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Saturday, December 18, 2010


16 December 2010


Pharmaceutical company Pharmaxis (ASX:PXS) today announced positive first results for the open label component of its second international Phase III trial of Bronchitol in people with cystic fibrosis. In this part of the trial, all participants were treated with Bronchitol, including those that were in the control arm for the first six months. The key findings were:

Lung function change (FEV1) for those participants treated with Bronchitol for 6 months was 8.2% (p=0.001 versus baseline) and this was maintained out to 12 months (FEV1 improvement of 8.2%). The withdrawal rate in the open label phase was 7%.

Subjects who were switched from control to Bronchitol at the end of the first 6 months had a 6.3% improvement in lung function relative to baseline at the end of 12 months (p=0.031).

Dr Alan Robertson, Pharmaxis Chief Executive Officer said: "We are very pleased with this result which confirms the robust clinical response and good safety profile we have demonstrated with Bronchitol over a number of clinical trials. Cystic fibrosis is a disease that leads to slow decline in lung performance over time and, in this trial, Bronchitol was again able to improve lung function at commencement of treatment, at week 26, and maintain that improvement over 52 weeks for patients who were already receiving best standard of care. The repeated demonstration of sustained benefit in this second trial with Bronchitol holds out the promise that long term use of Bronchitol can change the course of the disease."

The trial objective was to determine the safety of Bronchitol in patients with cystic fibrosis following twelve months treatment and to assess the long term effects on lung function. This clinical trial of Bronchitol was conducted in two phases. The first six months was controlled and blinded and designed to assess efficacy and safety. The second six months was open label, unblinded and not controlled. Patients initially randomized to the control group were switched to receive Bronchitol during the subsequent six month open phase.

A total of 260 subjects (Bronchitol=153, placebo=107) participated in the open label phase and of these, 242 subjects (93%) completed this six month phase. For the subjects that entered the open label phase, the average age was 19.6 years and the mean lung function on entry was 64.6% of the predicted normal FEV1. The ages ranged from 6 years to 53 years and the lung function ranges were from 34% to 96% of the predicted FEV1.

In all subjects in the open label phase, the most commonly reported adverse events were haemoptysis (5.7%), headache (4.2%) and cough (8.8%). Haemoptysis and cough are common clinical features of cystic fibrosis.

The trial was conducted in 53 centres in the United States, Argentina, Canada, Belgium, France and Germany. Additional data from the trial including other lung function parameters and effects on exacerbation will be presented at a forthcoming scientific meeting.

Bronchitol is designed to hydrate the airway surface of the lungs, and promote normal lung mucus clearance. It has received Orphan Drug Designation and fast track status from the U.S. Food and Drug Administration and Orphan Drug Designation from the European Medicines Agency. A marketing application is under review by the European Medicines Agency and it has been recommended for marketing approval by the Advisory Committee on Prescription Medicines in Australia.

SOURCE: Pharmaxis Ltd, Sydney, Australia

CONTACT: Alan Robertson - Chief Executive Officer

Ph: +61 2 9454 7200 or email alan.robertson@pharmaxis.com.au



Felicity Moffatt, phone +61 418 677 701 or email felicity.moffatt@pharmaxis.com.au

About Pharmaxis

Pharmaxis (ACN 082 811 630) is a specialist pharmaceutical company involved in the research, development and commercialization of therapeutic products for chronic respiratory disorders. Its development pipeline of products includes Aridol for the assessment of asthma, Bronchitol for cystic fibrosis, bronchiectasis and chronic obstructive pulmonary disease (COPD), PXS25 for the treatment of lung fibrosis and ASM8 and PXS4159 for asthma. Pharmaxis is listed on the Australian Securities Exchange (symbol PXS). The company is headquartered in Sydney at its TGA-approved manufacturing facilities. For more information about Pharmaxis, go to www.pharmaxis.com.au or contact Investor Relations on phone +61 2 9454 7200.

About Bronchitol

Pharmaxis Ltd is developing Bronchitol for the management of chronic obstructive lung diseases including cystic fibrosis, and bronchiectasis. Bronchitol is a proprietary dry-powder mannitol, precision formulated for delivery to the lungs through an easy-to-use, pocket-size, portable inhaler. Once inhaled its five-way action on mucus helps restore normal lung clearance mechanisms. Bronchitol has received Orphan Drug Designation and fast track status from the US Food and Drug Administration and Orphan Drug Designation from the European Medicines Agency.

Denufosol Offers Hope for Early Intervention in Cystic Fibrosis Patients

Novel Drug Offers Hope for Early Intervention in Cystic Fibrosis Patients

ScienceDaily (Dec. 17, 2010) — Cystic fibrosis (CF) patients with normal to mildly impaired lung function may benefit from a new investigational drug designed to help prevent formation of the sticky mucus that is a hallmark of the disease, according to researchers involved in a phase 3 clinical trial of the drug. Called denufosol, the investigational medication can be given early in the CF disease process, and may help delay the progression of lung disease in these patients, the researchers found.

The findings were published online ahead of the print edition of the American Thoracic Society's American Journal of Respiratory and Critical Care Medicine.

"Although the lungs of children with CF are thought to be normal at birth, studies have demonstrated significant lung damage that occurs early in life in children suffering from cystic fibrosis," said lead investigator Frank Accurso, MD, professor of pediatrics, University of Colorado School of Medicine, Denver. "Many patients continue to suffer progressive loss of lung function despite treatment of complications. Because denufosol can be used early in life, it offers hope for delaying or preventing the progressive changes that lead to irreversible airflow obstruction in CF patients."

Denufosol belongs to a class of drugs known as ion channel regulators. These drugs help balance the flow of ions through cell membranes, helping normalize the airway surface hydration and mucus clearance impairment present in patients who suffer from the disease. In cystic fibrosis, the ion sodium chloride does not flow normally through cell membranes, resulting in thick, sticky mucus which is difficult to cough out of the airways. In addition to causing breathing problems, the mucus becomes a breeding ground for bacteria and can cause serious respiratory infections.

Denufosol works by increasing chloride secretion, inhibiting sodium absorption and increasing the beat frequency of the tiny hairs, or "cilia," lining the airways move to clear mucus. Combined, these effects enhance airway hydration and aid in clearing mucus. The drug is different from other CF medications, which primarily treat the symptoms rather than the underlying causes, said Dr. Accurso, who is also the director of University of Colorado's cystic fibrosis center.

This study is the first large, phase 3 trial of an ion channel regulator in cystic fibrosis patients with little or no baseline pulmonary function impairment.

"Abnormal ion transport and defective mucociliary clearance are fundamental defects that contribute to complications of CF lung disease, including mucus plugging, chronic bacterial infection, inflammation and progressive airway damage," Dr. Accurso noted. "Although currently available drugs target these complications, denufosol was designed to treat the underlying defects that cause the complications, and could potentially modify the course of the disease, particularly when administered early in the disease process."

Researchers enrolled 352 cystic fibrosis patients 5 years of age or older, and enrolled them to receive either inhaled denufosol or placebo three times daily for 24 weeks, followed by a 24-week open-label period when all patients received denufosol. At baseline, most patients enrolled had mild impairment of lung function and were taking multiple medications to control their symptoms. Because the study outcomes were measured using spirometry, a lung function test that can be difficult to accurately use in young children, patients under five years of age were excluded.

Patients' exhalation rates and lung volume were measured throughout the study, and also were monitored for adverse events, such as cough, congestion, fever or sinusitis. At the end of the 24-week period, researchers determined patients who received denufosol had better lung exhalation rates than those in the placebo group, whose exhalation volumes remained relatively unchanged from the start of the study. Both groups had similar numbers and types of adverse events, with the denufosol patients experiencing significantly fewer headaches and lower rates of sinusitis and runny nose.

Although children under five years of age were excluded from this study, Dr. Accurso said future studies likely would address the use of denufosol in this younger population.

"Considering the evidence that early inflammation and infection results in impaired lung function and structural damage in early childhood, future studies of the effects of denufosol during the first 5 years of life is warranted," he said.

A second, similar phase 3 trial incorporating a longer placebo-controlled treatment phase is ongoing to further investigate the effectiveness of denufosol in patients with CF, Dr. Accurso added.


Friday, December 3, 2010

Estrogen aggravates inflammation in PA pneumonia in CF mice

Estrogen aggravates inflammation in PA pneumonia in CF mice

Among patients with cystic fibrosis (CF), females have worse pulmonary function and survival than males, primarily due to chronic lung inflammation and infection with Pseudomonas aeruginosa (P. aeruginosa).

A role for gender hormones in the causation of the CF "gender gap"has been proposed. The female gender hormone 17beta-estradiol (E2) plays a complex immunomodulatory role in humans and in animal models of disease, suppressing inflammation in some situations while enhancing it in others.

Helper T-cells were long thought to belong exclusively to either T helper type 1 (Th1) or type 2 (Th2) lineages. However, a distinct lineage named Th17 is now recognized that is induced by interleukin (IL)-23 to produce IL-17 and other pro-inflammatory Th17 effector molecules.

Recent evidence suggests a central role for the IL-23/ IL-17 pathway in the pathogenesis of CF lung inflammation. We used a mouse model to test the hypothesis that E2 aggravates the CF lung inflammation that occurs in response to airway infection with P.aeruginosa by a Th17-mediated mechanism.

Results: Exogenous E2 caused adult male CF mice with pneumonia due to a mucoid CF clinical isolate, the P. aeruginosa strain PA508 (PA508), to develop more severe manifestations of inflammation in both lung tissue and in bronchial alveolar lavage (BAL) fluid, with increased total white blood cell counts and differential and absolute cell counts of polymorphonuclear leukocytes (neutrophils).

Inflammatory infiltrates and mucin production were increased on histology. Increased lung tissue mRNA levels for IL-23 and IL-17 were accompanied by elevated protein levels of Th17-associated pro-inflammatory mediators in BAL fluid.

The burden of PA508 bacteria was increased in lung tissue homogenate and in BAL fluid, and there was a virtual elimination in lung tissue of mRNA for lactoferrin, an antimicrobial peptide active against P. aeruginosa in vitro.

Conclusions: Our data show that E2 increases the severity of PA508 pneumonia in adult CF male mice, and suggest two potential mechanisms: enhancement of Th17-regulated inflammation and suppression of innate antibacterial defences.

Although this animal model does not recapitulate all aspects of human CF lung disease, our present findings argue for further investigation of the effects of E2 on inflammation and infection with P. aeruginosa in the CF lung.

Author: Yufa WangElvis CelaStephane GagnonNeil Sweezey

Credits/Source: Respiratory Research 2010, 11:166