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VX-770
(Cystic Fibrosis)

Cystic Fibrosis (CF) affects about 30,000 people in the United States and approximately 70,000 people worldwide. Cystic fibrosis is caused by genetic mutations that result in a malfunctioning or missing Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) proteins on cell surfaces. These missing or malfunctioning CFTR proteins result in an imbalance of salt and water in the airways, causing a cascade of mucus plugging, infection and inflammation that characterizes CF. This cascade accounts for a large portion of the morbidity and mortality seen with CF.

VX-770, an investigational CFTR potentiator, aims to increase chloride ion transport through the defective CFTR protein. VX-770 was advanced into preclinical development based on successful collaborative research with Cystic Fibrosis Foundation Therapeutics, Inc. (CFFT) that incorporated capabilities and proprietary ion channel research from Vertex's San Diego research site.

Based on positive results announced in 2008 from a Phase 2 trial of VX-770 in patients with CF who carry the G551D mutation in CFTR, Vertex initiated the Phase 3 ENDEAVOR registration program designed to support registration of VX-770 in patients with the G551D mutation. The G551D mutation is present in approximately 4% of CF patients.

The ENDEAVOR Phase 3 registration program consists of three ongoing clinical trials, known as STRIVE, ENVISION and DISCOVER.

• The STRIVE trial, which is evaluating VX-770 in patients aged 12 years and older who carry the G551D mutation on at least one allele, has completed planned patient enrollment. Vertex expects that all patients in STRIVE will have received their first dose of VX-770 or placebo by the end of February 2010.

• The ENVISION trial, which is evaluating VX-770 in patients aged six to 11 who carry the G551D mutation on at least one allele, is ongoing. Vertex expects to complete enrollment for ENVISION in the first half of 2010.

• The DISCOVER trial is evaluating VX-770 in patients 12 years and older who are homozygous for the F508del mutation. Vertex expects to enroll approximately 120 patients in DISCOVER and that all patients will have received their first dose of VX-770 or placebo by the end of February 2010.

The primary endpoint for patients with the G551D mutation (STRIVE and ENVISION trials) is change in forced expiratory volume in one second (FEV₁), which will be measured at 24 weeks, with additional FEV₁ measurements at 48 weeks as a secondary endpoint to assess durability of any observed response. For patients with the F508del mutations (DISCOVER trial), the primary endpoints are safety and change in FEV₁, which will be measured at 16 weeks. Additional secondary endpoints, including sweat chloride, will be measured in each trial to evaluate the potential effect of VX-770 on improving the function of the defective CFTR protein.

Based on 48-week clinical data from the STRIVE and ENVISION trials, and on 16-week clinical data from the DISCOVER trial, Vertex plans to submit an NDA for VX-770 in patients with the G551D CFTR mutation in the second half of 2011.