be less likely to lead to evolution of resistant micro-organisms.

In June 2008, we completed a multi-center 14-day treatment Phase 2a trial in Australia and New Zealand in 21 CF patients to investigate safety, efficacy and pharmacokinetics, with the primary efficacy endpoint being the reduction in the density of the pathogenic microorganism Pseudomonas aeruginosa. The primary efficacy endpoint in this Phase 2a study was the change from baseline in the sputum Pseudomonas Aeruginosa colony forming units (CFU), an objective measure of the reduction in pulmonary bacterial load. Data analysis in 21 patients who completed the study demonstrated that the Pseudomonas CFU decreased by a mean 1.43 log over the 14-day treatment period (p<0.0001). Evaluation one week after study treatment was discontinued showed that the Pseudomonas bacterial density in the lung was still reduced from the baseline without additional antibiotic use. 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.

Following the trial we intend to finalize development plans and budgets for this program in conjunction with discussions with the FDA. In order to expedite anticipated time to market and increase patient acceptance, we have elected to deliver our initial formulation of ciprofloxacin via nebulizer, as most CF patients already own a nebulizer and are familiar with this method of drug delivery. We intend to examine the potential for delivery of ciprofloxacin via our AERx® delivery system as well, as it could provide additional convenience for the patient in the form of a small portable device with a faster administration time than a nebulizer.

In June 2008, we initiated a multicenter Phase 2 clinical trial of our inhaled liposomal ciprofloxacin in adult patients with non-CF bronchiectasis. Following an antibiotic washout period, we intend to enroll 36 patients to receive daily inhaled liposomal ciprofloxacin for a period of 28 consecutive days. The primary efficacy endpoint will be treatment of respiratory infection measured as the change in the density of Pseudomonas Aeruginosa bacterial colony forming units (CFU) in the sputum over the treatment period. Secondary endpoints will include pulmonary function measurements and respiratory symptoms. The study is being conducted in leading bronchiectasis centers in the United Kingdom.

Scientific Publications
Aradigm scientists have published extensively on aerosol formulation and pulmonary drug delivery. Following are citations relating to cystic fibrosis and/or liposomal ciprofloxacin.

Geller, D. et al.: "Bolus Inhalation of rhDNase with the AERx System in Subjects with Cystic Fibrosis" Journal of Aerosol Medicine 2003. 16(2): 175-182.

Cipolla, D. et al., Bolus Administration of INS365: Studying the Feasibility of Delivering High Dose Drugs Using the AERx® Pulmonary Delivery System, in Respiratory Drug Delivery VII, 2000, Eds. Dalby, R., et al., Serentec Press, Inc., Raleigh, NC, pp. 231-239 (2000).

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