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Sunday, January 30, 2011

Breakthrough On Cystic Fibrosis One Step Closer As New Research Alliance Formed

Breakthrough On Cystic Fibrosis One Step Closer As New Research Alliance Formed

Article Date: 27 Jan 2011 - 3:00 PST

McGill University and GlaxoSmithKline plc (GSK) have signed a collaboration agreement to develop a potential breakthrough approach to treat cystic fibrosis, a fatal genetic disease. The trans-Atlantic effort between researchers from McGill's Faculty of Medicine and their GSK collaborators in the UK, will focus on developing molecules that could treat the disease by correcting the dysfunction caused by the mutated gene. This revolutionary approach will be a departure from current treatments, which only manage the symptoms or complications of the disorder. The collaborative research is co-sponsored by the Canadian Institutes of Health Research (CIHR).

Cystic fibrosis (CF) is one of the most common fatal genetic diseases. It is a multi-organ disease but primarily affects the lungs and digestive system, causing mucous to thicken and leaving patients at higher risk of infections. CF is caused by a mutation in the gene for the protein cystic fibrosis transmembrane conductance regulator (CFTR). About 90 per cent of those living with cystic fibrosis have a particular mutant form of this gene, which makes a protein that could still work but has a defect that prevents it getting to the right place in the cell to function correctly.

Dr. David Thomas, Chair of McGill's Department of Biochemistry and Canada Research Chair in Molecular Genetics, is an expert in protein quality control. Dr. John Hanrahan is Professor in McGill's Department of Physiology and an expert in chloride transport and epithelial biology. They are uniquely qualified as lead investigators on McGill's side, having conducted extensive research on the CFTR protein and have identified a number of molecules that look to restore normal CFTR function.

"If we can restore normal function to the mutant cystic fibrosis protein, we can radically transform the lives of millions of children. It will move us from treatment of symptoms to prevention of the disease and would ultimately save lives," said Dr. Thomas. "We will now be looking at enhancing these small molecules to improve their ability to "rescue" or "correct" the mutant protein, allowing it to reach its proper location and be more active," added Dr. Hanrahan.

"GSK is excited to be applying our expertise in areas including medicinal chemistry to this innovative area of research," said Dr. Roberto Solari, head of respiratory biology at GSK. "We hope at the end of this two year collaboration we will have a compound that is be ready to be investigated as a potential new medicine. Collaborations such as these - where we share knowledge, expertise and resource - provide a highly effective way of progressing cutting edge research."

"This strong collaboration between an industry partner, government granting agencies and the University is a superb example of partners building on mutual strengths and collaborating where our research interests converge," said Dr. Rose Goldstein, Vice-Principal (Research and International Relations). "We are grateful for the support provided by GSK and CIHR, facilitating our work together to give people with cystic fibrosis a healthy and full life expectancy." 

"Health research successes in the 21st century will be very much dependent on the ability of organizations from the public, academic and private sector to combine efforts and pool resources," said Dr. Marc Ouellette, Scientific Director for The Canadian Institutes of Health Research's Institute of Infection and Immunity. "In particular, this grant will increase our understanding of the cellular mechanisms causing cystic fibrosis and provide novel ways of targeting genetic based diseases. Research done through the support of this partnership will add to groundbreaking work done by Canada's strong Cystic Fibrosis research community, including those funded under the Canadian led Human Microbiome Initiative."

This research program has funding from both GSK and from an R&D operating grant from CIHR. It builds on previous work carried out with support from the Canadian and US CF Foundations, Génome Québec, CIHR and the Canadian Foundation for Innovation (CFI). It is the flagship project of a new cystic fibrosis translational research CFTR centre at McGill that has been established with support from the CFI.

About the Cystic Fibrosis

Cystic Fibrosis is caused by a single faulty gene that controls the movement of salt in the body. In people with Cystic Fibrosis, the internal organs become clogged with thick, sticky mucus resulting in infections and inflammation making it hard to breathe and digest food. There is no cure for the disease. About one in every 3,600 children born in Canada has CF. Treatment is aimed at controlling symptoms and infections. All disease-causing mutations in the gene for CFTR prevent the chloride channel from functioning properly, blocking movement of salt and water into and out of cells. As a result, cells that line the passageways of the lungs, pancreas, and other organs produce abnormally thick, sticky mucus. This viscous mucus cannot be easily cleared by the body, leading to obstruction of airways and glands and trapping bacteria that give rise to chronic infections.

McGill University
Canadian Institutes of Health Research 

New Method Attacks PA

New Method Attacks Bacterial Infections on Contact Lenses

ScienceDaily (Jan. 25, 2011) — Researchers at National Jewish Health and the University of Texas Southwestern Medical Center have discovered a new method to fight bacterial infections associated with contact lenses. The method may also have applications for bacterial infections associated with severe burns and cystic fibrosis. The results were published online January 18 in the journalInvestigative Ophthalmology and Visual Science.

"Infections by the bacteriaPseudomonas aeruginosa can cause severe scarring and vision loss when they spread to the cornea," said senior author Jerry Nick, MD, Associate Professor of Medicine at National Jewish Health. "By breaking apart a molecular scaffolding that encases the organisms and makes them more difficult to eradicate, we were able to significantly reduce bacterial infection of the cornea."
The eye normally fights infections through a variety of defense mechanisms including blinking of the eyes, which helps remove bacterial organisms from the surface of the eye. Contact lenses, however, inhibit the effectiveness of blinking eyelids.
Thus, bacteria can adhere to the surface of the contact lens that sits against the eye. If those bacteria infect the corneal surface they can destroy the delicate corneal cells, which can lead to scarring and vision loss. The condition is known as microbial keratitis, and affects about two to four lens wearers per 10,000 each year.
Eye infections can be treated with antibiotics. However, it can be difficult to eliminate the bacteria on the contact lenses, especially when they form a biofilm. A biofilm is a matrix that harbors and encases communities of the organisms, making them harder to eradicate.
The researchers confirmed earlier findings that cellular debris from immune cells fighting the infection actually provide the raw materials for the biofilm -- DNA, actin and histones. So, they used the enzyme DNAase together with negatively charged poly aspartic acid to break down the chemical bonds of these elements that support the biofilm.
This treatment reduced biofilms on the contact lenses by 79.2 percent. The same treatment reduced infection of the cornea in an animal model by 41 percent. There was no evidence of any harm caused by the treatments. (Abstract)
"These are very promising early results that point to potentially new methods for removing bacterial biofilms from contact lens surfaces, thereby reducing the risk of microbial keratitis, as well as the for the treatment of infections by Pseudomonas that are associated with cystic fibrosis and severe burns,' said Danielle Robertson, OD, PhD, first author and Assistant Professor of Ophthalmology at UT Southwestern, and first author on the study.

Monday, January 10, 2011

Mpex Initiates Phase 3 Clinical Trial Program with Aeroquin

Mpex Initiates Phase 3 Clinical Trial Program with Aeroquin™ for the Treatment of Chronic Bacterial Infections in Cystic Fibrosis Patients

SAN FRANCISCOJan. 10, 2011 /PRNewswire/ -- Mpex Pharmaceuticals, Inc. today during the JP Morgan 29th Annual Healthcare Conference, announced that it has initiated its Phase 3 clinical trial program with Aeroquin™ (MP-376) for the treatment of pulmonary infections in patients with cystic fibrosis (CF). Aeroquin is Mpex's proprietary aerosol formulation of levofloxacin, an antibiotic that has potent activity against key bacterial pathogens in CF including Pseudomonas aeruginosa.
The first study in this program is a multi-center, international, randomized, double-blind, placebo-controlled trial (Mpex 207) that is expected to enroll approximately 300 stable CF patients to evaluate the safety, tolerability and efficacy of 240 mg of Aeroquin administered twice daily using an optimized, Investigational eFlow Nebulizer System for 28 days. To ensure that results from this trial are predictive of efficacy in heavily treated cystic fibrosis patient and consistent with current clinical practice, the study will enroll patients that have recently received multiple courses of inhaled antibiotics and in most cases are receiving concomitant medication such as dornase alpha, azithromycin and hypertonic saline.  Patient enrollment in this study has already begun.
The primary efficacy endpoint to be assessed in the trial will be time to exacerbation. Additional endpoints include time to need for anti-pseudomonal antimicrobials, as well as change from baseline to Day 28 in lung function, the respiratory domain score of the CFQ-R and sputum Pseudomonas aeruginosa density.
An additional Phase 3 trial comparing Aeroquin to TOBI® (tobramycin inhalation solution) over three 28-day cycles (Mpex 209) is expected to begin enrolling patients in the next several weeks.
A previous Phase 2b study in 151 CF patients (Mpex 204) demonstrated that Aeroquin had a significant impact on 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 primary endpoint, a reduction in sputum Pseudomonas aeruginosa density at Day 28 (end of treatment) was achieved, with a twice daily 240mg dose showing the greatest effect. Statistically significant improvements in respiratory function including percent predicted FEV1, FEF25-75 and percent predicted FVC at Day 28 versus placebo were also observed with the 240mg twice-daily dose. Consistent with these results, a statistically significant reduction in the need for other inhaled and/or systemic anti-pseudomonal antimicrobials was also observed.  There were no safety concerns identified in Mpex 204 and there was no evidence for emergence of bacterial resistance during the study.
"The Phase 2b study with Aeroquin showed strong, consistent results in a very heavily treated patient population which bodes well for Phase 3," stated Jeff Loutit, Chief Medical Officer of Mpex Pharmaceuticals, Inc.  "A new inhaled antimicrobial with potent activity against a broad spectrum of pathogens, good tolerability, and with a low treatment burden would be a significant advance for CF patients.  We are very excited to be starting this Phase 3 program and look forward to working with patients and clinical investigators to extend the results we observed in our Phase 2b trial."
Results from the Aeroquin Phase 3 program are expected in mid-2012.  
About Cystic Fibrosis
Patients with CF suffer from chronic infections of the lower respiratory tract that can be caused by multiple bacteria, includingPseudomonas aeruginosa. Chronic pulmonary infection is associated with a decrease in lung function over time caused by inflammation arising from bacteria and their toxins. Periodic exacerbations in the lung result from bacterial overgrowth (requiring antibacterial intervention), and these exacerbations are implicated as a major cause of morbidity and mortality in CF patients.
About Aeroquin (MP-376)
Aeroquin is a proprietary formulation of levofloxacin that has been optimized for aerosol delivery using an optimized 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 Pseudomonas aeruginosa. Administration of Aeroquin with a high efficiency nebulizer to the lungs allows for the delivery of high concentrations of active drug directly to the site of infection in approximately 5 minutes, while minimizing systemic exposure.
About Mpex Pharmaceuticals
Mpex Pharmaceuticals is a clinical stage biopharmaceutical company whose mission is to develop important new therapies to combat the growing issue of antibiotic resistance. Mpex's most advanced product candidate, Aeroquin™ (MP-376), is a proprietary aerosol formulation of levofloxacin that is being developed clinically as a therapy for patients with cystic fibrosis. The Company has a number of additional antibiotic programs designed to address antibiotic resistance in gram negative organisms, including a collaboration with GlaxoSmithKline focused on developing multiple drug candidates utilizing Mpex's efflux pump inhibitor (EPI) technology. Company website: www.mpexpharma.com.
About the Investigational eFlow Nebulizer System and PARI Pharma
Aeroquin (MP-376) is delivered via an Investigational eFlow Nebulizer System, an inhalation delivery device optimized specifically for Aeroquin. The Investigational eFlow Nebulizer System uses eFlow® Technology to enable highly efficient aerosolization of medication via a vibrating, perforated membrane that includes thousands of small holes to produce the aerosol mist. Compared to other nebulization technologies, eFlow Technology produces 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 quiet mode of operation, small size (it fits in the palm of the patient's hand), light weight and battery use, eFlow Technology reduces the burden of taking daily, inhaled treatments. PARI Pharma focuses on the development of aerosol delivery devices and comprehensive inhalation drug development to advance aerosol therapies where drug and device can be optimized together.
SOURCE Mpex Pharmaceuticals, Inc.

Monday, January 3, 2011

Denufosol TIGER II - Fail

RALEIGH, N.C. (AP) — Inspire Pharmaceuticals Inc. said Monday that its potential cystic fibrosis drug failed to meet key treatment goals in a late-stage study. Its shares tumbled more than 54 percent in pre-market trading.

The company is studying denufosol tetrasodium as a treatment for the genetic condition, which results in thick mucus buildup in the lungs. The results from the latest Tiger-2 test mark a reversal from the prior successful Tiger-1 study of the drug candidate.

"These Tiger-2 results were disappointing and unexpected given the treatment effect observed in the Tiger-1 trial," President and CEO Adrian Adams said in a statement. "We will conduct a thorough analysis of the data to fully understand the results from this trial and the impact on any future development of denufosol and on the company going forward."

The latest study involved 466 patients taking either denufosol or placebo.

Adams said the company will continue to focus on its drug candidates aimed at treating glaucoma.
Shares of Inspire fell $4.58, or 54.5 percent, to $3.82 in pre-market trading on Monday. The stock closed at $8.40 on Friday.