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.

http://www.bloomberg.com/news/2011-01-03/inspire-cystic-fibrosis-drug-fails-in-study.html

Improving Clinical Trials Act passes!

I know many of you wrote to your Congress people over the past year and I want to THANK YOU for your efforts.


WE HAVE BEEN SUCCESSFUL! This new bill will translate into more CFers participating in clinical trials for life-changing drugs for CF.



-----------------------------------------------------------

"Improving Clinical Trials Act" Passes House and Senate, Heads to President for Signature



Sept 23, 2010





Today the U.S. House of Representatives passed the “Improving Access to Clinical Trials Act” (I-ACT), in a victory for the Cystic Fibrosis Foundation, its advocates and 120 other health advocacy organizations.

The bill, which passed the Senate Aug. 5, now goes to President Obama’s desk for his signature. He is expected to sign it.



This legislation enables patients with rare diseases to participate in clinical trials without losing eligibility for public healthcare benefits. Passage of this legislation is particularly important for people with CF, a rare genetic disease.







A limited patient population makes it challenging to find enough people to participate in research studies evaluating the effectiveness of promising new drugs.



“Because of this groundbreaking legislation, people with CF and other rare diseases will no longer be forced to choose between critical health care coverage and participation in research that could lead to the development of a cure for our most serious illnesses,” said Robert J. Beall, Ph.D., president and CEO of the Cystic Fibrosis Foundation.



“We are grateful to our champions in Congress for approving this bill, which will help move new treatments more swiftly from the lab to the patients who need them most.”



Cystic Fibrosis Caucus Co-Chairs, Reps. Edward Markey, D-Mass., and Cliff Stearns, R-Fla., led the effort to pass the bill in the House. The House version of this legislation, HR 2866, has 141 co-sponsors.



"No one should have to choose between participating in a clinical trial and accessing the essential benefits they need. Today's bill will open doors of hope and offer the possibility of better health to those with rare diseases like cystic fibrosis. I am proud to partner with my friend and co-chairman of the Congressional Cystic Fibrosis Caucus, Congressman Cliff Stearns, in the passage of this bi-partisan bill, which now will be signed into law by President Obama. I also want to commend the Cystic Fibrosis Foundation for its incredible work on this vital issue. Today represents an important and hopeful milestone in the battle to beat devastating rare diseases that afflict millions of Americans around the country," Markey said.



Added Stearns: "As co-chair and co-founder of the Congressional Cystic Fibrosis Caucus, I commend my colleagues for approving this legislation allowing people with rare diseases such as cystic fibrosis to participate in life-saving clinical trials that provide nominal compensation without the risk of losing their health care coverage. I also deeply appreciate the work of the Cystic Fibrosis Foundation in supporting my legislation."



The Senate version of the legislation, S. 1674, was introduced by Sen. Ron Wyden, D-Ore., with Sens. Chris Dodd, D-Conn., James Inhofe, R-Okla., Richard Shelby, R-Ala., and Dick Durbin, D-Ill., as original co-sponsors. An additional 17 co-sponsors signed on.



Current law prevents many people who receive Supplemental Security Income (SSI) from accepting research compensation because it makes them ineligible to receive government medical benefits. This penalty has stopped significant numbers of people with rare diseases from participating in clinical studies.

Cystic Fibrosis (CF) Exacerbation and Insulin Treatment

Cystic Fibrosis (CF) Exacerbation and Insulin Treatment



Sponsor:
Hadassah Medical Organization

Purpose
The purpose of the study is to evaluate whether insulin treatment during pulmonary exacerbation (PE) in patients with Cystic Fibrosis (CF)and normoglycemia improves their short term outcome by normalizing the glycemic profile and enhancing recovery. the investigators would like to evaluate whether insulin treatment during exacerbation improves both the general clinical condition of these patients and also has a protecting effect on ß-cells by preventing the deleterious effect of "chronic" hyperglycemia.


Drug: novorapid / humalog short acting insulinDrug: Novo Rapid Insulin (Novonordisk)

Study Type:
Interventional

Study Design:

Allocation: RandomizedEndpoint Classification: Efficacy StudyIntervention Model: Parallel AssignmentMasking: Open LabelPrimary Purpose: Treatment
O
fficial Title:
Evaluation of Glucose Tolerance and Insulin Treatment in Non Diabetic Patients With Cystic Fibrosis During Acute Pulmonary Exacerbation



Primary Outcome Measures:
delta Forced Expiratory Volume in 1 second (FEV1%) predicted [ Time Frame: day 0 of the pulmonary exacerbation, to day 14 of the pulmonary exacerbation ] [ Designated as safety issue: No ]
change in lung function parameter %FEV1 predected from baseline before the exacerbatio to day 0, the day of hospitalization due to the pulmonary exacerbation and to day 14, after 2 weeks of Intra Venous (IV)Antibiotic therapy, due to Pulmonary Exacerbation (PE).

Secondary Outcome Measures:
change in Body Mass Index (BMI) [ Time Frame: baseline BMI will be compared with BMI on day 0- the day of hospitalization due to the pulmonary exacerbation, and to day 14, after 2 weeks of Intra Venous (IV)Antibiotic therapy, due to Pulmonary Exacerbation (PE). ] [ Designated as safety issue: No ]
weight and hight will be measured on arrival to hospital (day 0)of the pulmonary exacerbation and again on day 14 of the pulmonary exacerbation and. BMI will be calculated and compared to BMI perior to the exacerbation

Estimated Enrollment:
30

Study Start Date:
June 2010

Estimated Study Completion Date:
December 2015

Estimated Primary Completion Date:
June 2015 (Final data collection date for primary outcome measure)

insulin: Experimental
patients who will get insulin with main meals during Intravenous (IV) antibiotic therapy due to pulmonary exacerbation

Drug: novorapid / humalog short acting insulin

1-4 units will be injected Subcutaneously (SC), before every main meal. Drug: Novo Rapid Insulin (Novonordisk)

Novo Rapid Insulin (Novonordisk) will be administered before each main meal 1-4 units depends on the patients weight Detailed Description:

The life expectancy of patients with cystic fibrosis (CF) has increased over the last decades due to improved understanding of the disease and new treatments. CF patients who live longer develop glucose intolerance and cystic fibrosis related diabetes (CFRD), in fact, routine annual screening by Oral Glucose Tolerance Tests (OGTT) shows that the prevalence of CFRD increases with age. CFRD is primarily an insulinopenic condition characterized by an impaired and delayed insulin secretion, as a consequence of fibrosis in the exocrine pancreatic tissue that compromises the ß-cell function.

The occurrence of CFRD is significantly related to increased morbidity and mortality. Based on data from the CF Patients Registry in the USA, the mortality rate of patients with CFRD is six-fold higher than that of patients without CFRD.

Our pilot study proved that during pulmonary exacerbation (PE), CF patients with Normal Glucose Tolerance (NGT) exhibited early latent diabetic glucose intolerance in Oral Glucose Tolerance Test(OGTT) which becomes completely normalized 3-4 weeks after resolution of PE. These patients who are considered to be normoglycemic may experience relatively long periods of hyperglycemia during recurrent events of pulmonary infections. Chronically increased glucose values during PE have an adverse impact on pulmonary function both during PE and in the long-term. Hyperglycemia may increase the duration and extent of recovery from PE. Furthermore it may impair the ability to overcome lung infections by directly stimulating the growth of respiratory pathogens. Finally, hyperglycemia per-se during stressful conditions may worsen the general outcome.

Insulin therapy is considered routine treatment for patients with CFRD. In addition to normalizing glucose levels, insulin has a beneficial effect on general pulmonary function and nutritional status, possibly due to its anabolic effect. No routine or formal guidelines for treating PE hyperglycemia are currently available. Normal Glucose Tolerance (NGT)patients, who are hyperglycemic during PE only, are generally not intensively treated for this condition, except if the treating physician decides on interventional insulin treatment. Some patients may experience relatively long periods of hyperglycemia during recurrent events of pulmonary infections.

Eligibility
Ages Eligible for Study:
10 Years and older

Genders Eligible for Study:
Both


Inclusion Criteria:
Confirmed diagnosis of CF according to standard criteria
Pancreatic insufficiency
Age > 10 years
Normal oral glucose tolerance test (OGTT) in the past 12 month.
Acute pulmonary exacerbation (PE) according to the treating physician requires treatment with intravenous antibiotics

Exclusion Criteria:
CF-related diabetes/impaired glucose tolerance test (IGTT) in a mixed meal tolerance test performed during full remission from pulmonary exacerbation

Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01149005

Locations
Israel
Hadassah Hospital
Jerusalem, Israel

Bronchitol Phase III Clinical Trial Results

Pharmaxis can breathe easy, say the bullish

DAVID SYMONS June 24, 2010

IT WAS a case of shoot first and ask questions later when Pharmaxis shareholders responded to clinical results for Bronchitol, a drug that improves lung function in cystic fibrosis patients by reducing mucus.

For many years a darling of the biotech sector, Pharmaxis shares fell as much as 47 per cent on the announcement that the company's second phase-three study of Bronchitol fell fractionally short of recording a statistically significant increase in the amount of air that patients could exhale over one second, as compared with a control group.

But the data was otherwise impressive, building on studies showing that Bronchitol increases lung function by 6 to 8 per cent.

This is important as the greatest cause of death for cystic fibrosis patients, who have a life expectancy of about 37 years, is the cumulative effect of lung-function decreases of 1 to 2 per cent a year.

What's spooked investors is the possibility a statistical quirk will mean Bronchitol fails to receive US Federal Drug Administration approval without a further clinical study.
It's a legitimate concern, particularly in light of spectacular failures from a clutch of biotech hopefuls already this year.

However, there's little reason to think Pharmaxis is going to join the ranks of fallen stars such as Chemgenex, Avexa, and Novagen. For a start, there's universal acceptance that Bronchitol is an effective drug that will obtain FDA approval.

The only question is whether another clinical study will be required, setting the timetable back from current plans for a US market launch in early 2012 and costing about $10 million to complete.

However, sector analysts reckon there's a good chance that Bronchitol will receive FDA approval based on the data already produced.

The most pessimistic view approval as a 50:50 proposition, while others are more bullish.
Shaw Stockbroking analyst Matthias Smith left his Pharmaxis share-price target unchanged at $4.30 after drilling into the data, commenting that he would be ''very surprised if further data is required for FDA approval''.

Key to the conclusion is the demonstrated safety of Bronchitol, and an expectation that the FDA has a strong desire to find an improved treatment for America's 30,000 cystic fibrosis sufferers.
Smith sees Pharmaxis's profits growing strong once Bronchitol is launched in Europe and the US, hitting $180 million in 2015.

After staging a modest recovery in afternoon trade, Pharmaxis shares closed yesterday at $2.10, down 33 per cent, and valuing the company at about $470 million.

Gilead's Head-to-Head Study Of Cayston Vs. TIS In Cystic Fibrosis Patients Achieves Co-Primary Efficacy Endpoint Of Non-inferiority

Gilead's Head-to-Head Study Of Cayston Vs. TIS In Cystic Fibrosis Patients Achieves Co-Primary Efficacy Endpoint Of Non-inferiority -
6/18/2010 12:51 PM ET

(RTTNews) - Gilead Sciences, Inc. (GILD: News ) said Friday that its head-to-head Phase III clinical trial of Cayston compared to tobramycin inhalation solution in cystic fibrosis patients with Pseudomonas aeruginosa achieved one of its co-primary endpoints of non-inferiority for mean percent change in forced expiratory volume in one second percent predicted after 28 days of treatment.

Patients receiving Cayston had a mean increase in FEV1 percent predicted from baseline to Day 28 of 8.35% compared to 0.55% for patients receiving tobramycin inhalation solution, which meets the statistical definition of superiority. Safety results were similar across both arms of the study, with lower incidence of cough in patients receiving Cayston.

Cayston was approved by the U.S. Food and Drug Administration in February 2010 and by the Australian Therapeutic Goods Administration in January 2010. Cayston received conditional marketing authorizations in the European Union and Canada in September 2009. These conditional approvals are contingent upon results from this Phase III study.

Gilead said it plans to begin submitting data from this study to regulatory agencies later this year.

Click here to receive FREE breaking news email alerts for Gilead Sciences Inc and others in your portfolio

by RTT Staff Writer

For comments and feedback: contact editorial@rttnews.com

ARIKACE Demonstrates Sustained Benefit in the Treatment of Cystic Fibrosis Patients Who Have Pseudomonas Lung Infections

MONMOUTH JUNCTION, N.J., June 17 /PRNewswire/ -- Transave, Inc., today reported interim results from a multi-cycle Phase II open label clinical trial in cystic fibrosis (CF) patients on its lead investigational drug, ARIKACE™ (liposomal amikacin for inhalation). The data indicated that ARIKACE, delivered once daily for 28 consecutive days followed by 56 days off-treatment for four cycles demonstrated statistically significant improvement in lung function that was sustained during the 56 days off study drug. ARIKACE was well-tolerated during the four cycles. Results were presented today at the 33rd European Cystic Fibrosis Society (ECFS) Conference in Valencia, Spain, by Predrag Minic, MD, Professor of Pediatrics and Head of Pediatrics Pulmonology Department, Mother and Child Health Institute, Belgrade, Serbia, and co-lead investigator of the study.

The open label study is an extension of a previously reported randomized, placebo controlled Phase II study, and was designed to evaluate ARIKACE over multiple treatment cycles in CF patients with Pseudomonas aeruginosa lung infections. Forty nine patients were enrolled to receive ARIKACE 560 mg daily for 28 days of therapy followed by a 56-day off-treatment observation period. ARIKACE was administered once daily using an eFlow® Nebulizer System (PARI Pharma GmbH), a novel, highly efficient and portable aerosol delivery system.

"The sustained improvement in lung function with significant reduction in bacterial density over multiple treatment cycles with ARIKACE is encouraging and indicative of benefit for cystic fibrosis patients who have chronic Pseudomonas lung infections," said Renu Gupta, MD, Transave's Executive Vice President for Development and Chief Medical Officer. Dr. Gupta indicated that preparations are underway to launch Phase III studies to confirm efficacy of ARIKACE. "These results support the potential value of delivering amikacin through Transave's advanced pulmonary liposome technology designed for sustained release and penetration of the mucus and bacterial biofilm in the lungs."

Pulmonary function (FEV1) increased significantly among patients receiving 560 mg of ARIKACE, with an estimated relative change from baseline in FEV1 of 9.2% (95% CI +5.0%, +13.4%; p less than or equal to 0.0001) at the end of treatment during cycles one to four. The improvement in lung function was sustained at the end of the 56-day off-treatment period during the four cycles with an estimated relative change from baseline in FEV1 of 4.7% (95% CI +1.0%, +8.5%; p=0.015).

ARIKACE demonstrated statistically significant reduction in Pseudomonas density, including mucoid strains, which was sustained over the treatment period of four cycles for 12 months. Mucoid strains of Pseudomonas are often difficult to suppress with antibiotics and play a greater role in progression of CF lung disease.

ARIKACE was well-tolerated for four cycles of treatment over 12 months, and demonstrated adverse effects that are consistent with those expected in a population of CF patients receiving inhalation medicines.

"ARIKACE development continues to show promise in improving lung function for CF patients," said Robert J. Beall, Ph.D., President and CEO of the Cystic Fibrosis Foundation. "We are pleased to support Transave's work in potentially bringing an important new treatment option to CF patients."

Cystic Fibrosis Foundation Therapeutics, Inc., a nonprofit affiliate of the Cystic Fibrosis Foundation, provided $3.9 million to support the development of ARIKACE. The Foundation is the leading organization devoted to curing and controlling cystic fibrosis.

"A once-daily drug that may offer advantages in maintaining improvements in lung function during off-treatment periods over multiple cycles would be an important advance in the treatment of cystic fibrosis patients," said Dr. Minic. "These results show significant improvement in lung function with ARIKACE and are especially important since these patients are living in a state of chronic infection often requiring continuous treatment cycles over time.

The data presented today at the 33rd European Cystic Fibrosis Society Conference are currently available on the company's website: (http://www.transaveinc.com/NewsEvents.aspx?category=Articles&archive=false).

About ARIKACE™

ARIKACE is a form of the antibiotic amikacin, which is enclosed in nanocapsules of lipid called liposomes. This advanced pulmonary liposome technology prolongs the release of amikacin in the lungs while minimizing systemic exposure. The treatment uses biocompatible lipids endogenous to the lung that are formulated into small (0.3 micron), neutral liposomes that enable penetration of the biofilm.

Positive results were announced in October 2009 from pooled results of two Phase II clinical trials in the treatment of CF patients with Pseudomonas lung infections. The company also previously announced positive Phase II results in September 2009 in the treatment of non-CF bronchiectasis patients who have Pseudomonas lung infections.

Transave and the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH), will collaborate on the planning, design and implementation of a clinical trial beginning later this year to evaluate ARIKACE in patients with nontuberculous mycobacteria (NTM) lung disease who have failed to respond to standard, guideline-based treatment regimens. Current treatment requires lengthy multi-drug regimens that are often poorly tolerated and not very effective. No new drugs have been assessed in clinical trials for this disease in many years.

ARIKACE has been granted orphan drug status in the United States by the FDA, and has received an orphan drug designation in Europe by the European Medicines Agency for the treatment of Pseudomonas infections in patients with CF. ARIKACE has also been granted orphan drug status by the FDA for the treatment of bronchiectasis in patients with Pseudomonas or other susceptible pathogens.

About eFlow® Technology and PARI Pharma

ARIKACE is delivered by an eFlow® Nebulizer System developed by PARI Pharma and optimized specifically for ARIKACE. The eFlow Nebulizer System uses eFlow Technology to enable highly efficient aerosolization of medication including liposomal formulations via a vibrating, perforated membrane that includes thousands of laser drilled holes. 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. eFlow Technology is not an ultrasonic nebulizer technology. 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. Online at www.paripharma.com.

About The Cystic Fibrosis Foundation

The Cystic Fibrosis Foundation is the world's leader in the search for a cure for cystic fibrosis. The Foundation funds more CF research than any other organization and nearly every CF drug available today was made possible because of Foundation support. Based in Bethesda, Md., the Foundation also supports and accredits a national care center network that has been recognized by the National Institutes of Health as a model of care for a chronic disease. For more information, please visit www.cff.org.

About Transave, Inc.

Transave, Inc., is a biopharmaceutical company focused on the development of innovative inhaled pharmaceuticals for the site-specific treatment of chronic lung diseases. The company's major focus is on developing antibiotic therapy delivered via proprietary advanced pulmonary liposome technology in areas of high unmet need in lung diseases. The Transave team is dedicated to leveraging its development and commercialization expertise, along with its intellectual property, to bring life-extending and life-enhancing medicines to patients. For more information about Transave's technology and development programs, visit www.transaveinc.com.

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.

Pharmaxis Completes Phase 3 Trial Of Bronchitol

Pharmaxis Completes Phase 3 Trial Of Bronchitol

Published: 14-Apr-2010

Pharmaxis, a specialist pharmaceutical company, has completed second six month, Phase 3 international trial assessing the effectiveness of Bronchitol in people with cystic fibrosis.

The double blind, placebo controlled, randomised study comparing 400mg of Bronchitol twice a day to control included 305 participants, and was conducted across 53 sites in 7 countries. Pharmaxis said that the last participant has completed the final clinical visit and the trial has run on time and on budget.

Pharmaxis has now completed blinded efficacy and safety period, an optional 26 week open-label uncontrolled Bronchitol extension is still running.

The trial is the second of two trials in cystic fibrosis, required by the FDA, before a marketing application can be submitted in the US. A total of 600 cystic fibrosis patients have now been recruited into the two Bronchitol Phase 3 clinical trials.

The primary efficacy end-point is change in lung function from baseline as determined by FEV1 (forced expiratory volume in one second) over 26 weeks. The results of the trial is expected to be available shortly after data review and statistical analysis of the various endpoints have been completed.

Pharmaxis said that the trial has been designed under the FDA’s Special Protocol Assessment (SPA) scheme. Pharmaxis has received Orphan Drug Designation and fast track status from the FDA for Bronchitol in cystic fibrosis.

Based on the results of the first Phase III trial reported in May 2009, Pharmaxis had filed a marketing authorisation application with the European Medicines Agency in October 2009. The regulatory review is expected to conclude during the second half of 2010.

Alan Robertson, CEO of Pharmaxis, said: “We are very pleased to announce this important milestone. The support of the US Cystic Fibrosis Foundation has been important in conducting this trial efficiently and there has been considerable enthusiasm from patients and the clinical centres involved. It is hoped this trial will confirm that Bronchitol has the opportunity to impact the way people with cystic fibrosis live their lives.”


http://clinicaltrials.pharmaceutical-business-review.com/news/pharmaxis_completes_phase_3_trial_of_bronchitol_100414/

Statins To Treat Adult Cystic Fibrosis (CFStatin)

Statins To Treat Adult Cystic Fibrosis (CFStatin)




Sponsor:
University of British Columbia

Information provided by:
University of British Columbia

ClinicalTrials.gov Identifier:
NCT01092572

Purpose
Cystic fibrosis (CF) is a lethal genetic condition that affects 30,000 children and adults in the United States. Although CF management has improved substantially over the past two decades, there is still no cure and most patients with CF die before reaching their 50th birthday, largely due to lung failure. There is growing evidence that excess lung and blood inflammation that occurs in response to infections in the lungs cause CF patients to be sicker. Simvastatin is a drug that is used to lower cholesterol, but many researchers have found that this drug may also treat blood and lung inflammation. In this study, we will determine whether or not simvastatin can treat blood and lung inflammation in patients with CF and most importantly determine whether or not it can make these patients feel better and have better lung function.

Cystic FibrosisSystemic Inflammation
Drug: SimvastatinDrug: placebo

Phase IPhase II

Study Type:
Interventional

Study Design:
Allocation: RandomizedControl: Placebo ControlEndpoint Classification: Efficacy StudyIntervention Model: Parallel AssignmentMasking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)Primary Purpose: Treatment

Official Title:
The Effect of Simvastatin on Systemic Inflammation in Adult Cystic Fibrosis Subjects: A Pilot Study

Primary Outcome Measures:
C-reactive protein [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]
The difference in the change in plasma C-reactive protein concentrations from baseline to 12 weeks of treatment between those randomized to simvastatin 40 mg/d and those randomized to placebo

Secondary Outcome Measures:
Changes in forced expiratory volume in one second (FEV1) [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]
The differences in the above parameters over 12 weeks between those assigned to simvastatin 40 mg/d and those assigned to placebo.
Changes in exacerbation rates [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]
The differences in the above parameters over 12 weeks between those assigned to simvastatin 40 mg/d and those assigned to placebo.
Changes in blood pro-inflammatory markers such as IL-6, TNF, IL-1beta, LPS, LBP, sCD14, EndoCAB, SP-D, CCL-18) [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]
The differences in the above parameters over 12 weeks between those assigned to simvastatin 40 mg/d and those assigned to placebo.

Estimated Enrollment:
120

Study Start Date:
May 2010

Estimated Study Completion Date:
July 2012

Estimated Primary Completion Date:
January 2012 (Final data collection date for primary outcome measure)


Simvastatin 40 mg/d: Experimental
simvastatin 40 mg per day taken orally

Drug: Simvastatin
simvastatin 40 mg per day orally for 12 weeks.
Sugar pill: Placebo Comparator

Study Objectives
To determine the effect of 12 weeks of 40 mg once daily simvastatin on general inflammatory molecules, IL-6 and CRP in the blood of CF patients.
To determine the effect of simvastatin on LPS-related pathway molecules in the blood.
To determine the effect of simvastatin on inflammatory pneumo-proteins in the blood.
To determine exacerbation and safety data on statins in preparation for a large phase III trial of statins in CF.

Study Endpoints
The primary endpoint will be the quantitative changes in serum levels of CRP.
Secondary endpoints will include:
blood biomarkers IL6, LPS related proteins, LPS, LBP, sCD14 and EndoCAb, and pneumoproteins, SPD and CCL18; and molecules such as TNF-α and IL-1beta;
changes in FEV1 over 12 weeks ; and
exacerbations over 12 weeks

Please refer to this study by its ClinicalTrials.gov identifier: NCT01092572
Contacts
Contact: Don D Sin, MD
604-806-8395
don.sin@hli.ubc.ca
Contact: Paul Man, MD
604-806-8495
pman@providencehealth.bc.ca
Locations
Canada, British Columbia
St. Paul's Hospital
Vancouver, British Columbia, Canada, V6Z 1Y6
Sponsors and Collaborators
University of British Columbia
Investigators
Principal Investigator:
Paul Man, MD
University of British Columbia
More Information
No publications provided
Responsible Party:
University of British Columbia ( Shu-Fan Paul Man, Professor of Medicine )

CF Investigational Drug VX-809 Shows Encouraging Resultsin Phase 2a Trial

CF Investigational Drug VX-809 Shows Encouraging Resultsin Phase 2a Trial

(from the CFF)
February 3, 2010

Vertex Pharmaceuticals Incorporated announced today results from a Phase 2a trial of VX-809, an oral investigational drug that aims to correct the basic defect in cystic fibrosis. VX-809 was found to be well-tolerated and to reduce sweat chloride levels — a key indicator of CF.

The 28-day, Phase 2a trial of VX-809 examined the drug in cystic fibrosis patients who have the Delta F508 gene mutation, the most common mutation in CF. The study focused primarily on the safety and tolerability of the drug and changes in sweat chloride.

A reduction in sweat chloride levels in the Phase 2a data suggests that VX-809 may improve the function of CFTR, the faulty protein in CF.“These are very exciting and important results in our effort to find ways to treat the basic defect in cystic fibrosis,” said Robert J. Beall, Ph.D., president and CEO of the CF Foundation. “The VX-809 data further supports our hypothesis that small molecules can be used to treat the underlying genetic cause of cystic fibrosis.”

The data from this trial pave the way for future studies of VX-809, including testing the therapy in combination with VX-770. Also developed by Vertex, VX-770 is an oral investigational drug that showed encouraging Phase 2 results in restoring the function of CFTR in patients with the G551D mutation of CF.

Research in the laboratory suggests that using two therapies in combination may increase CFTR function in cells with the Delta F508 mutation when compared to using a single therapy alone.
The first trial examining VX-809 and VX-770 in combination in cystic fibrosis patients is currently in the planning phases, and is expected to begin in the United States in the second half of 2010.

In addition, Vertex is further reviewing the Phase 2a data and may explore the option of studying VX-809 as a single drug in higher doses in a separate clinical trial.

Through its Therapeutics Development Program, the CF Foundation collaborated with Vertex to discover and develop VX-809 and VX-770, investing approximately $76 million in the effort. This represents the largest single investment in CF drug discovery by the Foundation.

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Vertex press release

Vertex Announces Results from Phase 2a Trial of VX-809 Targeting the Defective Protein Responsible for Cystic Fibrosis

-VX-809 was well-tolerated at all dose levels when dosed once daily for 28 days-

-Statistically significant changes observed in measurement of sweat chloride suggest increased CFTR activity- -Data support planned combination trial of VX-809 and VX-770 in second half of 2010 for CF patients with the F508del mutation- \

CAMBRIDGE, Mass., Feb 03, 2010 (BUSINESS WIRE) -- Vertex Pharmaceuticals Incorporated (Nasdaq: VRTX) today announced results from a preliminary analysis of data from a 28-day Phase 2a clinical trial of VX-809 in patients with cystic fibrosis (CF) who are homozygous for the F508del mutation. VX-809, an oral investigational Cystic Fibrosis Transmembrane Conductance Regulator protein (CFTR) corrector, was well-tolerated across all four dose groups studied. In the trial, VX-809 showed a statistically significant decline in sweat chloride at both the 100 mg and 200 mg once-daily doses, suggesting that the activity of the CFTR protein was increased in patients during dosing. Additionally, VX-809 demonstrated a dose response in change in sweat chloride across the four dose groups. On the basis of these results, Vertex plans to initiate a combination trial of VX-809 and VX-770, an investigational CFTR potentiator, in the second half of 2010. VX-809 and VX-770 were developed with support from Cystic Fibrosis Foundation Therapeutics, Inc., the nonprofit affiliate of the Cystic Fibrosis Foundation.

"This Phase 2a trial evaluated the potential effect of an oral compound to improve trafficking of the defective CFTR protein, and its results represent an encouraging step forward in the development of new therapies to treat the underlying cause of CF in patients with the most common CFTR mutation, known as F508del," said J.P. Clancy, M.D., Director of the Pediatric Pulmonary Center at the University of Alabama at Birmingham and Principal Investigator for the VX-809 Phase 2a trial. "In the trial, VX-809 was well-tolerated across the dose groups, and statistically significant changes in sweat chloride, an important biomarker of CFTR activity, were observed at certain dose levels. There is high interest in the CF community in new approaches to CF therapy, and we look forward to the future exploration of VX-809 and VX-770 as part of a novel combination regimen aimed at treating the majority of CF patients."

"While the median predicted age of survival for patients with CF has increased to more than 37 years of age, there are no approved therapies that directly target the underlying defect of this disease," said Robert J. Beall, Ph.D., President and Chief Executive Officer of the Cystic Fibrosis Foundation. "We believe that compounds such as VX-770 and VX-809 represent a promising potential approach to future CF treatment, and the results announced today for VX-809 support future clinical trials of this compound, including a planned clinical trial in combination with VX-770 expected to begin later this year."

About the Phase 2a Trial

The preliminary results reported today are from a randomized, double-blind, placebo-controlled, multiple dose Phase 2a clinical trial that enrolled 89 patients aged 18 or older who are homozygous for the F508del CFTR mutation. Patients in the trial received one of four doses of VX-809, or placebo, in addition to standard therapies for 28 days. The primary endpoint of the trial was to evaluate the safety and tolerability of VX-809. Multiple secondary endpoints were utilized to evaluate any effect of VX-809 on CFTR function or lung function.

Safety Evaluation

Through 28 days of 25 mg, 50 mg, 100 mg and 200 mg once-daily dosing, VX-809 was well-tolerated. In the trial, one patient discontinued treatment in each of the VX-809 treatment arms due to adverse events. Respiratory-related adverse events were the most commonly reported adverse event in the trial. Safety and tolerability were the primary endpoints of the trial, and a detailed safety analysis is ongoing.

Evaluation of CFTR Activity

At both the 100 mg and 200 mg dose levels, a statistically significant decline in sweat chloride, a secondary endpoint, was observed in analyses comparing each patient to baseline and to placebo. Additionally, a dose response for change in sweat chloride was observed across all four dose groups. The mean change in sweat chloride compared to placebo for each of the dose groups is as follows:

Treatment Arm
Mean Change in Sweat Chloride Compared to Placebo*

*Across the arms of the trial, patients' mean baseline sweat chloride measurements were approximately 100 mmol/L, which is consistent with sweat chloride measurements of patients who are homozygous for the F508del mutation.

Elevated sweat chloride levels are a diagnostic hallmark that occur in all CF patients and result directly from defective CFTR activity in epithelial cells in the sweat duct. The amount of chloride in the sweat is measured using a standard test. Patients with CF typically have elevated sweat chloride levels in excess of 60 mmol/L, while normal values are less than 40 mmol/L.

"This trial was meant to provide clinical data for VX-809 to inform the direction of future development for this compound," said Dr. Robert Kauffman, Vertex's Senior Vice President, Clinical Development and Chief Medical Officer. "Based on data generated in this Phase 2a trial, we plan to move forward with a proof-of-concept clinical trial of VX-809 dosed in combination with VX-770 in the F508del patient population, planned for the second half of 2010. We are pleased with the safety and biomarker data observed in this preliminary analysis, which, together with the Phase 2 data for VX-770, could contribute to the future treatment of CF with novel CFTR modulators."

The trial also included additional secondary endpoints, including exploratory endpoints, to evaluate CFTR function, including CFTR trafficking, and lung function. The trial was not powered to demonstrate a statistically significant effect in these additional secondary endpoints. Additional sub-analyses of the secondary endpoints are ongoing to determine any potential trends in other measures of CFTR-dependent chloride ion transport, such as nasal potential difference; or CFTR maturation, as measured by an exploratory Western blot assay, however no statistically significant changes in these measures were observed in the preliminary analysis of data from this trial. As expected, the results did not show any change in lung function, as measured by FEV1.

Vertex expects to report additional results of this Phase 2a trial at a medical meeting in 2010.
Future Development Plans for VX-809

Based on the Phase 2 data announced today, Vertex plans to initiate a combination trial of VX-809 with the CFTR potentiator VX-770 in patients with the most common CFTR mutation, F508del, in the second half of 2010. In in vitro studies, a combination regimen of VX-770 and VX-809 has been shown to increase CFTR activity when compared to dosing of VX-770 or VX-809 as single agents. In addition, Vertex is conducting further analyses of the Phase 2a data and may explore the option to evaluate VX-809 doses of greater than 200 mg when dosed as a single agent.

About VX-809 and VX-770

VX-809 is a novel oral CFTR corrector drug candidate aimed at increasing the concentration of F508del CFTR proteins at the cell surface. Vertex recently completed a Phase 2a trial of VX-809, as announced today.

Vertex is also developing VX-770, a novel oral CFTR potentiator drug candidate aimed at increasing the activity of defective CFTR proteins at the cell surface. Vertex is currently conducting the ENDEAVOR Phase 3 registration program of VX-770, an investigational Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) potentiator compound for the treatment of CF. The program consists of three ongoing clinical trials, known as STRIVE, ENVISION and DISCOVER, and is designed to evaluate the utility of VX-770 across different age groups and genotypes, including children as young as six years of age.

Patients interested in further information about clinical trials of VX-809 or VX-770 should visit www.clinicaltrials.gov or http://www.cff.org/clinicaltrials.

Collaborative History with Cystic Fibrosis Foundation Therapeutics, Inc. (CFFT)
Vertex initiated its CF research program in 1998 as a part of a collaboration with CFFT, the non-profit drug discovery and development affiliate of the Cystic Fibrosis Foundation. Vertex and CFFT expanded the agreement in 2000 and again in 2004, and in March 2006, entered into a collaboration for the accelerated development of VX-770. In addition to the development collaboration for VX-770, in January 2006 Vertex and CFFT entered into an expanded research collaboration to develop novel corrector compounds. Vertex has received approximately $75 million from CFFT to support CF research and development efforts.

Study of VX-770 on Midazolam and Rosiglitazone and the Effect of Fluconazole on VX-770

Study of VX-770 on Midazolam and Rosiglitazone and the Effect of Fluconazole on VX-770

Sponsor:
Vertex Pharmaceuticals Incorporated

Information provided by:
Vertex Pharmaceuticals Incorporated

Purpose
The objectives of this study are to evaluate the effects of VX-770 on Midazolam and Rosiglitazone, and the effect of Fluconazole on VX-770.

Drug: VX-770

Phase I

Study Design:
Treatment, Non-Randomized, Open Label, Uncontrolled, Crossover Assignment, Pharmacokinetics Study

Official Title:
An Open-Label Phase 1 Study to Examine the Effect of VX-770 on Midazolam and Rosiglitazone and the Effect of Fluconazole on VX-770 in Healthy Subjects

Primary Outcome Measures:
Midazolam, Rosiglitazone and VX 770 pharmacokinetic (PK) parameter [ Time Frame: 11 days ] [ Designated as safety issue: No ]

Fluconazole and VX 770 PK parameters [ Time Frame: 10 days ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
1´ hydroxy midazolam PK parameters in plasma [ Time Frame: 11 days ] [ Designated as safety issue: No ]

Safety as measured by adverse events, physical examinations, vital signs, ECGs, and clinically significant laboratory assessments [ Time Frame: 21 days ] [ Designated as safety issue: Yes ]

Metabolites PK parameters in plasma [ Time Frame: 21 days ] [ Designated as safety issue: No ]

Estimated Enrollment:
24

Study Start Date:
February 2010

Estimated Study Completion Date:
March 2010

Estimated Primary Completion Date:
March 2010 (Final data collection date for primary outcome measure)

VX-770: Experimental
Drug: VX-770

In period 1, subjects will receive a single oral dose of midazolam (2 mg) and on Day 1 and Day 8. Subjects will receive single oral dose of rosiglitazone 4 mg and on Day2 and Day 9. Subjects will receive multiple doses of VX-770 150 mg q12h Day 3-10. Drug: VX-770

In period 2, subjects will receive 150 mg VX-770 q12h orally from Day 1 through the morning of Day 8. On the morning of Period 2 Day 1, subjects will receive a 400 mg loading dose of fluconazole. Thereafter, subjects will receive 200 mg fluconazole qd orally from Day 2 through Day 9.

Ages Eligible for Study:
18 Years to 55 Years

Accepts Healthy Volunteers:
Yes

Inclusion Criteria:

Subjects must be male or female and between 18 and 55 years of age.
Subjects must be judged to be in good health.
Subjects must have a body mass index (BMI) from 18 to 30 kg/m2.

Exclusion Criteria:
History of any illness that, in the opinion of the investigator or the subject's general practitioner, might confound the results of the study or pose an additional risk in administering study drug(s) to the subject.

Subjects who have human immunodeficiency virus (HIV), hepatitis C, or active hepatitis B.
Female subjects and female partner(s) of male subjects who are pregnant, nursing, or planning to become pregnant during the study or within 90 days of the last dose of study drug.
History of cardiovascular disease, hypoglycemia, or edema.

Contacts
Contact: Medical Monitor
617.444.6777
medicalinfo@vrtx.com

Locations
United States, Florida
Covan CRU, Inc.
Daytona Beach, Florida, United States, 32117

Sponsors and Collaborators
Vertex Pharmaceuticals Incorporated
Investigators
Principal Investigator:
H. Frank Farmer, MD
Covance CRU, Inc.

Safety and Efficacy Study of Aztreonam for Inhalation Solution (AZLI) in Patients With Cystic Fibrosis and Chronic Burkholderia Species Infection

Safety and Efficacy Study of Aztreonam for Inhalation Solution (AZLI) in Patients With Cystic Fibrosis and Chronic Burkholderia Species Infection

Sponsor: Gilead Sciences


The purpose of this research study is to see if an experimental drug called Aztreonam for Inhalation Solution is safe and effective to treat Burkholderia lung infections in patients with Cystic fibrosis.

Drug: Aztreonam for Inhalation solution

Study Type: Phase III

Study Design: Treatment, Randomized, Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Placebo Control, Crossover Assignment, Safety/Efficacy Study

Official Title:
Phase 3b Randomized, Double-Blind, Placebo-Controlled Two-Part Trail to Assess the Safety and Efficacy of Continuous Aztreonam for Inhalation Solution (AZLI) in Subjects With Cystic Fibrosis(CF) and Chronic Burkholderia Species Infection

Primary Outcome Measures:
Change from baseline in FEV1 percent predicted as measured by the AUCave through week 24.

Secondary Outcome Measures:
AUCave of relative change from baseline in FEV1, FVC, and FEF25 to 75 percent through week 24.

Estimated Enrollment:
76

Aztreonam for inhalation solution(75mg)will be administered three times a day, with at least 4 hours between doses, for up 48 hours via the PARI investigational eFlow electronic nebulizer.
lactose and sodium chloride: Placebo Comparator

Aztreonam for inhalation solution(75mg)will be administered three times a day, with at least 4 hours between doses, for up 48 hours via the PARI investigational eFlow electronic nebulizer.

Eligibility

Ages Eligible for Study:
6 Years and older

Inclusion Criteria:
Male or female ≥ 6 years of age

Subjects with CF as diagnosed by one of the following:
Documented sweat chloride ≥ 60 mEq/L by quantitative pilocarpine iontophoresis test
Documented sweat sodium ≥ 60 mmol/L
Two well characterized genetic mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene
Abnormal NPD with accompanying symptoms characteristic of CF

Chronic infection with Burkholderia spp. defined by:
One sputum culture positive for Burkholderia spp. within 6 months prior to baseline assessment,
At least 50% of sputum cultures collected at least one month apart over the previous 12 months prior to baseline assessment positive for Burkholderia spp. (minimum of 2 positive cultures), and
At least one positive sputum culture (obtained at any point in time) confirmed to be Burkholderia spp. by the CFF Burkholderia cepacia Research Laboratory and Repository at the University of Michigan (or equivalent Canadian reference laboratory)

Concomitant aerosolized antibiotic treatment: subjects receiving intermittent (alternating month on/month off) aerosolized antibiotic treatment are eligible, but must be at least 1 week into their off-treatment cycle at the time of baseline assessment.

Subjects receiving continuous aerosolized antibiotic treatment will be eligible without restriction on their aerosolized antibiotic treatment

Chest radiograph, computed tomography (CT) or magnetic resonance imaging (MRI), (most recent, obtained within 90 days of screening) without significant acute findings (e.g., infiltrates [lobar or diffuse interstitial], pleural effusion, pneumothorax), and no significant intercurrent illness; chronic, stable findings (e.g., chronic scarring or atelectasis) are allowed

Subjects (and parent/guardian as required) must be able to provide written informed consent/assent prior to any study related procedures

Ability to perform reproducible pulmonary function tests

Sexually active females of childbearing potential must agree to use a highly effective method of contraception during heterosexual intercourse throughout the study period and for 30 days following discontinuation of study drug. A highly effective method of birth control is defined as a method that results in a low failure rate (i.e., less than 1% per year) when used consistently and correctly, such as implants, injectables, combined oral contraceptives, some intrauterine devices (IUDs), or a vasectomized partner

Exclusion Criteria:
Administration of any investigational drug or use of any investigational device within 28 days of randomization/baseline and within six half-lives of the investigational drug (whichever is longer)
Administration of AZLI treatment within the 28 days prior to randomization/baseline

Known local or systemic hypersensitivity to monobactam antibiotics

History of lung transplantation

Abnormal renal or hepatic function results at most recent test within the previous 90 days, defined as:
AST or ALT > 5 times upper limit of normal (ULN) range
Serum creatinine > 2 times ULN

Known portal hypertension or complications of CF hepatopathy

Positive urine pregnancy test (confirmed by serum pregnancy test) at screening; all women of childbearing potential will be tested

Female of childbearing potential who is lactating or not practicing a highly effective method of birth control as defined in Section 7.8

Any serious or active medical or psychiatric illness which, in the opinion of the investigator, would interfere with subject treatment, assessment or compliance with the protocol

Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01059565
Contacts
Contact: Sheila Leitzinger
2062564904
sheila.leitzinger@gilead.com
Contact: Jennifer Glover
2067923039
jennifer.glover@gilead.com Hide Study Locations

Locations

United States, Alabama
Pulmonary Associates of Mobile, P.C.
Mobile, Alabama, United States, 36608

United States, Arizona
Phoenix Children's Hospital
Phoenix, Arizona, United States, 85016

United States, Arkansas
University of Arkansas for Medical Sciences
Little Rock, Arkansas, United States, 72205

United States, California
University of Southern California
Los Angeles, California, United States, 90033

United States, Colorado
National Jewish Health
Denver, Colorado, United States, 80206

United States, Connecticut
Hartford Hospital
Hartford, Connecticut, United States, 06102

United States, Delaware
Alfred I. duPont Hospital for Children
Wilmington, Delaware, United States, 19803

United States, Florida
Tampa General Hospital
Tampa, Florida, United States, 33606

University of Miami
Miami, Florida, United States, 33136
Nemours Children's Clinic
Jacksonville, Florida, United States, 32207

United States, Illinois
The Cystic Fibrosis Institute
Glenview, Illinois, United States, 60025

United States, Massachusetts
Children's Hospital Boston
Boston, Massachusetts, United States, 02115
UMass Medical Center
Worcester, Massachusetts, United States, 01605

United States, Michigan
Harper University Hospital/Wayne State University
Detroit, Michigan, United States, 48201
University of Michigan
Ann Arbor, Michigan, United States, 48109

United States, Minnesota
University of Minnesota
Minneapolis, Minnesota, United States, 55455

United States, Mississippi
University of Mississippi Medical Center
Jackson, Mississippi, United States, 39216

United States, Missouri
Washington University School of Medicine
St. Louis, Missouri, United States, 63110

United States, Nevada
Childrens Lung Specialists
Las Vegas, Nevada, United States, 89107

United States, New Jersey
Robert Wood Johnson Medical School
New Brunswick, New Jersey, United States, 08903

Morristown Memorial Hospital
Morristown, New Jersey, United States, 07962

United States, New Mexico
Univesity of New Mexico
Albuquerque, New Mexico, United States, 87131

United States, New York
The Long Island Jewish Medical Center
New Hyde Park, New York, United States, 11040

United States, North Carolina
UNC Chapel Hill
Chapel Hill, North Carolina, United States, 27599

United States, Ohio
Children's Hospital Medical Center of Akron

Akron, Ohio, United States, 44308
Toledo Children's Hospital/The Toledo Hospital
Toledo, Ohio, United States, 43606

United States, Oklahoma
Santiago Reyes, M.D.
Oklahoma City, Oklahoma, United States, 73112

United States, Oregon
Oregon Health and Sciences University
Portland, Oregon, United States, 97239

Kaiser Permanente Northwest
Portland, Oregon, United States, 97227

United States, Pennsylvania
Children's Hospital of Pittsburgh of UPMC
Pittsburgh, Pennsylvania, United States, 15201
Penn State Inst & Milton S. Hershey Med Ctr
Hershey, Pennsylvania, United States, 17033
University of Pennsylvania
Philadelphia, Pennsylvania, United States, 19104

United States, South Carolina
MUSC
Charleston, South Carolina, United States, 29425

University of South Carolinas School of Medicine
Columbia, South Carolina, United States, 29203

United States, Virginia
Virginia Commonwealth University
Richmond, Virginia, United States, 23298

Children's Hospital of The King's Daughters
Norfolk, Virginia, United States, 23507

United States, West Virginia
Pediatric Infectious Diseases
Morgantown, West Virginia, United States, 26506

United States, Wisconsin
Medical College of Wisconsin, Children's Hospital Wisconsin
Milwaukee, Wisconsin, United States, 53201

Canada, Ontario
St Michael's Hospital
Toronto, Ontario, Canada, M5B 1W8

High Frequence Chest Wall Oscillation and Cystic Fibrosis study in the UK

Wow I feel so fortunate to have had HFCC available to me for a very low cost since 1997.....

High Frequence Chest Wall Oscillation and Cystic Fibrosis

This study is not yet open for participant recruitment.

Verified by Imperial College London, January 2010

Sponsor: Imperial College London

Collaborators: Royal Brompton & Harefield NHS Foundation TrustHill-Rom

Purpose : High frequency chest wall oscillation (HFCWO) has been shown to increase tracheal mucus clearance compared with a control group. These observations led to the development of The Vest® which is a non-stretchable jacket connected to an air-pulse generator and worn by the patient over the chest wall. The generator rapidly inflates and deflates The Vest®, which gently compresses and releases the chest wall between 5 and 20 times per second. This generates mini-coughs that are said to dislodge mucus from the bronchial walls and to facilitate its movement up the airways. The Vest® has been shown to reduce the viscosity of mucus and this should further enhance mucus clearance.

People with cystic fibrosis (CF), admitted to hospital with an acute infective pulmonary exacerbation, should increase the frequency and duration of their airway clearance sessions owing to the increase in quantity and viscosity of purulent bronchial secretions.In the United Kingdom, and in many other countries, the availability of physiotherapists to assist with the recommended number of daily treatments is insufficient to meet patient need. If the use of high frequency chest wall oscillation, in addition to 'usual' self airway clearance techniques, in the early morning and evening was to facilitate recovery from an exacerbation, this would indicate an important place for high frequency chest wall oscillation in the management of people with cystic fibrosis.

Hypothesis: The addition of high frequency chest wall oscillation to twice daily supervised physiotherapy is as effective as the addition of self treatment in facilitating recovery from an acute infective pulmonary exacerbation, as measured by improvement in lung function, specifically forced expiratory volume in one second (FEV1).

Device: High Frequency Chest Wall Oscillation (HFCWO)

Other: Usual airway clearance

Study Design: Treatment, Randomized, Open Label, Parallel Assignment, Efficacy Study

Official Title:The Use of High Frequency Chest Wall Oscillation During an Acute Infective Pulmonary Exacerbation of Cystic Fibrosis

Primary Outcome Measures:
Mean percentage change in forced expiratory volume in one second (FEV1) [ Time Frame: 7days ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
Wet weight of sputum expectorated [ Time Frame: 24 hours ] [ Designated as safety issue: Yes ]
Length of time to next course of intravenous antibiotics [ Time Frame: Within 6 monthsof completing study ] [ Designated as safety issue: Yes ]
Rate of change of C-reactive protein [ Time Frame: 7 days ] [ Designated as safety issue: Yes ]

Estimated Enrollment: 56

Study Start Date: February 2010

Estimated Study Completion Date: July 2011

Estimated Primary Completion Date: July 2011 (Final data collection date for primary outcome measure)

Usual Airway Clearance Technique: Active Comparator

Two self administered treatment sessions a day and two treatments a day assisted by a Physiotherapist both using the patient's usual airway clearance method.

Other: Usual airway clearance
Airway clearance treatments using the active cycle of breathing techniques, autogenic drainage, positive expiratory pressure, manual techniques or oscillating positive expiratory pressure

High Frequency Chest Wall Oscillation (HFCWO): Experimental
Two self administered treatments a day using HFCWO and two treatment sessions a day assisted by a Physiotherapist using their 'usual' airway clearance method.

Device: High Frequency Chest Wall Oscillation (HFCWO)
Airway clearance using the high frequency chest wall oscillator device

Contacts
Contact: Elizabeth A Banks, MSc
0207 351 8935
e.banks@imperial.ac.uk
Contact: Penny Agent
0207 352 8121 ext 8056

Locations

United Kingdom
Royal Brompton & Harefield NHS Foundation Trust
London, United Kingdom

Sponsors and Collaborators
Imperial College London
Royal Brompton & Harefield NHS Foundation Trust
Hill-Rom

Investigators

Principal Investigator:
Margaret Hodson
Imperial College London

Phase II Inflammation Study at Stanford

GSK Study #2110399 in 2010 (Study Drug: SB-656933)

This study is currently recruiting participants.

Verified by Stanford University, January 2010

First Received: January 14, 2010 Last Updated: January 15, 2010 History of Changes

Sponsor: Stanford University

Information provided by: Stanford University

Purpose
Study Drug, SB-656933, is a selective CXCR2 antagonist in development as a novel, once-daily oral anti-inflammatory agent for the maintenance treatment of Cystic Fibrosis (CF) and Chronic Obstructive Pulmonary Disease (COPD). We want to find out if this experimental drug will help decrease inflammation and slow the progression of lung disease. This study compares how well different doses of the experimental study drug (SB-656933) control inflammation in patients with CF. Two doses of the study drug will be assessed against placebo to see which dose works best.

Condition Cystic Fibrosis
Intervention Drug: SB-656933
Phase Phase II


Study Design: Treatment, Randomized, Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Parallel Assignment, Safety/Efficacy Study

Official Title:A Randomized, Double Blind, Parallel Group, Placebo Controlled 28 Day Study to Investigate the Safety, Tolerability and Pharmacodynamics of SB-656933 in Patients With Cystic Fibrosis

Primary Outcome Measures: effect of study drug on safety and tolerability [ Time Frame: 28 days of dosing ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures: levels of neutrophil elastase in induced sputum and other sputum markers [ Time Frame: 28 days of dosing ] [ Designated as safety issue: No ]

Estimated Enrollment: 140
Study Start Date: January 2010
Estimated Study Completion Date: February 2011


Eligibility

Ages Eligible for Study: 18 Years and older
Genders Eligible for Study: Both
Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria: Diagnosis of CF based on the following: sweat chloride > 60 mEq/L and/or genotype with 2 identifiable mutations consistent with CF; (delta-F508 homozygote, or delta-F508 heterozygote with a second allele known to cause the disease, or two alleles known to cause a class I, II, or III mutation) and one or more clinical features consistent with CF.

Male and female subjects aged older or =18 years of age

A female subject is eligible to participate if she is of: Non-childbearing potential defined as pre-menopausal females with a documented tubal ligation or hysterectomy; or postmenopausal defined as 12 months of spontaneous amenorrhea [in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) > 40 MlU/ml and estradiol < 40 pg/ml (<140 pmol/L) is confirmatory]. Child-bearing potential and agrees to use one of the contraception methods listed in the Protocol for an appropriate period of time (as determined by the product label or investigator) prior to the start of dosing to sufficiently minimize the risk of pregnancy at that point. Female subjects must agree to use contraception until one week after the last dose.

Patients are non-smokers or former smokers by history. Former smokers will be defined as those who have not smoked for longer than or =6 months. Subjects who only use chewing tobacco products may be enrolled at the discretion of the Investigator and after consultation with the GSK medical monitor.

In the judgement of the investigator the patient is clinically stable with no change in symptoms or medication, no admissions to hospital, and no intravenous antibiotic therapy for at least 1 month prior to dosing.

Able to perform lung function tests reliably.

FEV1 >40% and <110% predicted.

Excluding periods of exacerbation, FEV1 has not decreased by >15% over the past 12 months

Clinically colonized by a bacterial organism commonly seen in cystic fibrosis other than Burkholderia cepacia (i.e. Pseudomonas spp., Staphylococcus aureus, Stenotrophomonas, B. Gladioli) as evidenced by identification in sputum culture within the past year. To be eligible a CF patient must have colonization of at least one typical CF organism.

To be eligible, female patients must have a negative pregnancy test (urine or serum) and not be nursing at screening or prior to dosing.

Subjects must have a QTcB or QTcF < 450 msec at screening as determined by the investigators review.

Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) within twice (2x) the upper limit of normal at screening and bilirubin within 1.25x ULN at screening. AST, ALT, alkaline phosphatase and bilirubin smaller or =2.0 xULN (isolated bilirubin >2.0xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%).

Male subjects must agree to use one of the contraception methods listed in the Study Protocol. This criterion must be followed from the time of the first dose of study medication until one week after the last dose.

Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form.

The subject is able to understand and comply with protocol requirements, instructions and protocol-stated restrictions.

Exclusion Criteria:
Any clinically relevant abnormality identified on the screening medical assessment, laboratory examination, or ECG, that is not associated with cystic fibrosis:

Neutrophil count < 1.5x109 /L

In the judgment of the PI, the patient:

suffers from clinically unstable pancreatic function

has clinically significant weight loss(bigger than or =5% after a previously stable period).

has evidence of uncontrolled hyperglycemia or recent hypoglycemia

has recent change in pancreatic enzyme requirements in the past 2 months.

Recent viral infection (within 4 weeks of dosing), with or without steroid or antibiotic treatment.

Presumed viral infection will be determined according to the judgment of the Investigator and no specific testing for virus will be required.

Subjects unable to produce a technically acceptable sputum sample.

Clinically significant hepatic impairment:

Evidence of cirrhosis

Patients with elevated INR that is due to suspected vitamin K deficiency may be enrolled at the discretion of the Investigator and after consultation with the GSK medical monitor

Blood pressure persistently >155/95 mmHg at screening.

Positive HIV, Hepatitis B surface antigen or Hepatitis C antibody at screening.

History of regular alcohol consumption averaging >7 drinks/week for women or >14 drinks/week for men. One drink is equivalent to (12 g alcohol) = 5 ounces (150 ml) of wine or 12 ounces (360 ml) of beer or 1.5 ounces (45 ml) of 80 proof distilled spirits) within 6 months of screening.

Urinary cotinine levels indicative of smoking.

Use of oral or parenteral corticosteroids within 4 weeks of screening; regular use (>3 x/wk) of high dose NSAIDS (e.g. >1.6g ibuprofen/day on a regular basis), within 4 weeks of screening.
Colonization with Burkholderia cepacia

Subjects currently being treated for mycobacterial infection

Subjects with presumed active Allergic Bronchopulmonary Aspergillosis (ABPA)

Subjects who have newly started therapy with azithromycin within the past 3 months.

In the judgment of the investigator, clinically significant hemoptysis (> 30 cc per episode) within the last 6 months

Donation of blood in excess of 500 mL within a 56-day period prior to dosing

Participation in a trial with any drug within 30 days or 5 half-lives (whichever is longer), or participation in a trial with a new chemical entity within 2 months prior to first dose of current study medication, unless in the opinion of the Investigator and sponsor the medication will not interfere with the study procedures or compromise subject safety.

The subject has a positive pre-study drug/alcohol screen. A minimum list of drugs that will be screened for include amphetamines, barbiturates, cocaine, opiates, and cannabinoids. Subjects who use benzodiazepines or other anxiolytic on a regular basis can be included at the discretion of the investigator and in consultation with the GSK medical monitor

Patients may not be on an inhaled antibiotic during the study (i.e. must be an "off- TOBI" month; cessation of TOBI or other inhaled antibiotics commences from one week prior to dosing until final PK draw). Patients on maintenance therapy with hypertonic saline solution or inhaled DNase may continue these therapies.

Unwillingness or inability to follow the procedures outlined in the protocol.


Please refer to this study by its ClinicalTrials.gov identifier: NCT01051453
Contacts
Contact: Colleen Dunn
(650) 736-0388
cedunn@stanford.edu

Locations
United States, California
Stanford University School of Medicine

Recruiting
Stanford, California, United States, 94305
Contact: Colleen Dunn 650-736-0388 cedunn@stanford.edu
Principal Investigator: Richard B Moss

Sub-Investigator: Carlos Milla
Sub-Investigator: Carol K. Conrad
Sub-Investigator: Paul K Mohabir
Sub-Investigator: David Weill
Sub-Investigator: Zoe Davies RN
Sub-Investigator: Colleen Dunn RCP
Sub-Investigator: Martha Hamilton
Sub-Investigator: Andrea Core
Sub-Investigator: Yan Ki Angela Leung
Sponsors and Collaborators
Stanford University
Investigators

Principal Investigator:
Richard B Moss
Stanford University

Scientists Restore Some Function to Cells from Cystic Fibrosis Patients

Scientists Restore Some Function to Cells from Cystic Fibrosis Patients

ScienceDaily (Dec. 7, 2009) — In an encouraging new development, a team led by Scripps Research Institute scientists has restored partial function to lung cells collected from patients with cystic fibrosis. While there is still much work to be done before the therapy can be tested in humans, the discovery opens the door to a new class of therapies for this and a host of other chronic diseases.

The results were published on December 6, 2009 in an advance, online edition of the high-impact journal Nature Chemical Biology.

"We are very excited by these results," said team leader Professor William Balch, a professor in the Departments of Cell Biology and Chemical Physiology and member of the Institute for Childhood and Neglected Diseases, who also receives support from the Skaggs Institute for Chemical Biology, all at Scripps Research. "Because we came at the problem of restoring cell function from a new perspective -- using biology to correct biology -- these findings have the potential to be game-changing."

The new study, performed in collaboration with a large number of cystic fibrosis investigators across the United States and Canada, showed that a compound called suberoylanilide hydroxamic acid (SAHA), which is already approved by the U.S. Food and Drug Administration as a treatment for lymphoma, can restore about 28 percent of normal function to lung surface cells with the most common, yet severe, cystic fibrosis mutation that results in complete loss-of-function in homozygous patients (those receiving a copy of the mutated gene from both parents).
"The results are very promising," said Balch. "We know that cystic fibrosis individuals with 15 to 30 percent of normal cellular function, as can occur with certain mutations, have milder cases of the disease and a more normal lifestyle than patients carrying a severe mutation. The added degree of function conveyed by SAHA or a compound like SAHA could make a tremendous difference to patients with acute disease."

A Life-Shortening Condition

Cystic fibrosis is an inherited disease that affects about 30,000 children and adults in the United States, and 70,000 worldwide, according to the Cystic Fibrosis Foundation.
In cystic fibrosis, patients produce thick, sticky mucus, which can clog the lungs and result in damaging inflammation and life-threatening infections. This thick mucus can also obstruct the pancreas and interfere with the proper digestion and absorption of food. Other symptoms include diabetes and infertility.

People with cystic fibrosis have mutations in the cystic fibrosis gene, which leads the body to produce a defective protein -- called the cystic fibrosis transmembrane conductance regulator (CFTR) protein -- which is normally found at the cell surface and is necessary for the proper movement of sodium and chloride (salt) in and out of cells. This process is necessary for the proper hydration of the lung, intestine, and pancreas.

Although more than 1,400 different mutations can lead to defects in CFTR, the most common mutation is a deletion of a phenylalanine residue at position 508 of the protein (DF508 CFTR). This mutation, which causes a severe form of the disease, is responsible for more than 90 percent of cystic fibrosis cases worldwide.

While 50 years ago few children with cystic fibrosis lived to attend elementary school, today it is not unusual for people with cystic fibrosis to live into their 30s and 40s. Most treatments available today focus on symptom management -- specifically clearing the airways through lung compression vests, antibiotics, inhaled medications, and anti-inflammatory drugs, as well as promoting proper nutrition through a healthy diet, substantive digestive enzyme supplements, and other dietary aids.

Unfortunately, still lacking are approved medications that address problems with the DF508 cystic fibrosis protein. (Balch notes that a potentiator drug (Vertex 770) affecting a very rare mutant population of cystic fibrosis patients (G551D CFTR) which is at the cell surface, but unable to mobilize chloride, did achieve significant clinical benefit in a recent clinical trial). A broadly effective therapeutic correcting DF508 CFTR protein delivery to the cell surface and restoring function would be a great boon for most cystic fibrosis patients and their families.
Such a development could alleviate the chronic need for the many drugs and therapies that attempt to mitigate the onslaught of symptoms and to enable patients to sustain a normal lifestyle.

Turning a Classical Approach on Its Head

In the new study, Balch took an original approach to correcting cystic fibrosis defects. This new approach grew out of a unique understanding of protein folding and misfolding that Balch had been working out for some time with Scripps Research colleague Jeffery Kelly, chair of the Department of Molecular and Experimental Medicine, Lita Annenberg Hazen Professor of Chemistry, and member of the Skaggs Institute for Chemical Biology. This perspective may also have implications for conditions as diverse as type II diabetes, arthritis, osteoporosis, and amyloid disease (including Alzheimer's).

While in many genetic diseases specific mutations within a particular gene cause the protein product of the gene to misfold, Balch and colleagues note that is not the end of the story. Critically, this defective protein must interact with the general biological machinery of the cell, which controls the protein folding and stability environment. This can contribute significantly to the protein's loss of function and a breakdown in tissue/organism function. This biological machinery controlling the folding and function environment of the cell is referred to as the proteostasis network and is central for life.

thinking and practices of the pharmaceutical industry that focuses on drugging single targets," Balch said. "This traditional view limits our ability to tackle pharmacologically many complex loss-of-function sporadic and inherited diseases which are really systems disorders. These diseases have multiple steps in the biological network that must be adjusted to regain a more normal function of the compromised protein and tissue."

In the case of cystic fibrosis, Balch suspected that the endoplasmic reticulum -- a compartment in the cell responsible for the synthesis of CFTR which normally works to protect the body by degrading potentially dangerous abnormal proteins -- could be viewed as doing its job too efficiently, eliminating mutant CFTR proteins that could still provide some function to the cell and tissue if given the opportunity.

In the new Nature Chemical Biology study, Balch and colleagues drew on their previous theoretical and experimental work to turn the classical model of drug development on its head. Rather than attempting to directly target or replace the mutant CFTR proteins present in cystic fibrosis patients -- an approach that had so far failed to yield dramatic new treatments for the DF508 disease -- Balch and colleagues sought instead to adjust the cell folding or maintenance proteostasis machinery of the cell to make a new cellular environment that would "work" with the mutant CFTR proteins.

In so doing, the scientists hoped that the mutated CFTR proteins, while not perfect, could now function more effectively in the cell, reducing the more severe effects of cystic fibrosis symptoms in the common DF508 variant.

Positive Results on Multiple Levels

To tweak the cellular machinery in this fashion, Balch and the team enlisted compounds that were known to inhibit a family of enzymes known as histone deacetylases (HDACs). Studies have shown that HDACs affect the packaging of the DNA in chromosomes and regulate gene expression. Based on earlier studies of the folding environment required for CFTR function published in the journal Cell, the scientists reasoned that altering HDAC function might also rebalance proteostasis networks in the cell to favor functional restoration.
For expertise in these compounds, Balch teamed up with Scripps Research colleague Professor Joel Gottesfeld and his group.

"Joel's lab and my lab worked very closely together on this," said Balch. "That's what's great about Scripps Research -- its collaborative nature. People just walk in next door and two hours later you are doing an experiment together!"

Working with Ray Frizzell and Joe Pilewski, cystic fibrosis investigators at the University of Pittsburg School of Medicine, the Balch laboratory treated human lung epithelial cells isolated from patients with the devastating ΔF508 mutation with known HDAC inhibitors. Intriguingly, the FDA-approved HDAC inhibitor SAHA was shown to be most effective in restoring surface channel activity -- one of the main markers of cystic fibrosis that is responsible for rehydration of the cells' surface. Control cells demonstrated negligible levels of channel activity, while SAHA-treated cells were restored to 28 percent of the normal level found in healthy individuals.
"It's a pretty solid rescue with some intriguing properties," commented Balch.

Using a bioinformatics approach led by the Gerard Manning laboratory at the Salk Institute of Biological Sciences, the team showed that the compound increased the functioning of mutated CFTR proteins at multiple levels in the proteostasis network. Not only were mutant CFTR proteins more protected from destruction in the endoplasmic reticulum, they were also more efficiently transported to the lung cell surface where they were found at comparable levels to that of wild-type (normal) CFTR. In addition, once at the surface of HDAC inhibitor-treated cells, mutant CFTR proteins were better able to resist destruction by additional degradation pathways than DF508 CFTR proteins in untreated cells.

"By rebalancing the proteostasis program to provide a more supportive cellular environment," said Balch, "the cells appear to treat the mutation more like a polymorphism [genetic differences that are responsible for individual diversity] rather than something dangerous needing to be completely eliminated."

Balch also likened this process to evolutionary adaptations to changes in protein structure, which support mutations providing a selective functional advantage.

The study showed that one specific HDAC -- HDAC7, one of 18 known human HDACs -- appeared to be largely responsible for the effects on the treated cells. Little is known about the function of HDAC7 in human physiology and efforts are currently under way by the laboratories of Balch, Gottesfeld, Manning, and Scripps Research Professor John Yates to understand its mechanism of action.

The Way Forward

Mindful that dosing would be a key issue in any attempts at drug development, the researchers also began to address dosing issues in the current study.
"We know that a compound won't make it into the clinic if patients have to take the equivalent of a cereal bowl of it several times a day," said Balch. "That's especially true because, given the nature of cystic fibrosis, this would need to be a sustained, life-long treatment to protect the patient from disease."

Remarkably, the team found that low doses of SAHA not only worked in cultures of cystic fibrosis lung cells, but also offered some significant advantages over acute doses. While acute doses of SAHA produced an increase in the surface channel activity the next day, the effects stopped soon after the drug was withdrawn. In contrast, much smaller doses began working efficiently after six to eight days and strong channel activity was observed after the drug was withdrawn, gradually declining over the following week. This feature is reminiscent of its potential mechanism of action, Balch said, perhaps involving chromatin remodeling leading to an altered, protective proteostasis environment in the lung cell that could be sustainable.
While thrilled with the results, Balch cautions that "there is much work to do" -- including further drug development, preclinical work, and clinical trials -- before any new therapy for cystic fibrosis becomes a reality using this approach. The FDA-approved drug SAHA, while initially approved as an acute dose regimen for cancer therapeutics, remains to be carefully examined for use in a low-dose, chronic treatment regimen that would be required for protecting cystic fibrosis patients from disease over a lifetime.

First authors of the paper are Darren Hutt and David Herman of Scripps Research. In addition to Balch, Hutt, and Herman, other authors include: Jeanne Matteson, Ben Hoch, Wendy Kellner, Jeffery Kelly, J. R. Yates IIIrd and Joel M. Gottesfeld of Scripps Research; Ana Rodrigues and Gerard Manning of the Salk Institute for Biological Studies; Sabrina Noel, Joe Pilewski and Ray Frizzell of University of Pittsburgh School of Medicine; Andre Schmidt and Philip Thomas of the University of Texas Southwestern Medical Center; Yoshihiro Matsumura and William Skach of Oregon Health and Sciences University; Martina Gentzsch and John R. Riordan of University of North Carolina, Chapel Hill; Eric J. Sorscher of University of Alabama at Birmingham; and Tsukasa Okiyonad and Gergely L. Lukacs of McGill University. Frizzel, Skach, Thomas, and Lukacs are members of the Cystic Fibrosis Consortium, a team of investigators supported by the Cystic Fibrosis Foundation that are encouraged to collaborate and share results to accelerate the pace for a cure for cystic fibrosis. Finanical disclosure: Balch is a Consultant and equity holder in Proteostasis Therapeutics Incorporated (PTI), 200 Technology Square, Boston MA, whose goal is to develop drugs that correct human misfolding disease. Kelly is a founder and equity holder in PTI.

This research was supported by National Institutes of Health (NIH) grants HL79442 (WEB/JRY), GM42336 (WEB), and the Cystic Fibrosis Consortium (CFC)(WEB/JRY); NS055781 to JMG; AG03197 to GM; AG84567 to JWK; DK68196, DK72506, and the CFC to RAF and JP; UR98647 and the CFC to ES; DK075302, the Canadian Institutes of Health Research and the CFC to GLL; DK51818 and the CFC to WRS; DK23567 to JRR. D. Hutt was supported by fellowships from the Canadian Cystic Fibrosis Foundation and the Canadian Institutes of Health Research; D. Herman was supported by a fellowship from the Friedreich's Ataxia Research Alliance.

Genta To Support Initiation Of New Clinical Trial Using Ganite(R) As Treatment For Life-Threatening Infections In Patients With Cystic Fibrosis

Genta Incorporated (OTCBB: GETA) announced that the Company will supply Ganite® (gallium nitrate injection) for a new clinical trial that will be initiated in patients with cystic fibrosis (CF) who may develop serious infections.

Infection is the most common cause of death in CF patients. Frequently, these infections are due to bacteria known as Pseudomonas aeruginosa, and patients are commonly treated with years of antibiotic therapy to control such infections. However, prolonged antibiotic use has greatly increased resistance due to genetic mutations. In addition, Pseudomonas has evolved protective mechanisms known as "biofilms" that encase colonies of bacteria and prevent antibiotics from reaching infection sites.

Bacteria in biofilms are far more resistant to being killed. Recent information has suggested that gallium may be used as an anti-bacterial agent against Pseudomonas, in part due to its ability to disrupt biofilms. The initial clinical trial using a gallium compound for this purpose will involve patients with cystic fibrosis who will be treated at the University of Washington in Seattle, WA and the University of Iowa, Iowa City, IA. If initial results are promising, additional trials will be conducted with additional medical centers and a larger number of patients.

Genta has provided cross-reference to its Investigational New Drug (IND) exemption for Ganite®, and the Company will supply the drug at no cost to patients in the trial. The study is also supported by grants awarded by the Orphan Products Division of the Food and Drug Administration (FDA) and by the Cystic Fibrosis Foundation.

"Work from our center has established that gallium can be used as a 'Trojan horse' that interferes with how iron is used by Pseudomonas," said Dr. Christopher H. Goss, Associate Professor of Medicine at the University of Washington, who is the Principal Investigator of the trial. "Our preliminary data suggest that gallium exploits potentially vulnerable mechanisms in Pseudomonas by disrupting biofilms and killing antibiotic-resistant strains of bacteria. This study is the first formal pharmacokinetic and safety evaluation of gallium in patients with cystic fibrosis." "

This trial represents the rapid clinical translation of enormously promising observations," said Dr. Raymond P. Warrell, Jr., Genta's Chief Executive Officer. "Initial results from our first CF patient showed that systemic treatment achieved target gallium levels in sputum, and that these levels could be sustained for a prolonged duration. Pseudomonas infections in CF are exceptionally difficult to eradicate. If initial results of the IV drug in this trial are promising, future patients might also benefit from extended therapy that could be afforded by one of our oral gallium compounds."

Further background on this work from the Universities of Washington and Iowa can be accessed here. About Ganite® Ganite® is exclusively marketed by Genta and is approved in the U.S. for treatment of cancer-related hypercalcemia that is resistant to hydration. The potential use(s) described in the release are investigational and have not been approved. SourceGenta Incorporated