Hayward, California-based Aradigm Corporation, an emerging specialty pharmaceutical company focused on the development and commercialization of drugs delivered by inhalation for prevention and treatment of severe respiratory diseases, has announced the appointment of Dr. Robert A. Reed, PhD as the company’s Vice President, Regulatory (CMC) and Quality.
Dr. Reed will be reporting directly to Aradigm’s President and Chief Executive Officer Igor Gonda. Dr. Reed joins Aradigm from Celsion Corporation where he was Senior Vice President of CMC and Technical Operations, overseeing CMC Regulatory and Operations for a liposomal delivery system Celsion has under clinical development for the treatment of primary liver cancer.
“We are delighted that Dr. Reed has joined our team at this critical juncture when our investigational drug Pulmaquin is in global Phase 3 clinical trials for the management of patients with non-cystic fibrosis bronchiectasis,” Dr. Gonda commented. “His rich experience in late stage product development and approval, as well the commercial scale manufacturing of respiratory and liposomal therapeutics, is a particularly important addition to our expertise.”
One focus of that expertise is 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 lung infections. The BE patient’s lung function is often irreversibly diminished compared to that of healthy individuals. Inhalation drug delivery is the preferred method of treatment for many respiratory diseases and Aradigm notes that it is gaining acceptance as a mode of delivery for treatment of systemic diseases.
While BE is frequently observed in patients with cystic fibrosis (CF). It also is estimated to afflict more than 110,000 people without CF in the United States, over 200,000 people in Europe, and many more in other countries. BE results from a cycle of inflammation, recurrent infection, and bronchial wall damage. Many BE patients are non-smokers and the origin of their BE is unknown. Aradigm notes that at present, no drug therapy is specifically approved for treatment of BE in the U.S. Poor quality of life and untimely death in BE patients is associated with chronic respiratory Pseudomonas aeruginosa — an opportunistic human pathogen that typically establishes biofilm infections in chronic wounds and in BE and CF patients’ lungs.
Staphylococcus aureus (“Staph”), is a frequent co-pathogen with Pseudomonas, and interspecies antagonism between the two bacteria strains can result in increased severity of Pseudomonas infections. However, Pseudomonas and Staph biofilms are often small and isolated from direct contact with each other, even when present in the same infection site.
Ciprofloxacin, an antibiotic available in oral and intravenous formulations, is widely prescribed to treat acute lung infections and is often preferred because of its broad-spectrum antibacterial activity against various bacteria, such as Pseudomonas aeruginosa.
Aradigm has 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 — designated DRCFI or ARD-3150) uses the slow release liposomal formulation.
Pulmaquin is an investigational dual release formulation composed of a mixture of liposome encapsulated and unencapsulated ciprofloxacin. It is being evaluated in two ongoing Phase 3 studies to determine its safety and effectiveness as a once-a-day inhaled formulation for the chronic treatment of non-cystic fibrosis bronchiectasis (non-CF BE). Pulmaquin has been tested in preclinical safety studies (up to 3 months in rodents and 9 months in dogs).
The Phase 3 clinical program for Pulmaquin in non-CF BE consists 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 to be conducted in one of the trials. Each trial is enrolling approximately 255 patients 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 will receive Pulmaquin (total treatment duration approximately one year).
Aradigm researchers previously 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. Aradigm reports that 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, Aradigm says 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).
The superiority of Pulmaquin vs. placebo during the double-blind period is being evaluated in terms of the time to first pulmonary exacerbation (primary endpoint), while key secondary endpoints include the reduction in the number of pulmonary exacerbations and improvements in the quality of life measures. Lung function is being monitored as a safety indicator.
Another Phase 2b study in BE patients — ORBIT-1 — was conducted with once daily inhaled Lipoquin (also called Ciprofloxacin for Inhalation CFI or ARD-3100) mixed with a small amount of ciprofloxacin dissolved in an aqueous medium. The trial’s primary endpoint was mean change in Pseudomonas aeruginosa CFUs from baseline to day 28. The company says 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. No statistically significant differences were observed between 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
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 activity (p=0.002) and a decrease 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. No serious adverse events were considered treatment related. There were no deaths reported during ORBIT-2.
Aradigm has been granted orphan drug designations for liposomal ciprofloxacin, as well as for ciprofloxacin for inhalation for non-CF BE in the U.S., and additionally the U.S. Food and Drug Administration (FDA) has classified Pulmaquin as a Qualified Infectious Disease Product (QIDP). The QIDP designation is granted for treatment of non-CF BE patients with chronic lung infections with Pseudomonas aeruginosa, and made Pulmaquin eligible for Fast Track designation which was granted by the FDA in September 2014.
In 2013, Aradigm granted an exclusive, world-wide license for the Company’s inhaled liposomal ciprofloxacin product candidates for the indication of non-CF BE and other indications to Grifols S.A. More information on the terms of this license may be found in the Company’s Annual Report on Form 10-K for the year ended December 31, 2013 filed with the SEC on March 13, 2014.
Dr. Robert Reed has more than 25 years of pharmaceutical industry experience in preclinical, CMC and regulatory activities spanning The Liposome Company, Merck & Company, XenoPort Incorporated and Celsion Corporation. While at Merck & Co., Dr. Reed directed the CMC activities of many late stage products, such as Crixivan, Singular and Januvia. At XenoPort, Dr. Reed oversaw CMC activities for their lead candidate, Horizant. Overall, Dr. Reed has supported the commercialization of 25 drugs for global registration.
Dr. Reed received his PhD from The University of North Carolina at Chapel Hill, followed by a NIH Post Doctoral Fellow at Princeton University. He has published 65 research articles and book chapters, over 110 posters and presentations, and is inventor on 5 patents.
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