Aeroquin (MP-376 - Levofloxacin Solution for Inhalation) Clinical Program for Cystic Fibrosis (CF)
Aeroquin is a novel formulation of levofloxacin specifically designed for aerosol administration. The product is being developed as a maintenance therapy in cystic fibrosis for the management of chronic respiratory infections due to Pseudomonas aeruginosa and other serious bacterial pathogens. Aeroquin contains high concentrations of levofloxacin in a novel formulation that enables safe and rapid administration by nebulization, improved lung pharmacokinetics and significant taste-masking.
Cystic Fibrosis and Pseudomonas aeruginosa Infections
CF is caused by a loss of gene function that results in diminished pulmonary mucociliary clearance mechanisms and a massive build-up of thickened mucus in the lungs. This creates an environment in the lungs that is conducive to chronic bacterial infections and local inflammation. These factors lead to a decrease in lung function over time. Pseudomonas aeruginosa is the primary bacterial pathogen associated with loss of lung function and subsequent death in CF patients. The only approved maintenance regimen for treating chronic Pseudomonas aeruginosa infections in CF patients is aerosolized tobramycin (TOBI) administered twice daily for 20 minutes for 28 day cycles. Currently approved dosage regimens call for patients take a 28 day break between cycles. While tobramycin provides benefit in treating infection, it does not eradicate the organism in patients with chronic infection, and both resistance and diminished antimicrobial effects have been reported over time. Additionally, patient adherence to the administration schedule can be poor, with most patients receiving significantly less than the recommended 6 treatment cycles per year.
Our Solution – Aeroquin (MP-376 – Levofloxacin Solution for Inhalation)
We are developing Aeroquin for the treatment of chronic bacterial infections in CF patients. Levofloxacin, the active ingredient in Aeroquin, was approved by the FDA in 1996 and has a well established history of safety and efficacy in the treatment of a variety of infections by the oral or IV route.
Aeroquin is supplied as a ready-to-use solution optimized for use with PARI eFlow technology. Doses can be administered quickly (3-5 minutes) and are being tested in once or twice daily dosage regimens for increased patient compliance. Aerosol administration allows high concentrations of levofloxacin to be deposited at the site of infection in the lung where it is needed, while significantly reducing systemic drug exposures compared to IV and oral routes of administration. As a result, Aeroquin is expected to achieve significant bacterial killing in the lung while reducing the potential for resistance and systemic side effects compared to other routes of administration.
Preclinical pharmacokinetic studies have demonstrated that the novel Aeroquin formulation promotes retention of active drug in the lungs as compared to aerosol delivery of levofloxacin saline solutions. This enhanced retention has been shown in animal models to translate into improved bacterial killing with Aeroquin compared to other formulations. Studies with inhaled Aeroquin in a lethal model of Pseudomonas aeruginosa in the lung have also demonstrated improved bactericidal activity and survival when given once per day vs. inhaled tobramycin or aztreonam when these other agents are administered twice daily. Additionally, Aeroquin has antimicrobial activity against a greater array of CF pathogens than other antibiotics being used or considered for inhaled delivery, including tobramycin, amikacin, and aztreonam.
Aeroquin Clinical Studies
A number of clinical trials have now been completed in CF patients, including a 40 patient Phase 1b study in which Mpex administered Aeroquin for 14 days at 3 different dose levels to CF patients. Aeroquin was well tolerated at all dose levels and pharmacokinetic analyses demonstrated high concentrations of levofloxacin in sputum. This study also provided preliminary evidence for reduction in bacterial counts of Pseudomonas aeruginosa in sputum, and improvement in pulmonary function. Mpex completed a Phase 2b study (Mpex 204; NCT00677365; http://clinicaltrials.gov/ct2/show/NCT00677365?term=MP-376&rank=4 ) in 2009 in the US and EU in 151 antibiotic experienced CF patients. Patients were randomized to 1 of 3 active dosing groups or placebo and received 28 days of treatment followed by a 28 day observation off-drug period. The efficacy endpoints included microbiology, FEV1 and time to requirement for anti-pseudomonal antibiotic treatment (a measure of exacerbations). Results from this study were positive and will be presented at the 2010 ATS meeting in May. The Company is now making preparations to commence Phase 3 trials in CF.
