Category: Therapies

Vertex Pharmaceuticals and the Cystic Fibrosis Foundation today announced positive results from an ongoing Phase 3 clinical trial of VX-770 for children age 6 to 11.

VX-770 is an oral drug in development that targets the underlying cause of cystic fibrosis.

Children who were on the drug showed a marked improvement in lung function through 24 weeks of a 48-week trial, compared to those who took the placebo.

The trial is designed to evaluate patients who carry at least one copy of a CF mutation called G551D and included 52 children.

Patients in the trial also showed improvements in secondary endpoints of the study, including weight gain and sweat chloride levels — areas critical to the health of people with CF.

VX-770 is being developed by Vertex Pharmaceuticals and was discovered in collaboration with the CF Foundation.

“The findings announced today are highly encouraging and reinforce the concept that we can significantly improve clinical outcomes for CF patients by repairing the defective protein that causes the disease,” said Robert J. Beall, Ph.D., president and CEO of the CF Foundation. “We are hopeful that by continuing on this path, we will ultimately have a profound impact on all who suffer from cystic fibrosis.”

The new data mirrors promising results announced in February 2011 of a Phase 3 trial of VX-770 in people with CF, ages 12 and older. In that trial, patients who received VX-770 showed marked improvements in lung function and other key clinical indicators of cystic fibrosis. 

Vertex plans to submit a New Drug Application for VX-770 to the U.S. Food and Drug Administration in the second half of 2011. Generally, the FDA takes between 6 and 12 months to review and rule on a drug application. 

About 4 percent of people with CF carry the G551D mutation. More studies are needed to determine whether other CF mutations may benefit from VX-770.

Click here to read the Vertex Pharmaceuticals press release announcing the findings.

Source: Cystic Fibrosis Foundation

Vertex Pharmaceuticals Incorporated today announced positive results from a 24-week analysis of the ongoing Phase 3 ENVISION study of VX-770, an oral medicine in development that targets the defective protein that causes cystic fibrosis (CF). ENVISION (n=52) was designed to evaluate VX-770 among children ages 6 to 11 with the G551D mutation in the CFTR gene. Approximately 4 percent of people with CF in the United States  have at least one copy of the G551D mutation. The study met its primary endpoint of mean absolute change from baseline in percent predicted FEV 1(forced expiratory volume in one second, or lung function) through week 24.

A difference in mean absolute improvement from baseline in lung function of 12.5 percent and a difference in mean relative improvement from baseline in lung function of 17.4 percent compared to placebo (p<0.0001) were observed through week 24. Significant improvements in other measures of disease, including weight gain and a reduction in sweat chloride, were also observed through week 24 among those who received VX-770. At the time of this analysis, the most commonly reported adverse events were respiratory in nature and comparable across treatment groups. The study is ongoing, and additional assessments of key endpoints will be conducted at the end of the 48-week study.

Vertex is on track to submit regulatory applications for approval in the United States in the second half of 2011. The submissions will be based on data from the Phase 3 STRIVE and ENVISION studies as well as the Phase 2 DISCOVER study. Vertex plans to submit data from all studies in the VX-770 Phase 3 registration program for presentation at upcoming medical meetings.

“In this study, children with CF treated with VX-770 showed the same profound improvements in lung function seen in the recently-announced STRIVE study among an older group of people with the G551D mutation,” said Robert Kauffman, M.D., Ph.D., Senior Vice President and Chief Medical Officer for Vertex. “We are committed to making VX-770 available as soon as possible and are moving ahead quickly with our U.S. and European applications for regulatory approval that we plan to submit in the second half of this year.”

“The data announced today are highly encouraging because children with CF tend to be healthier than adults and significant improvements in lung function may be harder to demonstrate in a clinical study,” said Robert J. Beall, Ph.D., president and CEO of the Cystic Fibrosis Foundation. “Data from Phase 3 studies of VX-770 in people with the G551D mutation provide strong support for the concept that addressing the defective protein that leads to CF may significantly improve outcomes for patients and give hope for the future of other CF treatments that repair the basic defect of the disease.”

Vertex’s medicines in development for CF were discovered as part of a collaboration with Cystic Fibrosis Foundation Therapeutics, Inc.(CFFT) to discover and develop novel CF Transmembrane Conductance Regulator (CFTR) modulators. CFFT is the nonprofit drug discovery and development affiliate of the Cystic Fibrosis Foundation. Vertex retains worldwide rights to develop and commercialize these potential medicines.

Summary of Key Data from ENVISION

In the ENVISION study, 52 children were enrolled and received VX-770 or placebo as a single 150 mg tablet every 12 hours. At the time of this analysis, the last patients had completed their week 40 visit. All children who remain on this study will be followed through 48 weeks. All children who complete 48 weeks of treatment in ENVISION, including those in the placebo group, and who meet eligibility criteria, may choose to receive VX-770 for up to an additional 96 weeks, or until VX-770 is approved, as part of an extension study called PERSIST.

ENVISION was designed to evaluate VX-770 in children between the ages of 6 and 11 with at least one copy of the G551D CFTR mutation. The primary endpoint of the study was mean absolute change from baseline in percent predicted FEV 1 through week 24. Lung function was assessed using a standard test that measures the amount of air a person can exhale in one second (forced expiratory volume in one second, or FEV).

Preliminary Efficacy Results

Lung Function: Absolute and relative changes in lung function are being reported in today’s announcement. Phase 3 results and product labeling for currently available CF medicines generally describe relative improvements in lung function.

Baseline lung function (FEV 1) in ENVISION was 84.7 percent predicted for children in the VX-770 treatment group and 83.7 percent predicted among those in the placebo group. Results of the ENVISION study showed that the difference in mean absolute improvement from baseline in lung function through 24 weeks in children treated with VX-770 was 12.5 percent (p<0.0001). The difference in mean relative improvement from baseline was 17.4 percent compared to placebo.

Additional secondary endpoints were measured to observe the effect of VX-770 through week 24. These secondary endpoints included:

Weight: Many people with CF have a hard time gaining and maintaining weight due to factors such as reduced pulmonary function, nutrition, chronic infection and inflammation. In the ENVISION study, those who received VX-770 experienced an average weight gain of approximately 8.1 lbs (3.7 kilograms) through 24 weeks compared to baseline while those in the placebo group gained approximately 3.9 lbs (1.8 kilograms) compared to baseline.

Sweat Chloride: Elevated sweat chloride levels are a diagnostic hallmark of CF and a marker of CFTR protein dysfunction, which is the underlying molecular mechanism responsible for CF. The amount of chloride in the sweat is measured using a standard test. People with CF typically have sweat chloride levels in excess of 60 mmol/L, while normal values are less than 40 mmol/L. Reduction in sweat chloride is considered to be a marker of improved CFTR function.

In ENVISION, the baseline sweat chloride level for both treatment groups was approximately 104 mmol/L. Significant decreases in measurements of sweat chloride were observed among those treated with VX-770 compared to those in the placebo group. Through week 24, mean sweat chloride level for individuals treated with VX-770 was below 60 mmol/L. Significant decreases in sweat chloride were not observed among those in the placebo group.

Patient Reported Outcomes: The Cystic Fibrosis Questionnaire — Revised (CFQ-R) is a validated patient reported outcome tool that was used in this study to measure the impact of VX-770 on overall health, daily life, perceived well-being and symptoms. One aspect of the CFQ-R, referred to as the respiratory domain, assesses patient reported symptoms such as coughing, congestion, wheezing and other respiratory symptoms. In the ENVISION study, children responded to the CFQ-R and reported a trend toward improvement in respiratory symptoms, which was a key secondary endpoint of the study.

Safety: At the time of this analysis, the most commonly reported adverse events were respiratory in nature and comparable between treatment groups. The most commonly reported adverse events through 24 weeks included cough, headache, CF pulmonary exacerbation, throat pain, and vomiting. Pulmonary exacerbations were uncommon in ENVISION regardless of treatment arm. There were no discontinuations due to adverse events in either treatment group of the study through 24 weeks. The ENVISION safety evaluation is ongoing through 48 weeks.

About the Cystic Fibrosis Transmembrane Conductance Regulator Protein (CFTR)

CF is caused by a genetic defect that results in defective or missing CF transmembrane conductance regulator (CFTR) proteins, which result in poor ion flow across cell membranes, including in the lungs, and the accumulation of abnormally thick, sticky mucus that leads to chronic lung infections and progressive lung damage. In people with the G551D mutation in the CFTR gene, CFTR proteins are present at the cell surface but do not function properly. VX-770, known as a CFTR potentiator, aims to increase the function of defective CFTR proteins by increasing the ability to transport ions across the cell membrane of CFTR at the cell surface. In people with the F508del mutation, CFTR proteins do not reach the cell surface in normal amounts. VX-809, known as a CFTR corrector, aims to increase CFTR function by increasing the movement of CFTR to the cell surface.

Combination Study of VX-770 and VX-809

Vertex is conducting a Phase 2a clinical trial to evaluate multiple combination regimens of VX-770 and VX-809 in people with two copies of the F508del mutation. The first part of the study is designed to evaluate VX-809 (200 mg), or placebo dosed alone for 14 days and in combination with VX-770 (150 mg or 250 mg), or placebo, for seven days. Vertex expects to obtain data from this part of the trial in the first half of 2011.

Vertex Pharmaceuticals Incorporated today announced positive results from the Phase 3 STRIVE study of VX-770, an oral medicine in development that targets the defective protein that causes cystic fibrosis (CF).

STRIVE was designed to evaluate people with a mutation in the CF gene known as G551D. In this study, profound improvements in lung function (forced expiratory volume in one second, or FEV1) were observed through week 24, and sustained through week 48, among those who received VX-770 (n=83) compared to those treated with placebo (n=78). Significant improvements in all key secondary endpoints were also observed through week 48 among those who received VX-770.

Data from the study showed a mean absolute improvement in lung function from baseline compared to placebo through week 24 of 10.6 percent among those treated with VX-770 (p<0.0001). Mean absolute improvement in lung function among those treated with VX-770 was 10.5 percent through week 48 (p<0.0001).

The primary endpoint of the study was mean absolute change from baseline compared to placebo in percent predicted FEV1 (lung function) through week 24. Data from the study showed a mean absolute improvement in lung function from baseline compared to placebo through week 24 of 10.6 percent among those treated with VX-770. Mean absolute improvement in lung function among those treated with VX-770 was 10.5 percent through week 48.

Highly statistically significant improvements in key secondary endpoints in this study were also reported through week 48. Compared to those treated with placebo, people who received VX-770 were 55 percent less likely to experience a pulmonary exacerbation (periods of worsening in signs and symptoms of the disease requiring treatment with antibiotics) and, on average, gained nearly seven pounds (3.1 kilograms) through 48 weeks. There was a significant reduction in the amount of salt in the sweat (sweat chloride) among people treated with VX-770 in this study. Increased sweat chloride is a diagnostic hallmark of CF. Sweat chloride is a marker of CFTR protein dysfunction, which is the underlying molecular mechanism responsible for CF. People who received VX-770 also reported having fewer respiratory symptoms.

Adverse events that were 5 percent greater among those treated with VX-770 compared to placebo were headache, upper respiratory tract infections, nasal congestion, rash, dizziness and bacteria in the sputum. The most commonly reported serious adverse events included pulmonary exacerbation (13 percent in the VX-770 group compared to 33 percent in the placebo group) and hemoptysis (or bloody cough; 1 percent in the VX-770 group and 5 percent in the placebo group). Discontinuations through 48 weeks due to adverse events were less frequent in the VX-770 treatment group compared to placebo (1 percent compared to 5 percent).

“Treating the underlying cause of cystic fibrosis with VX-770 led to clinical improvements that were far beyond our expectations, providing support for an entirely new approach to the treatment of this disease,” said Peter Mueller, Ph.D., Executive Vice President, Global Research and Development, and Chief Scientific Officer for Vertex. “All primary and key secondary outcome measures in this study supported VX-770 over placebo. Patients’ lung function improved, they gained weight, experienced fewer respiratory symptoms and felt substantially better. Due to the significance of these data and the great need for new, more effective medicines, we will work with regulatory agencies to determine the fastest way to get VX-770 approved for people with this specific type of CF.”

“The results from STRIVE are highly encouraging for the CF community and provide scientific evidence supporting our long-standing belief that targeting the underlying defect of CF may have a profound effect on the disease,” said Robert J. Beall, Ph.D., president and CEO of the Cystic Fibrosis Foundation. “We have much more to do to eliminate this disease, but these data are extremely exciting, especially for people with the G551D mutation and their families. They also offer significant hope that a similar approach to treatment may help others living with CF.”

All patients who completed 48 weeks of treatment in STRIVE (n=144), including those in the placebo group, were eligible to receive VX-770 as part of an extension study called PERSIST. All patients (n=77) who completed dosing in the VX-770 arm and all but one patient (n=67) in the placebo arm chose to enroll in the extension study and receive VX-770 for up to an additional 96 weeks or until VX-770 is approved.

STRIVE is one of three studies in the VX-770 registration program. Vertex plans to submit data from STRIVE for presentation at an upcoming medical meeting. The registration program for VX-770 also includes two other studies, the Phase 2 DISCOVER study and Phase 3 ENVISION study. Data from DISCOVER were also reported today. Data from ENVISION are expected in mid-2011. Vertex plans to submit regulatory applications for approval in the United States and Europe in the second half of 2011.

Vertex’s medicines in development for CF were discovered as part of a collaboration with Cystic Fibrosis Foundation Therapeutics, Inc. (CFFT) to discover and develop novel CFTR modulators. CFFT is the nonprofit drug discovery and development affiliate of the Cystic Fibrosis Foundation. Vertex retains worldwide rights to develop and commercialize these potential medicines.

Summary of Key Data from STRIVE

In the STRIVE study, 161 people were enrolled and received at least one dose of either VX-770 as a single 150 mg tablet or placebo twice daily. The study was designed to evaluate VX-770 in people with at least one copy of the G551D CFTR mutation. The primary endpoint of the study was mean absolute change from baseline in predicted FEV₁ (lung function) through week 24. Lung function was assessed using a standard test that measures the amount of air a person can exhale in one second (forced expiratory volume in one second, or FEV₁).

Preliminary Efficacy Results

Lung Function: Absolute and relative changes in lung function are being reported in today’s announcement. The primary endpoint of STRIVE was mean absolute improvement from baseline. Phase 3 results and product labeling for currently available CF medicines generally describe relative improvements in lung function.

Baseline lung function in STRIVE was 63.5 percent predicted for patients in the VX-770 treatment group and 63.7 percent predicted among those in the placebo control group. Results of the STRIVE study showed that people treated with VX-770 achieved a mean absolute improvement from baseline compared to placebo of 10.6 percent through 24 weeks (p<0.0001). Mean absolute improvement in lung function achieved by people who received VX-770 was sustained through 48 weeks (10.5 percent; p<0.0001).

In addition, people treated with VX-770 experienced a 16.7 percent relative mean improvement in lung function from baseline compared to placebo (p<0.0001) through week 24, which was sustained through week 48 (16.9 percent; p<0.0001).

Additional secondary endpoints were measured to observe the effect of VX-770 through week 48. These secondary endpoints included:

Pulmonary Exacerbations: People treated with VX-770 in STRIVE were 55 percent less likely to experience a pulmonary exacerbation compared to those treated with placebo through week 48. Through 48 weeks, 67 percent of people treated with VX-770 were exacerbation free compared to 41 percent of people treated with placebo.

Weight: Many people with CF have a hard time gaining and maintaining weight due to factors such as nutrition, chronic infection and inflammation. In the STRIVE study, those who received VX-770 experienced an average weight gain of approximately 6.8 lbs (3.1 kilograms) at 48 weeks compared to baseline. Those in the placebo group gained approximately 0.9 lbs (0.4 kilograms).

Sweat Chloride: Elevated sweat chloride levels are a diagnostic hallmark that occur in all people with CF 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. People with CF typically have elevated sweat chloride levels in excess of 60 mmol/L, while normal values are less than 40 mmol/L. Reduction in sweat chloride is considered to be a marker of improved CFTR function.

In STRIVE, the baseline sweat chloride level for both treatment groups was approximately 100 mmol/L. Statistically significant decreases in measurements of sweat chloride were observed among those treated with VX-770 but not those treated with placebo. Through week 48, mean sweat chloride levels for patients treated with VX-770 were below 60 mmol/L.

Patient Reported Outcomes: The Cystic Fibrosis Questionnaire — Revised (CFQ-R) is a validated patient reported outcome tool that was used in this study to measure the impact of VX-770 on overall health, daily life, perceived well-being and symptoms. One aspect of the CFQ-R, referred to as the respiratory domain, addresses patient reported symptoms including things such as coughing, congestion, wheezing and other respiratory symptoms. In this study, statistically significant and clinically meaningful improvements in respiratory symptoms (a secondary endpoint of the study) were reported among patients who received VX-770.

DISCOVER Data

Vertex also announced today the results of the Phase 2 DISCOVER study, which was primarily designed to provide additional safety data for VX-770 and is part of the registration program. DISCOVER enrolled 140 people who had two copies of the F508del mutation, which prevents the CFTR protein from moving to its proper location at the cell surface. The majority of people with CF have at least one copy of the F508del mutation.

The primary endpoints of DISCOVER were safety and absolute change from baseline in lung function through 16 weeks. Adverse events were similar between the treatment groups. Adverse events that occurred more frequently (≥5 percent) in the VX-770 treatment group compared to placebo were cough, nausea, rash and contact dermatitis. None of these events were serious or led to discontinuation of VX-770. Data from the DISCOVER study will be submitted for presentation at an upcoming medical meeting.

Mean baseline lung function (FEV₁) was 79.7 percent predicted for people who received VX-770 compared to 74.8 percent predicted for patients in the placebo group. Results of the DISCOVER study showed that people treated with VX-770 achieved a mean absolute improvement from baseline compared to placebo of 1.6 percent through 16 weeks (p=0.25). The improvement was not statistically significant and was not considered clinically meaningful. Data from the study also showed a mean relative improvement in lung function from baseline compared to placebo of 2 percent through week 16. A mean reduction in sweat chloride of 2.9 mmol/L compared to placebo through 16 weeks was observed among those treated with VX-770. This improvement was statistically significant but small (p<0.04).

“Based on the results of DISCOVER, we continue to believe the combination of a potentiator and corrector may be the best approach to treating people with two copies of the F508del mutation,” said Robert Kauffman, M.D., Ph.D., Senior Vice President and Chief Medical Officer for Vertex. “Data are anticipated later this year from the first study to evaluate the combination of VX-770 and VX-809 in this group of people with cystic fibrosis.”

ENVISION Study

In addition to the STRIVE and DISCOVER studies, a third study known as ENVISION is evaluating VX-770 in children 6 to 11 years old with CF who have at least one copy of the G551D mutation. Data from the ENVISION study are anticipated in mid-2011.

Combination Study of VX-770 and VX-809

Vertex is conducting a Phase 2a clinical trial to evaluate multiple combination regimens of VX-770 and VX-809 in people with two copies of the F508del mutation. The first part of the study is designed to evaluate VX-809 (200 mg), or placebo dosed alone for 14 days and in combination with VX-770 (150 mg or 250 mg), or placebo, for seven days. Vertex expects to obtain data from Part One of the trial in the first half of 2011.

Vertex Pharmaceuticals Inc. announced positive results from the Phase 3 STRIVE study of VX-770, a potential therapy that targets the defective protein that causes CF.

The FDA’s Gastrointestinal Drugs Advisory Committee (GDAC) has voted to recommend non-approval of Eli Lilly’s Solpura (liprotamase), a non-porcine pancreatic enzyme replacement therapy, currently under Agency review for the treatment of exocrine pancreatic insufficiency (EPI) associated with cystic fibrosis and pancreatectomy.

During the meeting, the GDAC had questions about the degree of efficacy of Solpura and recommended that additional studies be conducted prior to considering approval of Solpura for EPI.

Lilly stated that it will continue to work with the FDA to address the questions raised in the meeting as the Agency moves toward a final decision on the NDA. The company remains confident in the clinical trial data package submitted to the Agency in support of the Solpura application. The product was originally developed by Alnara Pharmaceuticals, which Lilly acquired in 2010.

Statement From Lilly on FDA Advisory Committee Recommendation Regarding Liprotamase New Drug Application for Treatment of Exocrine Pancreatic Insufficiency

Eli Lilly and Company (NYSE: LLY) announced the U.S. Food and Drug Administration (FDA) Gastrointestinal Drugs Advisory Committee voted today to recommend non-approval of liprotamase, a non-porcine pancreatic enzyme replacement therapy (PERT), currently under FDA review for the treatment of exocrine pancreatic insufficiency (EPI).

During the meeting, the committee had questions about the degree of efficacy of liprotamase and recommended that additional studies be conducted prior to considering approval of liprotamase for EPI.

“We appreciate the feedback the committee has provided, and we will continue to work with the FDA to address the questions raised in the meeting as the agency moves toward a final decision on the application,” said Eiry Roberts, M.D., Vice President, Autoimmune, Bone-Muscle-Joint, Liprotamase Product Development at Lilly. “We remain confident in the clinical trial data package submitted to the FDA in support of the liprotamase application.”

The FDA is not required to follow the recommendation of its advisory committees.

Source: Key Pharma News

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. 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.

Source: Mpex Pharmaceuticals press release

Inspire Pharmaceuticals, Inc. announced today the top-line results from its second Phase 3 clinical trial, TIGER-2, with denufosol tetrasodium for the treatment of cystic fibrosis.

The trial did not achieve statistical significance for its primary efficacy endpoint, which was change from baseline in FEV1 (Forced Expiratory Volume in One Second) at the Week 48 Endpoint (48 weeks or last observation carried forward). Patients receiving denufosol in the 466-patient, double-blind, placebo-controlled clinical trial had an improvement of 40 mL, compared to 32 mL for the patients receiving placebo (p=0.742).

Adrian Adams, President and CEO of Inspire, stated, “These TIGER-2 results were disappointing and unexpected given the treatment effect observed in the TIGER-1 trial. 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. We expect to provide a detailed corporate update by mid-February. Meanwhile, we will continue to focus on our ophthalmology business.”

Charles A. Johnson, M.D., Executive Vice President of Research and Development and Chief Medical Officer, stated, “We believe that the TIGER-2 trial was designed and executed appropriately and was sufficient to provide data on the efficacy of denufosol at 48 weeks. The analysis of the primary endpoint, key secondary endpoints and select subgroup populations in TIGER-2 indicates an absence of meaningful treatment benefit in this patient population. We want to thank the investigators, cystic fibrosis patients and caregivers for their involvement in this trial.”

Additional TIGER-2 Data

For the 466 patients randomized in TIGER-2, the treatment groups were balanced with respect to demographic and background characteristics: the mean age was 15.1 years, the mean lung function was 89.7% of the predicted normal value of FEV1 and the use of concomitant medications including inhaled antibiotics, dornase alfa (PULMOZYME(R)), and oral macrolide antibiotics was similar between the treatment groups. Patients were enrolled in the U.S. (82%), Australia and New Zealand (11%) and Canada (6%).

There were no statistically significant differences between denufosol and placebo for three key secondary endpoints, which were:

• Rate of change in percent predicted FEV1 over 48 weeks, a measure of lung function adjusted for a patient’s predicted normal based on height, weight and gender (-2.30% for denufosol and -3.02% for placebo; p=0.410);
• Change from baseline in FEF25%-75% (Forced Expiratory Flow) at the Week 48 Endpoint, a measure of small airways function (-0.034 L/sec for denufosol, -0.018 L/sec for placebo; p=0.728); and
• Time to first pulmonary exacerbation, as defined by treatment with I.V. antibiotics for at least one respiratory sign or symptom (p=0.132).

 

Patient retention rates were similar between treatment groups with approximately 82% completing the trial (82% for denufosol, 83% for placebo). Six percent of patients in both g roups withdrew from the trial due to adverse events (AEs). The most common AE was cough, which was similar in both treatment arms. The incidence of AEs and serious adverse events in the denufosol group was comparable to the placebo group. The incidence of pulmonary exacerbations, as defined by treatment with I.V. antibiotics for at least one respiratory sign or symptom, was similar in both treatment arms (21% for denufosol, 26% for placebo).

Update on DEFY Open-Label Trial

Patients that completed the TIGER-2 trial were eligible to enroll in a separate three-year open-label trial of denufosol called DEFY. Based on the lack of meaningful benefit observed in TIGER-2, Inspire will be recommending that patients in the DEFY trial discontinue treatment with denufosol. Inspire will be communicating with participating clinical trial sites on the next steps for the DEFY trial in the near future.

About the Denufosol Tetrasodium Clinical Program

TIGER-1, the first Phase 3 trial with denufosol for the treatment of CF, included a 24-week placebo-controlled portion, followed by a 24-week open-label safety extension. The placebo-controlled portion was a double-blind, randomized trial comparing 60 mg of denufosol to placebo, administered three times daily by jet nebulizer, in 352 patients with mild cystic fibrosis lung disease (baseline FEV1 greater-than or equal to 75% of predicted normal).

TIGER-2, the second Phase 3 clinical trial with denufosol for the treatment of CF, was a 48-week, placebo-controlled, double-blind, randomized trial comparing 60 mg of denufosol to placebo, administered three times daily by jet nebulizer in 466 patients with mild cystic fibrosis lung disease (baseline FEV1 greater-than or equal to 75% and less-than or equal to 110% of predicted normal).

Source: Inspire Pharmaceuticals Inc.

PTC Therapeutics, Inc. announced today that it has completed enrollment of a Phase 3 clinical trial of ataluren, an investigational new drug, in patients with nonsense mutation cystic fibrosis (nmCF).

The 48-week study is designed to determine whether ataluren can improve lung function in patients with nmCF. The trial has enrolled 238 patients at 36 sites in North America, Europe and Israel. Patients who complete the treatment phase of the Phase 3 trial are eligible to participate in a 48-week, open-label extension study, which has begun enrolling patients.

“The enrollment of this trial represents an important step forward in our efforts to develop disease-modifying treatments that advance the standard of care in CF and improve quality of life for CF patients,” stated Michael Konstan, MD, Chairman, Department of Pediatrics at Rainbow Babies and Children’s Hospital in Cleveland, Ohio. Dr. Eitan Kerem, Head, Department of Pediatrics and CF Center, Hadasash University Hospital, Jerusalem, Israel added, “Despite significant advances in the 21 years since the identification of the disease-causing gene, cystic fibrosis remains a debilitating and life-threatening disorder and available therapies focus only on alleviating symptoms. Ataluren couples a patient’s genetic diagnosis with a mutation-specific therapeutic approach designed to address the underlying cause of the disease.”

Ataluren is a protein restoration therapy designed to enable the formation of full-length, functional cystic fibrosis transmembrane regulator (CFTR) protein in patients with cystic fibrosis due to a nonsense mutation. CFTR is a critical protein lacking in CF patients. Nonsense mutations are categorized as Class I mutations that result in little or no production of the CFTR protein. CF patients with Class I mutations typically experience more severe disease symptoms than those with lower-risk genotypes, including a greater than twofold increased risk of death, a higher probability of end-stage lung disease and a higher prevalence of pancreatic insufficiency. A simple genetic test can determine if a patient’s disease is caused by a nonsense mutation.

“We are pleased to have completed enrollment of our second pivotal clinical trial of ataluren in patients with a nonsense mutation genetic disorder. This is a tremendous achievement and a testament to the commitment of clinical trial patients and their families, as well as study investigators and trial site staff,” stated Stuart Peltz, Ph.D., president and CEO of PTC Therapeutics. “PTC is committed to improving the quality of life of patients with serious and life-threatening diseases through our innovative scientific approach to the discovery of novel treatments.”

PHASE 3 STUDY DESIGN

The primary objective of the registration-directed, double-blind, placebo-controlled study is to determine whether ataluren can improve lung function in patients with nmCF, as measured by forced expiratory volume in 1 second (FEV1). Additional secondary endpoints are evaluating other aspects of patient function, drug activity, and safety. The 48-week trial enrolled 238 patients, ages six years and older, at multiple sites in North America, Europe, and Israel. Patients were randomly assigned to one of two treatment arms: ataluren (10 mg/kg morning, 10 mg/kg midday, 20 mg/kg evening) or placebo (morning, midday, evening).

ABOUT ATALUREN

An investigational new drug discovered by PTC Therapeutics, ataluren is a protein restoration therapy designed to enable the formation of a functioning protein in patients with genetic disorders caused by a nonsense mutation. A nonsense mutation is an alteration in the genetic code that prematurely halts the synthesis of an essential protein. The resulting disorder is determined by which protein cannot be expressed in its entirety and is no longer functional, such as the CFTR protein in nonsense mutation cystic fibrosis.

The development of ataluren has been supported by grants from Cystic Fibrosis Foundation Therapeutics Inc. (the nonprofit affiliate of the Cystic Fibrosis Foundation); FDA’s Office of Orphan Products Development; Muscular Dystrophy Association; National Center for Research Resources; National Heart, Lung, and Blood Institute; and Parent Project Muscular Dystrophy.

The FDA and the European Commission have granted ataluren Orphan Drug status for the treatment of nonsense mutation cystic fibrosis and nonsense mutation Duchenne and Becker muscular dystrophy. The FDA has also granted ataluren Subpart E designation for expedited development, evaluation, and marketing for CF and dystrophinopathy and Fast Track designation for the development of treatment for nonsense mutation dystrophinopathy.

COLLABORATION WITH GENZYME

PTC Therapeutics has an exclusive collaboration with Genzyme Corporation for the development and commercialization of ataluren. PTC Therapeutics will commercialize ataluren in the United States and Canada, while Genzyme will commercialize the product in other regions of the world.

Source: PTC Therapeutics Inc.

PTC Therapeutics, Inc. today announced the publication of data from a Phase 2a clinical trial of ataluren in children with nonsense mutation cystic fibrosis (nmCF) in the American Journal of Respiratory and Critical Care Medicine. The published data show that treatment with ataluren, an investigational new drug, resulted in statistically significant improvements in the production and function of cystic fibrosis transmembrane conductance regulator (CFTR), a critical protein lacking in CF patients.

“We are encouraged by the results of this study, which show that ataluren is pharmacologically active and generally well tolerated in children with nonsense mutation cystic fibrosis,” said Isabelle Sermet-Gaudelus, M.D., Ph.D., principal investigator at l’Hopital Necker-Enfants Malade. “There is a great need for new cystic fibrosis treatments to help prevent disease manifestations, particularly in younger patients. These safety and activity data in pediatric patients support the inclusion of children in long-term studies of ataluren.”

Patients with CF lack adequate levels of the CFTR protein, a chloride channel necessary for normal function of the lung, pancreas, liver and other organs. In nmCF, an interruption in the genetic code-known as a nonsense mutation-prematurely halts the synthesis of CFTR, causing the protein to be short and non-functioning. Nonsense mutations are categorized as Class I mutations that result in little or no production of the CFTR protein. CF patients with Class I mutations typically experience more severe disease symptoms than those with lower-risk genotypes, including a greater than twofold increased risk of death, a higher probability of end-stage lung disease, and a higher prevalence of pancreatic insufficiency. Ataluren, a protein restoration therapy, is designed to overcome the nonsense mutation and enable the production of a full-length, functional CFTR protein. A simple genetic test can determine if a patient’s disease is caused by a nonsense mutation.

“Results from this clinical study in children provide additional strong evidence of ataluren activity in nonsense mutation cystic fibrosis,” said Stuart W. Peltz, Ph.D., President and Chief Executive Officer of PTC Therapeutics. “This data adds to the growing body of published preclinical and clinical data showing ataluren’s activity in cystic fibrosis and other nonsense mutation genetic disorders. The results are important because they also document the potential for ataluren as a disease-modifying therapy in nonsense mutation cystic fibrosis.”

About the Phase 2a Trial

The randomized Phase 2a dose-ranging study was designed to evaluate the safety and activity of two ataluren doses in children with nmCF. The study enrolled 30 participants with nmCF aged 6 to 18 years at three trial sites in Belgium and France. Patients were assessed in two 28-day cycles, comprising 14 days on and 14 days off ataluren. Patients received a dose of 4-, 4-, 8- mg/kg in one cycle and a dose of 10-, 10-, 20- mg/kg in another cycle, in a randomized order.

The primary endpoint of the Phase 2a trial was CFTR chloride transport as assessed by nasal transepithelial potential difference (TEPD), a surrogate for the presence and activity of the CFTR protein. Results showed that ataluren induced statistically significant improvements in chloride channel activity, with some patients achieving chloride transport values in the range of healthy children. Overall, 50% of patients (significantly greater than the null hypothesis of 10%, p<0.0001) had a total chloride transport response (at least a -5 mV improvement) and the mean change for all evaluable patients was -4.2 mV (p=0.002) after two 28-day treatment cycles at two dose levels. Importantly, TEPD compliance was excellent with only 1 of 150 tests not completed suggesting repeated TEPD evaluations are feasible in children of this age group. Secondary outcome measures included the proportion of epithelial cells from the nostril showing CFTR protein expression as assessed by immunohistochemistry. Across all patients, there was a 17% (p<0.01) improvement in CFTR protein expression. In addition, efficacy results showed that multiple nonsense mutation genotypes responded to ataluren therapy. Safety results showed that ataluren was generally well tolerated and compliance was >93%. Adverse events were mild or moderate, and no patients discontinued treatment due to an ataluren-related adverse event.

The abstract entitled “Ataluren (PTC124) Induces CFTR Protein Expression and Activity in Children with Nonsense Mutation Cystic Fibrosis” is available online at: http://ajrccm.atsjournals.org/cgi/content/abstract/201001-0137OCv1
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More information on the Phase 2a clinical trial is available online at http://www.clinicaltrials.gov/NCT00458341

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In a study published in this week’s New England Journal of Medicine, treatment with a new drug candidate known as VX-770 resulted in improvements in lung function and markers of disease in a Phase 2 clinical trial of 39 people with cystic fibrosis. There were no discontinuations due to adverse events in the study, and the frequency of adverse events was similar across the study groups. VX-770 is an oral (tablet) medicine that is being developed by Vertex Pharmaceuticals Incorporated to directly target the defective protein known to cause CF. An accompanying editorial on this study was also published in this week’s New England Journal of Medicine.

“This study marks a significant step in the development of innovative CF therapies that target the defective protein known to be the underlying cause of CF,” said Frank Accurso, M.D., Lead Investigator for the VX-770 study and Director of the Cystic Fibrosis Center and Professor of Pediatrics at the University of Colorado Denver and Children’s Hospital in Aurora. “The increase in lung function and improvements in other markers of disease observed in this trial support the continued evaluation of VX-770 in late-stage trials.”

CF is a genetic disease that affects 30,000 people in the United States. The disease is caused by a mutated gene that produces defective or missing cystic fibrosis transmembrane conductance regulator (CFTR) proteins. The absence of functional CFTR proteins results in poor flow of fluids across certain cell membranes, including in the lung, and leads to accumulation of abnormally thick, sticky mucus that contributes to chronic lung infections and progressive lung damage. The study published in this week’s New England Journal of Medicine enrolled people with CF who have the G551D mutation in the CFTR gene, where the CFTR protein reaches the cell surface but does not function properly. VX-770, known as a CFTR potentiator, aims to increase the function of defective CFTR proteins by increasing the gating activity, or ability to transport chloride ions, across the cell membrane.

Robert J. Beall, Ph.D., President and CEO of the Cystic Fibrosis Foundation stated, “Nearly a decade ago, the CF Foundation recognized the need to develop new therapies that address the underlying cause of CF and not just the symptoms of the disease. We are encouraged by the data from this Phase 2 trial and see the trial as a milestone in our efforts to discover and develop new treatment options for this disease.”

VX-770 was discovered as part of a collaboration with Cystic Fibrosis Foundation Therapeutics, Inc. (CFFT) to discover and develop novel CFTR modulators. CFFT is the nonprofit drug discovery and development affiliate of the Cystic Fibrosis Foundation. Vertex retains worldwide rights to develop and commercialize VX-770.

About the Study

The Phase 2 study of VX-770 was a two-part, randomized, placebo-controlled clinical study that enrolled 39 people with cystic fibrosis who had at least one copy of the G551D mutation. Approximately 4 percent to 5 percent of people with CF carry the G551D mutation. In Part 1 of this study, 16 people received VX-770 (25, 75 or 150 mg; cross-over design) and 4 people received placebo for two, 14-day periods. In Part 2, 15 people received VX-770 (150 or 250 mg; parallel design) and 4 people received placebo for 28 days. VX-770 was dosed as two tablets taken by mouth every twelve hours. While in the study, patients continued to receive their standard medications for CF in addition to VX-770.

The primary objective of the study was to evaluate the safety and adverse event profile of VX-770 in people with CF. In addition, secondary endpoints of the study evaluated the effect of VX-770 on lung function and markers of disease. These markers of disease included assessments of sweat chloride and nasal potential difference (NPD), which were used to determine whether VX-770 impacted the function of the defective CFTR protein.

Primary Endpoint Analysis – Safety

All people enrolled in the study completed treatment with VX-770 or placebo. The frequency of adverse events was similar between the VX-770 and placebo groups and between Parts 1 and 2 of the study. The majority of reported adverse advents were mild or moderate in severity, with most adverse events being reported in one or two people from any study group. The most frequent adverse events observed in the study were fever, cough, nausea, pain and runny nose and occurred in people receiving VX-770 and placebo.

Secondary Endpoint Analysis – Lung Function and Markers of Disease

In Parts 1 and 2 of the study, lung function and CFTR function were measured as secondary endpoints. Lung function was assessed using measurements of Forced Expiratory Volume in one second (FEV1), a standard test that measures the amount of air that can be exhaled in one second. CFTR function was assessed using measurements of sweat chloride and NPD. High sweat chloride levels are observed in people with CF and result from dysfunctional CFTR proteins. NPD measures voltage changes across airway cells lining the inside of the nose and is used as a direct measure of CFTR function.

In the study, improvements in lung function were observed among patients who received treatment with VX-770 for 14 days or 28 days as compared to their lung function when they enrolled in the study. Additionally, measurements of sweat chloride and NPD showed that treatment with VX-770 was associated with improvements in CFTR function in the sweat duct and airway epithelial cells. For some patients in the trial, the sweat chloride levels observed after treatment with VX-770 decreased to within the range seen in people who do not have CF. Results from this study support the hypothesis that improving the function of the defective CFTR protein in people with CF may result in improvements in lung function. Additionally, the results suggest that improving CFTR function may represent a viable approach to treating the underlying cause of CF.

Additional data from the study, including data from all VX-770 dose groups and from other secondary endpoints, are discussed in the New England Journal of Medicine article.

“Based on these results, we are now evaluating VX-770 as part of a Phase 3 development program and expect data early next year,” said Robert Kauffman, M.D., Ph.D., Senior Vice President and Chief Medical Officer for Vertex. “Importantly, we also recently began a trial that will combine VX-770 with another CF drug candidate known as VX-809 as a first step toward addressing the underlying defect of CF in people with more common forms of the disease, such as the F508del mutation.”

Ongoing Phase 3 Studies of VX-770

Based on the results observed in the Phase 2 study, Vertex initiated a Phase 3 registration program that is designed to further evaluate the use of VX-770 for the treatment of people with CF who have the G551D mutation. In drug development, Phase 3 studies are intended to be the final step in the clinical trial process and are designed to generate data that the U.S. Food and Drug Administration (FDA) may use to determine whether a new medication is safe and effective for use in people with a specific disease.

The Phase 3 program for VX-770 consists of two 48-week Phase 3 trials (STRIVE and ENVISION) that enrolled patients with the G551D mutation, and a 16-week Phase 2 trial (DISCOVER) that enrolled patients with two copies of the more common F508del mutation. The DISCOVER trial was designed primarily as a safety study. Data from the Phase 3 registration program of VX-770 are expected in the first half of 2011. Pending the results, Vertex expects to submit a New Drug Application with the FDA and a Marketing Authorization Application with European regulatory authorities for VX-770 in the second half of 2011.

Studies in People with The Most Common Mutation of CF

The Phase 2 study published in the New England Journal of Medicine evaluated the use of VX-770 in people with CF who have a specific mutation in the CFTR gene, known as G551D. The majority of people with CF carry the F508del mutation, which is present in approximately 90 percent of those with CF in the United States. In people with the F508del mutation, CFTR proteins do not reach the cell surface in normal amounts. Vertex recently initiated a clinical trial designed to evaluate the use of VX-770 combined with another drug candidate known as VX-809 in people with two copies of the F508del mutation. VX-809, known as a CFTR corrector, aims to increase CFTR function by increasing the trafficking, or movement, of CFTR to the cell surface. The trial of VX-770 and VX-809 will be the first to evaluate whether a combination regimen of VX-770 and VX-809 can improve CFTR function by increasing both the gating and trafficking of CFTR in people with the F508del mutation. The trial is currently enrolling patients and is expected to include approximately 21 clinical trial sites in the United States, Europe, New Zealand and Australia.