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.