By JONATHAN D. ROCKOFF
More than two decades after scientists identified the gene responsible for cystic fibrosis, drug makers are finally edging closer to new treatments—a long journey that underscores the challenges of translating genetic discoveries into actual drugs.
Vertex Pharmaceuticals Inc., Pfizer Inc. and PTC Therapeutics Inc. are among the companies working on drugs that aim to arrest the disease’s destructive march through the lungs and airways by targeting its cellular underpinnings. Furthest along is a pill from Vertex, which on Wednesday filed for regulatory approval of its drug Kalydeco. The drug is for only a small fraction of cystic fibrosis patients with a specific genetic mutation, but in 48 weeks of clinical testing, Kalydeco improved the lung function of patients by 17%, while cutting their risk of getting intermittent sicknesses by 55%.
“We really believe with these new drugs that we should be able to add decades to the lives of patients in a very short period of time,” said Robert Beall, chief executive of the Cystic Fibrosis Foundation, which has given or committed $315 million to companies for drug research.
The new wave of drugs in the pipeline could cost as much as $200,000 a year per patient, according to one Wall Street analyst, and sales for the category could peak at $5.5 billion world-wide despite a small market.
Cystic fibrosis is an inherited, life-threatening disease that clogs airways with thick mucus, inviting bacterial infections and progressively robbing patients of their ability to breathe. The condition affects some 30,000 patients in the U.S. and a total of 100,000 world-wide.
To date, treatment has been limited. Sufferers can take drugs that address symptoms, such as antibiotics to tackle the infections, and they typically wear a mechanical vest for several hours each day that vibrates to dislodge the mucus.
Aggressive use of treatments has raised median life spans dramatically, but patients still can’t expect to survive much past their 30s or 40s. Hence patients’ interest in treatments ever since researchers identified the responsible gene in 1989.
That it’s taken two decades for the first drug to near approval provides some “important lessons” on the need to speed the development of genetic advances into treatments so that what turn out to be the nonviable compounds can be weeded out earlier on, said Francis Collins, a co-discoverer of the cystic fibrosis gene who now heads the National Institutes of Health. “It shouldn’t have to take that long in the future.”
After discovery of the cystic fibrosis gene, it took several years for scientists to develop a hypothesis explaining how a defective gene results in the disease. The gene makes the channels that carry chloride in cells up to airways, where it’s needed for clearing mucus that builds up, some scientists believe. Mutations impede the flow of chloride, causing the mucus to accumulate and impeding the hair-like particles called cilia from beating back and forth to clear out the mucus.
Researchers spent years at first on gene therapy—aiming to replace the mutated gene with a healthy substitute. But it proved difficult to introduce a healthy gene in patients without their immune systems thwarting the effort. Eventually researchers turned to drugs that could correct for the cellular hitches caused by the mutations and enable chloride to get into airways.
At Vertex, it took all of 2003 to find a way to test promising compounds. Company scientists wanted to test drug prospects on the lung cells of cystic fibrosis patients, but the donated lungs were too contaminated with mucus. Vertex scientists had to use tweezers to extract the mucus, then isolated the cells for use in testing, said Fred Van Goor, who led the project.
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With the test in place, the researchers could quickly see through their microscopes the compound that became Kalydeco having an impact: fluid containing chloride was on the surface of the cells and cilia had resumed beating back and forth. “You could actually see the restoration of the cellular defect. That’s when the organization started to believe that we really [had] something here,” Dr. Van Goor said.
In Kalydeco’s pivotal trial, patients experienced improved breathing and fewer of the illnesses associated with cystic fibrosis. Patients, who are typically underweight, gained an average of seven pounds.
Since joining the trial in 2009, cystic fibrosis patient Capri Faulk has added 24 pounds to her 49-pound frame, and can play outside with her brother and sister without getting exhausted. Her mother, Nicole Faulk, of Oklahoma City, Okla., says she now talks with the 8-year-old about one day having a family.
“I had hopes and dreams for her, and I was scared they would be robbed from her and from me” until the new drug came along, Ms. Faulk said.
The pill has limitations. It targets a mutation, called G551d, affecting just 4% of patients. Nor has the drug been shown to reverse the effects of the disease. So far, results haven’t been as strong for other compounds from Vertex and others that are further behind in development.
“It says we’re not quite there yet, but it suggests maybe we’re not too far off,” said Michael Welsh, a cystic fibrosis researcher at the University of Iowa and Howard Hughes Medical Institute.
PTC Therapeutics, a 13-year-old biotech that has received $100 million from Genzyme, is conducting a phase III trial of its compound, ataluren, in cystic fibrosis patients with a so-called nonsense mutation. Novartis AG has a compound in phase 1 clinical trials, a spokeswoman said. And Pfizer has begun screening for potential cystic fibrosis drugs, said Ed Mascioli, head of the drug giant’s orphan and genetic diseases unit.
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