Efficacy and safety of inhaled aztreonam lysine for airway pseudomonas in cystic fibrosis

Chest 2009 May;135(5):1223-32.

Efficacy and safety of inhaled aztreonam lysine for airway pseudomonas in cystic fibrosis.

Retsch-Bogart GZ, Quittner AL, Gibson RL, Oermann CM, McCoy KS, Montgomery AB, Cooper PJ.


Department of Pediatrics, 5126 Bioinformatics Building, CB No. 7217, 130 Mason Farm Rd, University of North Carolina, Chapel Hill, NC 27599-7217. gzrb@med.unc.edu.

BACKGROUND: We assessed the short-term efficacy and safety of aztreonam lysine for inhalation (AZLI [an aerosolized monobactam antibiotic]) in patients with cystic fibrosis (CF) and Pseudomonas aeruginosa (PA) airway infection. METHODS: In this randomized, double-blind, placebo-controlled, international study (AIR-CF1 trial; June 2005 to April 2007), patients (n = 164; >/= 6 years of age) with FEV(1) greater than or = 25% and less than or = 75% predicted values, and no recent use of antipseudomonal antibiotics or azithromycin were treated with 75 mg of AZLI (three times daily for 28 days) or placebo (1:1 randomization), then were monitored for 14 days after study drug completion. The primary efficacy end point was change in patient-reported respiratory symptoms (CF-Questionnaire-Revised [CFQ-R] Respiratory Scale). Secondary end points included changes in pulmonary function (FEV(1)), sputum PA density, and nonrespiratory CFQ-R scales. Adverse events and minimum inhibitory concentrations of aztreonam for PA were monitored. RESULTS: After 28 days of treatment, AZLI improved the mean CFQ-R respiratory score (9.7 points; p < 0.001), FEV(1) (10.3% predicted; p < 0.001), and sputum PA density (- 1.453 log(10) cfu/g; p < 0.001), compared with placebo. Significant improvements in Eating, Emotional Functioning, Health Perceptions, Physical Functioning, Role Limitation/School Performance, and Vitality CFQ-R scales were observed. Adverse events were consistent with symptoms of CF lung disease and were comparable for AZLI and placebo except the incidence of "productive cough" was reduced by half in AZLI-treated patients. PA aztreonam susceptibility at baseline and end of therapy were similar. CONCLUSIONS: In patients with CF, PA airway infection, moderate-to-severe lung disease, and no recent use of antipseudomonal antibiotics or azithromycin, 28-day treatment with AZLI significantly improved respiratory symptoms and pulmonary function, and was well tolerated. Trial registration: Clinicaltrials.gov Identifier: NCT00112359.

PMID: 19420195 [PubMed - in process]

CFF Response to Azli Rejection

CF Foundation Responds to FDA Decision Requiring More Study of Inhaled Aztreonam

February 19, 2009

The CF Foundation is very disappointed that a much-needed antibiotic treatment for cystic fibrosis will be further delayed. The U.S. Food and Drug Administration (FDA) reviewed data on the potential treatment, aztreonam lysine for inhalation (AZLI) developed by Gilead Sciences, Inc., and determined additional clinical trial data is necessary.

The FDA’s decision, issued yesterday, reiterated its September 2008 ruling that requires Gilead to complete an additional clinical trial for the drug before it will consider approval. Gilead filed a formal appeal with the FDA in November. Yesterday's ruling serves as a denial of the appeal.

The Foundation is exploring all options available to expedite the process of drug approval for AZLI. In the meantime, nearly 300 patients receive the drug through Gilead’s Early Access Program (EAP), which is being conducted in nearly 40 CF care centers nationwide. Gilead will continue to provide early access to AZLI for those CF patients with limited treatment options and a serious risk of disease progression. Individuals with CF should contact their care centers to determine their eligibility to participate in the EAP.

Gilead issued a press release stating that the company has two ongoing clinical studies evaluating this drug. “The company has not yet discussed with the FDA whether or not either of these studies would be sufficient to address the FDA’s requirements or whether Gilead will need to design and conduct a new study.”

Azli

Gilead Receives Response From U.S. FDA On Company's Request For Formal Dispute Resolution For Aztreonam For Inhalation Solution

22 Feb 2009

Gilead Sciences, Inc. (Nasdaq:GILD) announced that the company has received a response from the U.S. Food and Drug Administration (FDA) to its appeal, submitted under the formal Dispute Resolution process, regarding the Agency's Complete Response Letter for its New Drug Application (NDA) for aztreonam for inhalation solution. Gilead initiated the formal Dispute Resolution process in November 2008, following receipt of the Complete Response Letter in September 2008. In its review under the Dispute Resolution process, the FDA reiterated its position outlined in the Complete Response Letter, including the need for Gilead to conduct an additional clinical study of aztreonam for inhalation solution before the company can resubmit its NDA.

Gilead has two ongoing clinical studies evaluating aztreonam for inhalation solution. The company has not yet discussed with the FDA whether or not either of these studies would be sufficient to address the FDA's requirements or whether Gilead will need to design and conduct a new study. The company will provide further updates once it has more clarity regarding timelines.

About Aztreonam for Inhalation Solution

Aztreonam for inhalation solution is an antibiotic candidate for people with cystic fibrosis who have P. aeruginosa. Aztreonam has potent in vitro activity against Gram-negative bacteria such as P. aeruginosa. Aztreonam formulated with arginine is a FDA-approved agent for intravenous administration for treating various infections. Aztreonam formulated with lysine is a proprietary formulation of aztreonam developed specifically for inhalation. It has been designated with orphan drug status in the United States and Europe.

About Gilead Sciences

Gilead Sciences is a biopharmaceutical company that discovers, develops and commercializes innovative therapeutics in areas of unmet medical need. The company's mission is to advance the care of patients suffering from life-threatening diseases worldwide. Headquartered in Foster City, California, Gilead has operations in North America, Europe and Australia.

Forward-Looking Statement

This press release includes forward-looking statements, within the meaning of the Private Securities Litigation Reform Act of 1995, that are subject to risks, uncertainties and other factors, including the risk that ongoing clinical studies will not be sufficient to address the FDA's requirements and the risk that the FDA may ultimately decline to approve aztreonam for inhalation solution, even after additional data are submitted. These risks, uncertainties and other factors could cause actual results to differ materially from those referred to in the forward-looking statements. The reader is cautioned not to rely on these forward-looking statements. These and other risks are described in detail in Gilead's Annual Report on Form 10-K for the year ended December 31, 2007 and its Quarterly Report on Form 10-Q for the first, second and third quarters of 2008, as filed with the U.S. Securities and Exchange Commission. All forward-looking statements are based on information currently available to Gilead, and Gilead assumes no obligation to update any such forward-looking statements.

For more information on Gilead, please call the Gilead Public Affairs Department at 1-800-GILEAD-5 (1-800-445-3235) or visit http://www.gilead.com

Gilead




http://www.medicalnewstoday.com/articles/139643.php

Basically the Azli efficacy study was only 28 days long for the placebo controlled portion (not the open-label, which FDA doesn't consider to be a well designed and controlled study).

TOBI was submitted with 2 24 week placebo controlled studies.

Azli will need to complete a longer placebo controlled study in order to get approval....