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In May 2001 a 33-year-old scientist named Fredrick Van Goor showed up for his first day of work at a biotechnology company that had just been sold to a rival. His boss asked him if he knew anything about the genetic cause of cystic fibrosis, the deadly lung disease. He didn't, but the prospect of creating a cure intrigued him. "Just say 'yes,' and figure it out later," he told himself.
Van Goor's chutzpah led him on a decade-long quest involving dozens of scientists that resulted in the first drug to treat the disease at its genetic root. It could be approved early next year and is expected to generate hundreds of millions of dollars in annual sales for Van Goor's employer, Vertex Pharmaceuticals. Unlike other drugs, which mainly seem to slow decline from the fatal disease, which fills breathing passages with thick mucus, Vertex's VX-770 boosted patients' lung function 10%--and then preserved it for a whole year in clinical trials. An editorial in the New England Journal of Medicine hailed it as "a milestone."
But there's a catch or, actually, several of them. VX-770 works only for patients whose CF is caused by a very specific genetic mutation--meaning that it will work for only about 1,200 of the 30,000 kids and adults with CF (few patients survive their 40s, even today). Van Goor has helped invent a second drug that, when given in combination with VX-770, might allow it to help more people, but early clinical tests have been disappointing. And then there is cost: Wall Street analysts expect Vertex to charge $200,000 or more to treat one patient for a year. Vertex says no one will go without.
These are the stalking horses of personalized medicine, not only in rare diseases like cystic fibrosis but also in cancer, and maybe in heart disease and diabetes, too. A new age of medicines will work very well in a select few. But many disease sufferers may need several new drugs at once to have an effect--and, unlike older combination drugs, some of these medicines may work only as combinations, not by themselves. That scares the FDA and drug companies both. But pharmaceutical firms have shown new willingness to develop drugs for very rare diseases partly because they have found they can charge a small fortune for the ones that work. Van Goor is the first to admit these problems have yet to be worked out.
"This really is going to be one of the models of how do you do personalized medicine, using the science, using the genetics to develop drugs based on specific mutations in genes," he says. "And how do you have discussions with regulators? Can we still view the way we approve drugs the same way? I think VX-770 and the cystic fibrosis community will drive those discussions."
Cystic fibrosis was first described in 1938 in a child whose pancreas, intestines and lungs were all malfunctioning. In 1952 doctors learned that CF patients could be identified by their sweat, which was particularly salty. But what was causing all those symptoms? Defects in a single gene.
When scientists discovered the gene in 1989, the New York Times trumpeted that "the prospects for saving the lives of people with cystic fibrosis have been greatly enhanced." But treatments turned out to be far harder to find than anyone expected.
The Cystic Fibrosis Foundation wanted to pay for the development of drugs to fix the defect. A half-dozen drug companies it approached wanted no part in it because the market was too small and the goal was too hard. A small biotech called Aurora Biosciences--the company that was bought by Vertex--was interested, partly because the CF Foundation promised to keep funding the research. And despite his brashness, it was an ideal project for Fred Van Goor. The protein the CF gene makes, called the cystic fibrosis transmembrane conductance regulator, or CFTR, is what is known as an ion channel, and Van Goor had done his Ph.D. on the role ion channels play in goldfish reproduction, spending another five years at the National Institutes of Health studying their role in the human endocrine system.
Ion channels are the body's way of moving particles like salt and other ions into and out of cells--making body parts moist or dry, for instance. The lack of functioning CFTR proteins on the surface of cells throughout the body is what causes cystic fibrosis by thickening mucus in the lungs, pancreas and intestines.
Van Goor believed that the best way to treat the disease would be to fix these broken cell doorways. The problem was that there are 1,800 different mutations of the CFTR gene; get any one from each parent and a person will have CF. Most of these prevent CFTR proteins from even getting to the surface of a cell. But one, called G551D, results in cells covered with CFTR that doesn't work. For instance, the hairlike cilia that keep the lungs clean in healthy people are immobilized in these patients. Van Goor developed a way to test potential drugs on lung cells from one G551D patient. Within weeks the cilia were moving like tall grass in the breeze.
For the 4% or so of patients who have the G551D mutation, this is a godsend. Roe Van Epps, 41, lived a life of seclusion and coughing; she worked at home to avoid catching germs. Since entering a clinical trial of VX-770, she says, she barely coughs: "One minute you're thinking I might not live until next year, and the next you're not even coughing anymore." But how can we get that benefit for the other 96% of CF patients? Van Goor has tried a second drug that will get more CFTR protein to the cell surface for VX-770 to fix. But early results from a clinical trial were somewhat disappointing and caused Vertex shares to fall 10%. Van Goor thinks the approach will work but agrees the jury is still out.
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