Vertex Pharmaceuticals has had the world's attention for some time due to the potential of its hepatitis C drug, telaprevir, but now the company is showing it has more to offer with a potential "home-run" in cystic fibrosis.

While analysts expect a positive decision from the FDA in late May for the HCV treatment, all eyes are turned to Vertex's Phase III program for cystic fibrosis, an inherited orphan disease affecting about 70,000 worldwide and 30,000 in the U.S. In cystic fibrosis, any one of a group of genetic defects in the CFTR protein cause the body to produce sticky, thick mucus in the lungs and digestive system, leading inevitably to an early death, often by age 40.

Vertex announced Feb. 23 that the Phase III STRIVE study in 161 cystic fibrosis patients over age 12 showed that patients taking VX-770 had a statistically significant improvement in the ability to exhale compared with those given a placebo.

All of the patients in the trial had the G551D genetic mutation, which affects only about 4% of the U.S. cystic fibrosis population. But Vertex is also studying the drug in combination with another molecule it is developing, VX-809, in a much broader population of cystic fibrosis patients who have a more common defect in the CFTR protein, known as F508del. Vertex plans to file an NDA for use of the drug in G551D patients in the second half of 2011 and to present data from the combination trial during that time frame as well, executives said.

VX-770 has been heavily funded by the Cystic Fibrosis Foundation, a patient advocacy group with a pioneering venture philanthropy arm. CFF contributed more than $75 million to the discovery phase of Vertex's CF program, hoping that a high-profile screening technique invented by a company Vertex bought years ago would produce a few molecules that could evolve into disease-modifying drugs. In exchange, it will now receive a single-digit royalty on sales if the drug is approved.

The Foundation's bet has paid off: VX-770 is the first drug that has been able to show a disease modifying effect on cystic fibrosis. Essentially, it corrects a defect in the CFTR protein that hinders transportation of chloride ions between cells. Because it is disease-modifying, the drug has better efficacy than existing therapies and its effects are sustainable over time, said Robert Beall, PhD, president and CEO of the CFF.

"The foundation had been instrumental in laying important groundwork including identifying the CFTR gene as a cause of CF as well as characterization of the biological and biochemical function of the protein and its link to the disease process," Vertex Chief Scientific Officer Peter Mueller said on a conference call. Even after funding ended CFF has remained involved in the development program; by using its clinical trial network of 80 sites, Vertex was able to enroll patients in its trials rapidly.

Only a handful of drugs are currently available to treat CF, of which two are antibiotics made by Novartis and Gilead . These drugs can help thin mucus and fight off the lung infection to which CF patients are prone.

Results Exceed Analyst Expectations

Results from the STRIVE study showed that those who received VX-770 improved their lung function from baseline by 10.6 percentage points compared to placebo after 24 weeks, with sustained improvement over the next 24 weeks. Lung function, the primary endpoint of the trial, was determined by a standard test that measured how much breath a person could exhale in one second, or FEV1. The total FEV1 was about 17% higher in patients who received the drug.

Statistically significant improvements were also found in the trial's secondary endpoints. STRIVE patients on VX-770 were 55% less likely to have a pulmonary exacerbation, and 67% of people treated with VX-770 were free of exacerbations through 48 weeks compared to 41% in the controlled group. Patients on VX-770 gained 6.8 pounds, on average, compared to 0.9 pounds for those on placebo. Weight gain is often a problem for CF patients, who have severe digestive problems.

VX-770 also resulted in a reduction in the amount of salt in the sweat, which is a key marker of CFTR protein dysfunction, the underlying mechanism responsible for cystic fibrosis. While the reduced sweat chloride does not directly indicate improvement in the disease, it does represent a restoration of function to the CFTR protein.

The results of STRIVE far exceeded clinician and Wall Street expectations. Analysts and investors were generally predicting a 6% improvement on the FEV1 test, but the better results will help the company with pricing and positioning with providers and patients. Although it addresses a relatively small patient population, the drug could reach peak sales of $800 million, based on pricing and chronic use, according to J.P. Morgan analyst Geoff Meacham, who wrote in a note to clients that, "VX-770 hits a home run in STRIVE, in our view."

Vertex also presented results from the DISCOVER trial, which tested VX-770 in 140 patients with a different gene mutation called F508del, a very common CFTR mutation. VX-770 doesn't work well on its own in patients with F508del, but the study aims to demonstrate the drug's safety. Patients taking VX-770 experienced cough, nausea, rash and contact dermatitis. A third trial, nicknamed ENVISION, is studying '770 in G551D patients between the ages of six and 12. Results are expected later this year.

Vertex is studying a combination of VX-770 and a compound in earlier development called VX-809, an oral CFTR corrector compound, in a trial evaluating patients aged 18 and older who have two copies of the F508del mutation. More than 90% of cystic fibrosis patients have at least one copy of the F508del while about 50% have two copies. VX-809 aims to increase CFTR function by increasing movement of the CFTR protein to the cell surface.

"We believe that enhancement of trafficking could be a viable approach for patients that have not enough or intrinsically low levels of CFTR channels on their lung surface and thus cannot clinically benefit from the sole application of a potentiator such as VX-770," said Mueller. "Therefore we believe the best approach for people with this type of CF mutation may be the combination of a potentiator and a corrector."

-Lisa LaMotta (l.lamotta@elsevier.com)

CF Patients Breathe Easier With Vertex Drug

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