Copernicus earned the milestone payment by demonstrating a significant improvement in the level of CFTR gene activity in an animal model. This increased improvement in the level and duration of CFTR gene activity represents an important step in the path to developing a clinically relevant therapy.

Copernicus’ unique, non-viral nanoparticle formulation is intended to deliver a normal copy of the CF gene to the affected lung cells of CF patients, and may provide a therapy that treats the root cause of CF regardless of the specific mutations resulting in CF. Copernicus’ first clinical trial, supported by CFFT, demonstrated the desired safety profile and encouraging biological changes were observed.

Cystic fibrosis is a life threatening genetic disease that affects approximately 30,000 children and adults in the United States. People with CF develop serious lung infections and digestive complications. About 10 million Americans are unknowing carriers of a defective CF gene.

“We have had a productive relationship for a number of years with CFFT and we share the common goal of providing a safe and effective therapeutic for people with CF,” said Robert C. Moen, M.D., Ph.D., president and CEO of Copernicus. “We look forward to working with CFFT in meeting the critical need for an effective gene-based therapy for the lung manifestations of CF.”

“We are encouraged by the promise of Copernicus’ technology,” said Robert J. Beall, Ph.D., president and CEO of the CF Foundation. “Gene-based therapies offer hope for potentially lifesaving treatments that can be applied to all patients with CF, regardless of the specific type of gene mutation.”

About the Cystic Fibrosis Foundation and Copernicus

Copernicus Therapeutics, Inc., a privately held biotechnology company, is dedicated to delivering the promise of nucleic acid therapeutics. The Copernicus multi-component delivery platform can be used to develop nucleic acid therapies for numerous human diseases. The same technology that is being tested for its ability to deliver the CF gene to the lung of CF patients can be applied to treating serious disorders of the brain, such as Parkinson’s disease, as well as for treating a variety of blinding disorders. Additionally, this lung delivery technology may be utilized for RNAi -based therapeutics to treat lung infections caused by influenza A, bird flu, and other respiratory viruses. Additional information about Copernicus is available at http://www.cgsys.com.

The Cystic Fibrosis Foundation is the leading organization devoted to curing and controlling cystic fibrosis. Headquartered in Bethesda, Md., the Foundation funds CF research, has 80 chapter and branch offices throughout the country, and supports and accredits a nationwide network of 115 CF care centers, which provide vital treatments and other CF resources to patients and families.

Cystic Fibrosis Foundation

Researchers at the University of Alabama at Birmingham (UAB) studied a CF causing protein and another protein called epithelial sodium channel, or ENaC. Both proteins are known to play a role in CF, but exactly what role each plays is unclear.

The new pictures provide physical proof that these two proteins occur close enough to interact with each other, the UAB researchers said. When that interaction fails then a dangerous biochemical imbalance occurs in people diagnosed with CF.

Knowing more about this protein proximity will help scientists better understand the biological underpinnings of CF and may speed the discovery of new drugs to treat or cure the disease. CF affects 70,000 people worldwide, 30,000 in the United States.

The findings are published in the Journal of Biological Chemistry, which included a color photo from the UAB study on its cover.

“Our findings suggest a direct interaction between these two proteins and their proximity makes the evidence convincing,” said Bakhrom Berdiev, M.D., Ph.D., a UAB assistant professor of cell biology and lead author on the study.

The study was conducted using a laser-scanning microscope that captured images of the two proteins “within reach of each other. The absence of this interaction could shape the development of CF,” Berdiev said.

Normally, both proteins help make up the lining of the lungs and other membranes, and keep the balance of water and salt at safe levels. In the case of CF, ENaC is allowed to hyper-function in the presence of the CF-causing protein and disturb the balance of water and salt.

When this happens, a sticky mucus usually forms inside the airways which can lead to chronic lung infections, the most dangerous symptom of CF. Other symptoms involve digestive problems.

With the discovery of the CF gene in 1989, many scientists began searching for ways to repair the DNA or repair the faulty protein encoded by the DNA.

The new Journal of Biological Chemistry study shows that future research should look at other molecules not directly linked to CF but are involved in the disease process and its side effects, Berdiev said.

Also, the new pictures add to an ever changing biophysical “map” of CF used to design future research.

The new pictures were done through collaboration between UAB’s departments of Cell Biology, Physiology & Biophysics, High Resolution Imaging Facility and the Gregory Fleming James Cystic Fibrosis Research Center at UAB. Other collaborators are from Ohio State University, the University of Toronto, Ontario, the National Heart Lung and Blood Institute in Bethesda, Maryland and Lambert Instruments in the Netherlands.

Funding for the study came from the National Institutes of Health and the Cystic Fibrosis Foundation.

University of Alabama at Birmingham
701 20th St. S., AB 1320
Birmingham, AL 35294-0113
United States

http://main.uab.edu

The collaboration will combine two key strengths of BioFocus DPI – expertise in natural product drug discovery and screening in cells derived from patients. Specifically, the collaboration aims to identify small molecules derived from natural sources that improve the function of a defective protein found in people who have cystic fibrosis. The protein is called CFTR – cystic fibrosis transmembrane conductance regulator. To advance the search for a cure for cystic fibrosis, CFFT funds promising scientific research in the pharmaceutical and biotechnology industry and academia worldwide.

Under the terms of the agreement, Galapagos stands to receive up to €1.6 million ($2.4 million) in upfront and research fees over the next two years, and up to €3.8 million ($5.7 million) in success-based milestone payments, should certain clinical development criteria be met.

This drug discovery collaboration is in addition to an ongoing target discovery program established between CFFT and BioFocus DPI in April 2005.

“We are excited to take advantage of the innovative drug discovery approach developed by BioFocus DPI and the company’s extensive expertise in natural compounds,” said Robert J. Beall, Ph.D., President and CEO of the Cystic Fibrosis Foundation. “By exploring compounds derived from natural sources, our goal is to increase the number and diversity of drug candidates in development to treat cystic fibrosis.”

“The CFFT drug discovery collaboration is a prime example of the kind of innovation we aimed to achieve through our acquisition strategy,” said Onno van de Stolpe, CEO of Galapagos. “We have seen a growing interest in natural product based drug discovery since acquiring these capabilities last year. By combining this expertise with our know-how in cell-based screening, we are confident that we will contribute to the advancement of CFFT’s drug discovery program in novel ways.”

The NDA is supported by data from two Phase III clinical studies (AIR-CF1 and AIR-CF2) and interim data from an ongoing open-label extension study (AIR- CF3) of patients who participated in AIR-CF1 or AIR-CF2 where eFlow was used exclusively in these trials. The model of the eFlow device used in the trials was optimized from the eFlow platform to deliver the aerosol formulation of aztreonam lysine for inhalation. Aztreonam lysine for inhalation was administered over a two to three minute period in these studies. This represents a significant reduction in aerosol treatment times, as currently available inhalation therapies can average 20 to 25 minutes.

PARI Pharma GmbH, the developer of the eFlow, also contributed to the development and optimization of the drug formulation (aztreonam lysine for inhalation) for delivery with the specific eFlow.

eFlow, an electronic, portable nebulizer, enables extremely efficient aerosolization of liquid medications via a vibrating, perforated membrane that includes thousands of small holes that produce the aerosol mist. Compared to other nebulizer systems, eFlow can produce aerosols with a very high density of active drug, a precisely defined droplet size, and a high proportion of respirable droplets delivered in the shortest possible period of time. Combined with its silent mode of operation, small size (it fits in the palm of your hand), light weight, and battery use, eFlow helps reduce the burden of taking daily, inhaled treatments.

Aztreonam lysine for inhalation is an investigational therapy and has not yet been determined safe or efficacious in humans.

About Cystic Fibrosis

Today, more than 30,000 people in the United States have CF. CF is a chronic, debilitating genetic disease. A major characteristic of CF is production of abnormally thick, sticky mucus in the lungs, trapping bacteria and predisposing patients to lung infections, which continually damage their lungs.

Pulmonary infection with Gram-negative bacteria, particularly pulmonary P. aeruginosa, represents the single greatest cause of morbidity and mortality among CF patients. Currently there is no known cure for CF, and the goal of CF therapy is to control symptoms and prevent further lung damage.

About Gilead Sciences

Gilead Sciences is a biopharmaceutical company that discovers, develops and commercializes innovative therapeutics in areas of unmet medical need. Headquartered in Foster City, California, Gilead has operations in North America, Europe and Australia.

About PARI Pharma

PARI Pharma focuses on the development of aerosol delivery devices and therapies. Based on PARI’s 100-year history working with aerosols, PARI Pharma develops treatments for pulmonary and nasal administration optimized to advanced delivery platforms, such as eFlow.

PARI Pharma provides comprehensive inhalation drug development, including nebulizer formulation development and optimization, CMC, analytics, aerosol characterization, clinical protocol development, and regulatory guidance. PARI Pharma has several clinical development programs ongoing, either partnered or on its own. PARI Pharma, a PARI Medical Holding company, is located in Munich, Germany with a major presence in the United States. Online at http://www.paripharma.com

The findings argue strongly for a comprehensive look at determining which children with CF are the best candidates for lung transplants, said Theodore G. Liou, M.D., the study’s principal investigator and associate professor of internal medicine at the University of Utah School of Medicine.

Published in the Nov. 22 issue of The New England Journal of Medicine, the study analyzed the largest data set ever constructed of children with CF — 514 patients, 18 and younger, on the U.S. lung transplantation list from 1992-2002. Of the 248 children who actually received new lungs in that 11-year period, only one patient showed a clear benefit from transplantation, while 162 (nearly two-thirds), were at a higher risk of dying after the procedure — up to sevenfold in some cases. The researchers were unable to determine the harm or benefit of transplantation in the remaining 85 children who received new lungs.

“The implication is that most children with CF are going to be harmed by lung transplantation,” said Liou, also with the University’s Intermountain Cystic Fibrosis Center. “We shouldn’t expect lung transplantation to prolong their lives.”

The study underscores the need for CF patients to follow a consistent regimen of conventional therapy and medical care to maximize their survival, according to Liou and co-authors Frederick R. Adler, Ph.D., professor of biology and mathematics, Barbara C. Cahill, M.D., associate professor of internal medicine and medical director of University Health Care’s Lung Transplant Program (both from the University of Utah); and Sir David R. Cox, Ph.D., who in the 1970s developed proportional hazards modeling, a statistical technique that revolutionized the study of survival expectations related to events such as organ transplants. Cox, professor of statistics at the Oxford University, United Kingdom, aided the U of U investigators in using the proportional hazards model for their study.

Cystic fibrosis is a hereditary disease that attacks multiple systems in the body, most dramatically affecting the lungs and gastrointestinal tract. CF causes excess sticky mucus in the lungs, turning them into a breeding ground for bacteria. People with the disease often have a cough that produces phlegm and experience shortness of breath. Difficulty digesting food often leads to malnutrition. Although treatments can slow the disease, there is no cure yet. The median age at death for people with CF is 25 today, compared with median survival of less than one year a few decades ago. Advances in therapy now allow some CF patients to live into their 40s, 50s, and beyond.

Three Primary Factors

In using the proportional hazards model to estimate the risk of death in children who undergo transplantation, the researchers looked at 26 statistical variables that potentially could predict health hazards related to the procedure. The researchers eventually identified three primary factors affecting post-transplantation survival: age at transplantation — the older a child gets, the more likely the procedure will cause harm; the presence of S. aureus staph infection — children with the bacteria at or after transplantation faced a significantly higher risk of death; and whether a patient had diabetes before transplantation (recipients who had the disease before transplantation fared better than those who didn’t) A fourth factor, infection with B. cepacia — bacteria that cause pneumonia in CF patients — produced equally deleterious consequences whether or not a patient received new lungs.

Although the reason is not clear, the risk of death after lung transplantation increases steadily as children with CF get older, and is influenced markedly by whether a recipient was infected with S. aureus before or at the time of the transplantation. By age 17, children with S. Aureus had almost a sevenfold increased chance of dying after transplantation. The reason possibly stems from the compromised immune systems of transplant patients, making them more susceptible to harm from the bacteria, according to Liou.

Although it hurt survival rates after transplantation, S. Aureus infection actually helped increase survival in children before the procedure. That’s most likely explained by competition between S. aureus and Pseudomonas aeruginosa, a harmful organism that lodges in the airways of CF patients. This competition may help mitigate some of the damage from Pseudomonas aeruginosa.

“S. aureus is good before a transplant,” Liou said. “Afterward, it becomes a killer.”

But even lung recipients who didn’t have S. aureus were more likely to die as they got older: Recipients with neither the staph infection nor diabetes had a threefold greater risk of dying by age 18.

After 18, however, age seems to have little bearing on survival, but the reason why is also unknown, according to Adler. “Something fundamental seems to change as they reach adulthood,” he said. “But we don’t know what that is. We hope further studies on adults with CF will help us understand the reason.”

Diabetes didn’t harm a child’s chances of survival after receiving new lungs — as long as the patient already had the disease at the time of transplantation. Diabetes develops in most patients who receive new lungs, according to Liou, and the physical toll the disease takes may account for a large proportion of the harm to patients after transplantation. Children who have diabetes when they’re transplanted have, in effect, already paid the physical costs of the disease before receiving new lungs and don’t bear that added burden on their chances of survival.

Identify Children Likely to Benefit

Although lung transplants, as currently allocated, don’t help most children with CF, it doesn’t mean transplantation can’t benefit children, Liou and Adler say. But to make the most efficient use of lungs available, it’s critical to develop a way to identify the sickest children who would benefit from transplants.

Another key aspect of transplantation, its effect on quality of life, also needs to be studied.

In the current study, the U of U researchers found mixed indicators of how transplantation affected quality of life: some children spent fewer days in the hospital in the first two years following transplantation; others spent more. Many recipients also faced more medical complications, while others did not. “We couldn’t really answer the quality-of-life question,” Liou said, “but it can no longer be assumed that lung transplantation has a beneficial effect on quality of life or survival.”

Identifying children who will benefit from receiving new lungs is something the entire CF transplant community, including patients, physicians, families, and researchers needs to decide, Liou said. Currently, transplant candidates are selected because of low lung function, worsening symptoms of the disease, and other factors than may indicate a poor prognosis. Those criteria aren’t working, the researchers write in the NEJM.

“… The finding that only 1 of 248 children with CF transplanted during 1992-2002 had clearly improved survival suggests that factors actually used to select transplant candidates could not identify patients likely to have survival benefits,” they conclude.

With their study, the U of U researchers hope to start a discussion in the CF community to figure out how to determine the best candidates for transplantation.

“We can’t allocate lungs rationally right now,” Adler said, “because we don’t have all the data, particularly on quality of life.”

Julian Allen, M.D., who holds the Robert Gerard Morse Endowed Chair in Pediatric Pulmonary Medicine at The Children’s Hospital of Philadelphia, analyzed the study by a University of Utah research team, which found that cystic fibrosis (CF) patients younger than age 18 did not survive longer after a lung transplant than CF patients who did not receive a lung transplant.

In contrast to a previous study by the same researchers, led by Theodore Liou, M.D., which found a survival advantage for adult transplant recipients when the predicted five-year survival rate without transplantation was 30 percent or worse, the new study found no lower threshold at which transplantation provided better survival in children a finding that Allen called surprising.

“The study’s results make it clear that physicians must be more judicious than ever in referring children with cystic fibrosis for lung transplantation, with careful consideration of the severity of the child’s illness,” said Allen. He said that cystic fibrosis centers must provide appropriate social and psychological support to help families make the best choice for their children.

Allen added that it is possible that a lung transplant may improve a patient’s quality of life, as the current study had only limited information on that question. He urged that future studies of lung transplantation in CF patients ought to carefully measure quality of life as well as measuring how closely patients adhere to post-transplant medical treatments.

One fact that may change future results, said Allen, is that the new organ allocation system, initiated in 2005, takes into account the severity of a patient’s illness, in addition to other factors such as the length of time a patient remains on the waiting list for a donated organ. The system in place when the study was performed allocated lungs based only on the duration of the patient’s wait.

Allen’s co-author on the editorial is Gary Visner, D.O., a transplant surgeon formerly at The Children’s Hospital of Philadelphia, and now at Children’s Hospital, Boston.

The Cystic Fibrosis Center at The Children’s Hospital of Philadelphia provides comprehensive multidisciplinary care for children with CF, and has been recognized as a model program by the Cystic Fibrosis Foundation. One of the largest programs for cystic fibrosis in the U.S., it also offers lung transplantation among its treatments. The Center staff works in conjunction with the University of Pennsylvania Health System, which provides a program for adult CF patients.

About The Children’s Hospital of Philadelphia: The Children’s Hospital of Philadelphia was founded in 1855 as the nation’s first pediatric hospital. Through its long-standing commitment to providing exceptional patient care, training new generations of pediatric healthcare professionals and pioneering major research initiatives, Children’s Hospital has fostered many discoveries that have benefited children worldwide. Its pediatric research program is among the largest in the country, ranking third in National Institutes of Health funding. In addition, its unique family-centered care and public service programs have brought the 430-bed hospital recognition as a leading advocate for children and adolescents. For more information, visit http://www.chop.edu.

Children’s Hospital of Philadelphia
34th & Civic Center Blvd.
Philadelphia, PA 19104
United States

http://www.chop.edu

“Chronic pseudomonal airway infection represents the single greatest cause of morbidity and mortality for people with cystic fibrosis, and with a limited number of inhaled antibiotics, there remains a significant unmet medical need,” said A. Bruce Montgomery, MD, Senior Vice President, Head of Respiratory Therapeutics, Gilead Sciences. “The completion of this new drug application is reflective of Gilead’s commitment to developing novel therapies for people with this life-threatening disease.”

Data from AIR-CF1 demonstrated improvement in respiratory symptoms for people with cystic fibrosis as measured by the Respiratory Symptoms scale of the Cystic Fibrosis Questionnaire-Revised (CFQ-R), a patient-reported outcome (PRO) tool used to measure health-related quality of life for people with cystic fibrosis. AIR-CF2 data demonstrated that aztreonam lysine for inhalation significantly delayed the time to need for inhaled or intravenous (IV) antibiotics following a course of inhaled tobramycin. Both studies also demonstrated improvements from baseline in respiratory function, as measured by relative improvement of forced expiratory volume in one second (FEV1) compared to placebo.

The most common treatment-emergent adverse events in the AIR-CF studies were cough, productive cough, nasal congestion, wheezing and sore throat. The incidences of these events were not significantly different between the placebo and the aztreonam lysine for inhalation groups.

In August 2007, Gilead initiated an expanded access program (EAP) to provide aztreonam lysine for inhalation to people with cystic fibrosis and P. aeruginosa who have limited treatment options and are at risk for disease progression.

Aztreonam lysine for inhalation is an investigational therapy and has not yet been determined safe or efficacious in humans.

About the Expanded Access Program

The EAP is open to treatment centers in the United States for people with cystic fibrosis who are six years or older and have P. aeruginosa present in expectorated sputum or throat swab culture within two months prior to consent. The Cystic Fibrosis Foundation, through its affiliate pharmacy, Cystic Fibrosis Services, Inc. is assisting in drug distribution to treatment centers.

People with cystic fibrosis in the U.S. with severe lung function impairment as defined as having an FEV1 of less than 50 percent predicted or who have completed participation in the open-label AIR-CF3 trial are eligible to participate.

Participating patients are evaluated at screening, at baseline, at Day 28 and at Day 56 visits, and then every two months thereafter. In this program, patients will receive aztreonam lysine for inhalation, administered via the PARI eFlow Electronic Nebulizer, 75 mg three times daily, in 56-day cycles of therapy (28 days on drug followed by 28 days off) as provided by their physician until patients or physicians withdraw from participation in the study or the program is terminated by Gilead.

For more information regarding the expanded access program or to request registration materials, physicians log on to http://www.EAPforCF.com.

About the AIR-CF Phase III Program

The Phase III AIR-CF clinical program was designed to determine the safety and efficacy of aztreonam lysine for inhalation for use in people with cystic fibrosis who have pulmonary P. aeruginosa. In each of these studies, aztreonam lysine for inhalation was administered by the PARI eFlow Electronic Nebulizer.

AIR-CF1 was a double-blind, randomized, placebo-controlled study designed to assess the safety and efficacy of a 28-day treatment course of aztreonam lysine for inhalation in people with cystic fibrosis who have pulmonary P. aeruginosa. The primary endpoint was the change at day 28 from baseline in respiratory symptoms as assessed by the CFQ-R. This study enrolled 164 patients who were randomized to receive 28 days of treatment with aztreonam lysine for inhalation or volume-matched placebo administered three times daily.

AIR-CF2 was a randomized, double-blind, placebo-controlled study designed to assess the safety and efficacy of a 28-day treatment course with aztreonam lysine for inhalation following a 28-day treatment course of tobramycin inhalation solution in people with cystic fibrosis who have pulmonary P. aeruginosa. Patients were randomized to receive 28 days of treatment with 75 mg of aztreonam lysine for inhalation or volume-matched placebo each administered two times or three times daily. Patients were followed for an overall study period of 126 days, with 56 days of observation after receiving aztreonam lysine for inhalation therapy or placebo.

AIR-CF3 is an open-label, multi-center study of patients who participated in the AIR-CF1 or AIR-CF2 studies. The primary objective of the study is to evaluate the safety of repeated exposure to aztreonam lysine for inhalation in people with cystic fibrosis. Patients will receive treatment with aztreonam lysine for inhalation with the same dosing regimen they received in AIR-CF1 or AIR-CF2. This trial is ongoing.

About Aztreonam Lysine for Inhalation

Aztreonam lysine for inhalation is an antibiotic candidate currently being studied in an ongoing Phase III open label trial for people with cystic fibrosis who have pulmonary P. aeruginosa. Aztreonam has potent activity against Gram-negative bacteria such as P. aeruginosa. Aztreonam formulated with arginine is a FDA-approved agent for intravenous administration. Aztreonam lysine for inhalation is a proprietary formulation of aztreonam developed specifically for inhalation and has been designated with orphan drug status in the United States and Europe.

About PARI Pharma and the eFlow Electronic Nebulizer

Aztreonam lysine for inhalation is delivered by a novel inhalation device, the eFlow Electronic Nebulizer, developed by PARI Pharma GmbH. eFlow is a quiet, portable nebulizer that enables efficient aerosolization of liquid medications via a vibrating, perforated membrane. PARI Pharma also contributed to the development and optimization of the drug formulation (aztreonam lysine for inhalation) for delivery via eFlow. Based on PARI’s 100-year history working with aerosols, PARI Pharma is dedicated to advancing inhalation therapies by developing innovative delivery platforms and new pharmaceutical formulations that work together to improve patient care.

About Cystic Fibrosis

Today, more than 30,000 people in the United States have CF. CF is a chronic, debilitating genetic disease. A major characteristic of CF is production of abnormally thick, sticky mucus in the lungs that traps bacteria and predisposes patients to lung infections, which damage their lungs. Pulmonary infection with Gram-negative bacteria, particularly pulmonary P. aeruginosa, represents the single greatest cause of morbidity and mortality among CF patients. Currently there is no known cure for CF, and the goal of CF therapy is to control symptoms and prevent further lung damage.

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.

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 the FDA may not approve aztreonam lysine for inhalation for treatment of people with cystic fibrosis (CF) who have pulmonary P. aeruginosa infection. In addition, marketing approval, if granted, may have significant limitations on its use. 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, 2006 and Quarterly Reports on Form 10-Q for the first, second and third quarters of 2007, 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.

The guidelines, a result of a two-year review of original research and systematic review literature from 1983 to 2006, were published in the second issue for November of the American Thoracic Society’s American Journal of Respiratory and Critical Care Medicine.

CF is a complex genetic disease affecting the lungs and other organs, and is characterized by an unusually thick, sticky mucus that renders CF victims virtually incapable of fending off infections and pathogens. CF is always fatal, but thanks to advances in treatment in the last 60 years, life expectancy has increased from just a few years to 36 years. Lung disease accounts for 85 percent of the mortality among CF patients.

“Physicians treating patients with CF are faced with a growing number of treatment options” wrote lead author of the guidelines, Patrick A. Flume, M.D. “We are hopeful that clinicians will find these recommendations to be useful in their care of patients with CF.”

The pulmonary guidelines committee assessed the clinical efficacy and safety of the use of aerosolized antibiotics, recombinant human DNase (dornase alfa), hypertonic saline inhalation, anti-inflammatory agents, macrolide antibiotics, the use of bronchodilators and N-acetylcysteine. They analyzed the clinical results with regard to the number of studies, strength of the study designs and the quality and consistency of results to make their final recommendations. Because of the general dearth of studies on treatments in children under the age of six, the committee restricted their recommendations to CF patients six years of age and older.

The treatments with the strongest, most consistent results yielding an “A”-grade positive recommendation were:

* Inhaled tobramycin, an antibiotic, to suppress chronic Pseudomonas aeruginosa infections in CF patients with moderate to severe disease to improve lung function and reduce exacerbations; and

* Dornase alfa, which degrades the free DNA that accumulates in CF mucus, thereby loosening the mucus, promoting airway clearance, improving lung function and reducing exacerbations.

“B” grade recommendations by the committee are for:

* Inhaled tobramycin, to suppress chronic Pseudomonas aeruginosa infections in CF patients with mild disease or who are asymptomatic, to reduce exacerbations;

* Dornase alfa, for CF patients with mild disease or who are asymptomatic, to improve lung function and reduce exacerbations;

* Hypertonic saline, which hydrates surface liquid in patients with CF, thereby improving lung function and decreasing exacerbations; and

* B2-adrenergic receptor agonists, which relax smooth muscles and dilate bronchial passages, which improve lung-function in CF patients, and were well-tolerated.

The guidelines recommend against:

* Systemic corticosteroids in children because of “an excess number of adverse events,” including abnormalities in glucose metabolism, cataracts, and percentage of patients “colonized” with Pseudomonas (this recommendation excludes patients who have concomitant asthma);

* Inhaled corticosteroids, because there was no clinical benefit (this recommendation excludes patients who have concomitant asthma); and

* Prophylactic anti-Staphylococcal antibiotics because of the lack of clinical efficacy and an apparent increase in P. aeruginosa infections with their use.

All other treatments lacked sufficient evidence to recommend for or against their use.

The article includes recommendations for physicians to help determine which therapies to use, and the order in which they should be introduced. “There is a challenge for the clinician to decide what therapy to start first, or when to add another therapy,” explained Dr. Flume. “We are putting together an educational program to assist the community in implementation of the guidelines and hope to launch a web-based program in January.”

Still, much work remains to be done. “We were able to support our recommendations based on the quality of the evidence,” said Dr. Flume. “But also we could see clearly where we were lacking data. This will allow us to lay the foundation for how those studies should be performed.”

The committee plans to update the guidelines every five years.