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New Cystic Fibrosis Drug Offers Hope, at a Price

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Science  10 Feb 2012:
Vol. 335, Issue 6069, pp. 645
DOI: 10.1126/science.335.6069.645

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Last week, the news that U.S. regulators had approved a new drug for cystic fibrosis (CF) cheered patients and the biomedical research community. The drug, called Kalydeco and made by Vertex Pharmaceuticals, is the first to target the genetic defect discovered 23 years ago that causes a protein to malfunction in cystic fibrosis, resulting in a sticky buildup of mucus in the lungs and digestive tract that eventually causes fatal health problems.

“This is something we've all waited a long time for. So it is wonderful,” says Francis Collins, director of the National Institutes of Health, who helped lead the team that discovered the CF gene in 1989. He says he was in a coffee shop in downtown Washington, D.C., last week when a man approached him and said that his 13-year-old grandson with CF had just learned that he is eligible for the drug. “His grandfather started crying and I started crying. We've gotten to the point where an amazing potential future exists for this boy,” Collins says.

But as Collins acknowledges, the approval of Kalydeco illustrates both the promise and peril of personalized medicine, which in this case has resulted in a drug that's extremely expensive and helps only 4% of people with the disease, or 1200 patients.

Cystic fibrosis affects about 30,000 people in the United States; patients typically live only into their late 30s. When scientists discovered the causative gene—cystic fibrosis transmembrane conductance regulator (CFTR), which codes for a membrane protein—many thought a cure would soon follow. But early efforts focused on inserting a corrective DNA sequence with gene therapy, which has not yet worked (Science, 19 June 2009, p. 1504). Scientists moved ahead, however, on studying how hundreds of mutations cause defects in the CFTR protein that prevent chloride and water from passing through the cell membrane.

In the late 1990s, the Cystic Fibrosis Foundation decided to fund a search for small molecules that might correct these defects. Academic labs weren't doing high-throughput screening, says foundation CEO Robert Beall: “We had to move faster.” The foundation gave $75 million to a company called Aurora Biosciences in San Diego, California, later bought by Vertex Pharmaceuticals. Aurora-Vertex screened 230,000 compounds using cell assays—an unusual approach at the time, says Vice President for Discovery Biology Paul Negulescu. They found a compound that could target a rare mutation, G551D, that makes the CFTR protein structure open too slowly. Two clinical trials found that a version of the compound, VX-770, “helps the gate open,” Negulescu says. It improved lung function and weight gain and resulted in fewer infections in patients 6 years and older with the G551D mutation. Last week, the U.S. Food and Drug Administration approved VX-770, Kalydeco, after an unusually fast 3-month review.

On target.

Fred Van Goor (left) and Paul Negulescu of Vertex Pharmaceuticals helped develop the first drug aimed at the gene defect that causes cystic fibrosis.

CREDIT: JOHN GASTALDO/UT SAN DIEGO/AP PHOTO

Vertex is now testing Kalydeco in combination with another new compound that targets a more common mutation carried by 90% of cystic fibrosis patients. This defect, ΔF508, prevents the CTFR protein from folding properly and moving to the cell surface. Although correcting this problem is more challenging, some are encouraged by the Kalydeco results: “This provides a proof of concept suggesting that if you can repair a CFTR defect, you can have an impact on this disease,” says cystic fibrosis researcher Michael Welsh of the University of Iowa in Iowa City, who was not involved with the trial. Results from an efficacy trial are expected later in 2012.

Some have been taken aback by the price of Kalydeco, which will cost $294,000 a year for the twice-daily pill, to be taken for a lifetime. Beall says this is “not totally out of line” with prices for other drugs for rare diseases. His group is encouraged that Vertex will make the drug available for free to uninsured patients with household incomes below $150,000 and will cover up to 30% of copayments for some with insurance.

Still, Kalydeco joins other drugs targeted to patients with a particular disease mutation—such as a wave of new cancer drugs—that cost upward of $100,000. As more such costly drugs emerge, “there's going to have to be a reality check,” Collins says. He anticipates a “complicated conversation” between companies, insurers, and “society as a whole” to make the drugs an affordable part of health care.

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