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Sunday, May 30, 2010

Mpex Pharmaceuticals Presents Positive Phase 2 Clinical Trial Results of Aeroquin

Mpex Pharmaceuticals Presents Positive Phase 2 Clinical Trial Results of Aeroquin(TM) (MP-376) Treatment in Cystic Fibrosis Patients

SAN DIEGO, May 17 /PRNewswire/ -- Mpex Pharmaceuticals, Inc. today announced the presentation of data from its Phase 2b clinical trial with Aeroquin™ (a proprietary aerosol formulation of levofloxacin, MP-376) in cystic fibrosis (CF) at the American Thoracic Society (ATS) Annual Meeting in New Orleans. Trial results demonstrated statistically significant improvements in bacterial load, respiratory function and time to need for anti-pseudomonal antibiotics (a measure of exacerbations) versus placebo in a heavily treated patient population. The results were presented by Dr. Douglas Conrad from the University of California at San Diego School of Medicine, the principal investigator for the study.

The Phase 2b, multi-center randomized, double-blind, placebo-controlled trial (Mpex 204) studied 151 CF patients to evaluate the safety, tolerability and efficacy of three dose levels of inhaled Aeroquin (120mg QD, 240 mg QD and 240 mg BID) administered for 28 days using an customized investigational eFlow® Nebulizer System (PARI Pharma GmbH). Patients were then followed for an additional 28 days after completion of dosing. The trial was conducted in the U.S., Germany and the Netherlands.

To ensure that results from this trial were as predictive as possible for the future Phase 3 program and consistent with current clinical practice, the study enrolled patients that had recently received multiple courses of inhaled antibiotics and in most cases were receiving concomitant medication such as dornase alpha, azithromycin and hypertonic saline that have been shown in previous studies to improve lung function and/or reduce exacerbations.
The trial met the primary endpoint of a reduction in sputum Pseudomonas aeruginosa density at Day 28, the end of treatment. All three doses of Aeroquin demonstrated statistical significance (p < 0.01 for each group versus placebo), with the highest dose (240 mg BID) showing the greatest effect of approximately 1 log reduction. There was no evidence for emergence of bacterial resistance during the study.

Improvements in respiratory function were also demonstrated in the trial. A greater proportion of patients had improvement in percent predicted FEV1 with any dose of Aeroquin compared to placebo, with a difference of 10.9% in percent predicted FEV1 between the 240mg BID group and placebo at day 28 (p=0.0008). Patients treated with 240 mg BID also had a 22% improvement in FEF25-75 (p<0.0001) and a 7.3% improvement in percent predicted FVC (p=0.014) at day 28 versus placebo. FEV1, FEF25-75 and FVC are standard measures of lung function in CF patients.

Consistent with these results, a statistically significant reduction in the need for other inhaled and/or systemic anti-pseudomonalantimicrobials was observed in all Aeroquin groups vs. placebo (risk reduction of 79% for 240mg BID vs. placebo; p=0.0007). The percent of patients with adverse events (AEs) was similar across all treatment groups, with no evidence of increasing incidence or severity of AEs with increasing Aeroquin dose.

"The results from the Aeroquin Phase 2b CF trial are very encouraging both in terms of the improvement in lung function and the reduction in the need for other anti-pseudomonal antimicrobials," stated Dr. Conrad. "The combination of these outcomes with an attractive safety profile to date and a convenient dosing regimen makes Aeroquin a potentially important new agent. These results were especially impressive because they were obtained in a heavily treated patient population, where demonstrating benefit can be more difficult."

"I am impressed with both the strength and quality of the data from this Aeroquin trial", stated Dr. Patrick Flume, Professor of Medicine and Pediatrics at the Medical University of South Carolina and Co-Chair of the Pulmonary Guidelines Committee of the Cystic Fibrosis Foundation. "Importantly, Aeroquin represents a new class of inhaled antibiotics for the treatment of CF. If we are to achieve our treatment objective of reducing bacterial exacerbations over the long term, it is critical that chronically infected patients be treated frequently with inhaled antibiotics. Having multiple classes of aerosol antibiotics available will give clinicians the ability to rotate classes and tailor treatment to the needs of each individual patient. Clinicians believe this is the best way to maximize efficacy and tolerability while minimizing resistance and side effects over the long term."

Mpex has been cleared to proceed to Phase 3 trials with Aeroquin by the U.S. FDA and is scheduled to meet with European regulatory authorities later this quarter. Phase 3 studies are expected to begin shortly thereafter.

About Aeroquin (MP-376)

Aeroquin is a proprietary formulation of levofloxacin that has been optimized for aerosol delivery using a customized Investigational eFlow Nebulizer System (PARI Pharma GmbH). Levofloxacin is a fluoroquinolone antibiotic that has been widely used in a variety of indications for over a decade and has established safety and efficacy when administered orally or intravenously against many bacterial pathogens, including Pseuomonas aeruginosa. Administration of Aeroquin with a high efficiency nebulizer to the lungs allows for the rapid delivery of high concentrations of active drug directly to the site of infection, while minimizing systemic exposure.

Comparison of settings used for high-frequency chest-wall compression in cystic fibrosis.

Respir Care. 2010 Jun;55(6):695-701.

Comparison of settings used for high-frequency chest-wall compression in cystic fibrosis.

Kempainen RR, Milla C, Dunitz J, Savik K, Hazelwood A, Williams C, Rubin BK, Billings JL.
Department of Medicine, Hennepin County Medical Center, University of Minnesota School of Medicine, Mail Stop G-5, 701 Park Avenue, Minneapolis MN 55415. kempa001@umn.edu.


BACKGROUND: Cystic fibrosis (CF) patients commonly use a high-frequency chest-wall compression (HFCWC) device for airway clearance that generates oscillatory flow with a sine-wave configuration. Typical HFCWC settings combine a lower Vest inflation pressure setting (eg, 5 on the Vest's arbitrary 1-10 scale for the setting that controls the background pressure of the inflatable vest) with mid-range frequency (14-16 Hz) (lower-pressure/mid-frequency HFCWC). OBJECTIVE: To determine whether HFCWC with higher pressure settings (6-10 on the Hill-Rom Vest's arbitrary 1-10 scale) combined with variable mid-frequencies (8, 9, and 10 Hz, plus 18, 19, and 20 Hz) (higher-pressure/variable-frequency HFCWC) results in greater sputum expectoration than lower-pressure/mid-frequency HFCWC.

METHODS: This was a controlled randomized crossover study. Sixteen clinically stable, adult CF patients participated. Patients performed airway clearance with HFCWC, once each with lower-pressure/mid-frequency HFCWC and higher-pressure/variable-frequency HFCWC, on separate occasions. All sputum produced during each session was collected. Patients completed pulmonary function tests before and after each session.

RESULTS: Median sputum wet weight was greater with higher-pressure/variable-frequency HFCWC than with lower-pressure/mid-frequency HFCWC (6.4 g, range 0.49-22.0 g, versus 4.8 g, range 0.24-15.0 g, P = .02). Dry sputum weight differences did not reach statistical significance (higher-pressure/variable-frequency HFCWC 0.20 g, range 0.009-0.62 g, lower-pressure/mid-frequency HFCWC 0.12 g, range 0.0001-1.0 g, P = .23). Higher-pressure/variable-frequency HFCWC and lower-pressure/mid-frequency HFCWC resulted in similar increases in FEV(1) (70 mL vs 90 mL, P = .21) and forced vital capacity (80 mL vs 80 mL, P = .94). Post-therapy sputum viscoelastic properties did not differ. Patients perceived the 2 regimens as equally comfortable and effective (P = .35 and P = .35, respectively).

CONCLUSIONS: In adult CF patients, single-session higher-pressure/variable-frequency HFCWC resulted in greater sputum expectoration by wet weight, but not other differences, compared to the commonly used lower-pressure/mid-frequency settings. Longer-term comparisons are needed in a larger, more diverse population to determine whether sustained use of the higher-pressure/variable-frequency settings results in clinically important differences in outcomes.

(Clinicaltrials.gov registration NCT00685035).

Effects of Gender and Age of Diagnosis on Disease Progression in Long-term Cystic Fibrosis Survivors

Am J Respir Crit Care Med. 2010 May 6.

Effects of Gender and Age of Diagnosis on Disease Progression in Long-term Cystic Fibrosis Survivors.

Nick JA, Chacon CS, Brayshaw SJ, Jones MC, Barboa CM, St Clair CG, Young RL, Nichols DP, Janssen JS, Huitt GA, Iseman MD, Daley CL, Taylor-Cousar JL, Accurso FJ, Saavedra MT, Sontag MK.

Department of Medicine, National Jewish Health, Denver, Colorado, United States; Department of Medicine, University of Colorado Denver School of Medicine, Aurora, Colorado, United States.

RATIONALE: Long-term CF survivors (age >40 years) are a growing population comprised of both patients diagnosed with classic manifestations in childhood, and non-classic phenotypes typically diagnosed as adults. Little is known concerning disease progression and outcomes in these cohorts.

OBJECTIVES: Examine effects of age at diagnosis and gender on disease progression, setting of care, response to treatment, and mortality in long-term CF survivors.

METHODS: Retrospective analysis of the Colorado CF database (1992-2008), CF Foundation Registry (1992-2007), and Multiple Cause of Death Index (1992-2005).

MEASUREMENTS AND MAIN RESULTS: CF patients diagnosed in childhood that survive to age 40 have more severe CFTR genotypes and phenotypes compared to adult diagnosed patients. However, past age 40 the rate of FEV1 decline and death from respiratory complications were not different between these cohorts. Compared to males, childhood diagnosed females were less likely to reach age 40, experienced faster FEV1 declines, and no survival advantage. Females comprised the majority of adult diagnosed patients, and demonstrated equal FEV1 decline and longer survival than males, despite a later age of diagnosis. Most adult diagnosed patients were not followed at CF Centers, and with increasing age a smaller percentage of CF deaths appeared in the CFF Registry. However, newly diagnosed adults demonstrated sustained FEV1 improvement in response to CF Center care.

CONCLUSIONS: For CF patients older than 40, the adult diagnosis correlates with delayed but equally severe pulmonary disease. A gender-associated disadvantage remains for females diagnosed in childhood, but is not present for adult diagnosed females.