A Healthy Gamble for Cystic Fibrosis

In an unusual move, a foundation is paying pharmaceutical companies to develop drugs to fight the disease, with promising results

Ten years ago, Dr. Robert Beall worried that an opportunity to develop new drugs for cystic fibrosis patients was being squandered. The faulty gene that causes the inherited disease had been discovered nearly a decade before. Researchers had made great strides understanding the biological defect, which leads to progressively worse lung disease.

But aside from failed attempts at gene therapy, no drug companies had joined the quest for new treatments. "We were frustrated," says Beall, president of the Cystic Fibrosis Foundation. "Companies only wanted blockbuster drugs, and no one was willing to spend money on cystic fibrosis," a disease that afflicts just 35,000 people in the U.S. But rather than fuming, "I took the biggest gamble I ever made," Beall recalls. If the pharmaceutical industry wouldn't try to develop cystic fibrosis (CF) drugs on its own, the foundation would pay it to do so.

A New Funding Model

Until then, foundations devoted to specific diseases mainly used the donations they received to provide care and support for patients or to fund basic university research that usually didn't focus on drug development. Beall made the controversial decision to get private industry involved. Since then, the Cystic Fibrosis Foundation has handed drug companies $175 million, a figure that could rise to nearly $300 million if the companies reach certain milestones in the assorted projects.

It has taken plenty of patience, but now the bold move is beginning to pay off. In late March, a partner named Vertex Pharmaceuticals (VRTX) released results showing, for the first time ever, that a drug could actually fix the biochemical flaw in some CF patients. "When they showed us the data, it was one of the happiest days of my life," says Beall.

Yet there could be disappointments ahead. The experimental Vertex drug has only been given to 16 patients for just 14 days, so its long-term safety is unknown. In addition, its potential benefit only applies to a small fraction of CF patients. But the results "mean to me that we do have hope of working directly with the abnormal protein to treat the disease," says Dr. Frank Accurso, director of the CF center at the University of Colorado School of Medicine in Denver. Even better, Vertex has developed a second experimental drug that may treat a larger group of CF patients.

Assay Assist

The results, scientists say, prove Beall's gamble was the right move, one that has since been copied by other nonprofit groups. But when Beall first decided to partner with industry, the response was not overwhelming. "I called up five or six companies, but only two even returned my phone call," he recalls. Big Pharma wants drugs that can be used by millions of people, not tens of thousands. Then Beall heard about a company named Aurora Biosciences in San Diego. Its claim to fame: creating biological tests, known as assays, that could be used to screen hundreds of thousands of chemicals to look for drug candidates.

At the time, "we didn't even know if it was possible to make an assay" to look for drugs to treat CF, Beall explains. CF patients have a defect in their cells. Normal cells produce proteins that create channels in their membranes, or outer shells, that enable important substances to enter and leave. Think of them like the gates of a walled city. But for CF sufferers, the gate for chloride ions and other molecules is missing or defective, causing a variety of symptoms. The most dire is that their lungs produce thick mucus that impairs breathing and fosters infections that damage the lungs. The lungs lose function at an average rate of about 2% per year. "So by age 30, patients have lost 60% of lung function," says Beall. Life expectancy has been increasing thanks to treatments for the mucus and infections, but the average sufferer still succumbs before age 40.

The first challenge for drug development, therefore, was to create a test that would allow researchers to screen drugs that might fix the channel. When Beall called Aurora, later acquired by Vertex, the company was willing to try. It helped that the scientist he called, Paul Negulescu, had done training in a CF lab and had an interest in the disease. Beall agreed to pay the company $2 million to create the needed test.

"A Needle in a Haystack"

Negulescu's team engineered a cell that contained the defective channel and then devised a method for measuring the flow of chloride across its membrane. That meant they could start testing potential drugs, which would require more money. Beall went to the Bill & Melinda Gates Foundation, which provided $20 million for the project, and quickly added $20 million from the Cystic Fibrosis Foundation's coffers, making it possible for Aurora to screen more than 1 million chemicals. "It was a long shot," Negulescu admits. "We were looking for a needle in a haystack."

Many scientists thought that needle might not even exist. They believed the chloride channel was so irrevocably broken that no drug could have an effect. Those naysayers were wrong. True, nothing panned out in the first round of screening. But Negulescu improved the assay, and the team screened the million chemicals again in 2003. This time, they found a few that changed the channel. The scientists then made several thousand variations of the best one, searching for a version that was more potent and better suited to becoming an actual drug. No one knows exactly how the one they ultimately chose works, but "we do know it increases the probability that the channel will be open," Negulescu says.

Hope for Longer Lives

When it came time to begin testing the drug in patients, the researchers faced several challenges, says the University of Colorado's Accurso. While it was easy to see the drug working in the test tube, researchers weren't sure how to determine whether it was working in patients. Accurso's group settled on three indicators: They measured patients' lung function, voltage changes across cells in their noses, and the saltiness of their sweat, which is typically laden with sodium chloride. The results surprised Accurso. "I would have been happy if we had found positive changes in any one of these three things," he says. But all three showed improvement. "It's very exciting. We've never had a treatment that could change the sweat chloride," says Accurso.

If the drug proves to be safe in the long run, those changes "could theoretically add decades to patients' lives," says Beall. It doesn't offer hope to all sufferers, however. The drug may help those patients whose cell walls have a defective channel, but they represent only a minority of CF sufferers. For the majority, the protein the cell produces to create the channel is so defective it never makes it to the membrane in the first place.

Yet there's cause for optimism among these patients as well. "We have a drug that's even more magical," says Vertex CEO Joshua Boger. In the course of screening those million chemicals, Negulescu's team found one that frees up the stuck protein inside the cell, enabling it to make it to the membrane. "The real experiment will be the combination of the two," says Boger.

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