Bonnie Ramsey said three years ago that a cystic fibrosis drug from Vertex Pharmaceuticals was a huge medical advance in the making, and would end up being an achievement on par with putting a man on the moon, at least for her patients.
Yesterday, she says, was the day it truly felt like she was part of a team that reached the moon-shot goal. The good news came when the FDA approved Vertex’s ivacaftor (Kalydeco) as the first drug of its kind to work by treating an underlying genetic defect for cystic fibrosis.
“It’s a really big day,” says Ramsey, a leading CF physician/scientist at Seattle Children’s Hospital and the University of Washington. “Even though it’s for a small subpopulation, the treatment paradigm has completely changed. It’s no longer about just treating the symptoms, it’s about treating the genetic defect. That’s a real game-changer.”
The drug from Cambridge, MA-based Vertex (NASDAQ: VRTX) is now FDA approved for patients age six and older who have what’s known as a Class 3 gene mutation called G551D. This mutation is found in about 4 percent of the 30,000 patients in the U.S. with cystic fibrosis. The disease, the result of various mutations to a gene called CFTR, causes the poor transfer of water and salt across cell membranes, which leads to the buildup of thick, sticky mucus in the lungs, and poor absorption of nutrients. It means patients have to endure hours a day of treatment their entire lives, and the median life expectancy is about 39 years. Doctors currently treat the symptoms of the disease, through things like inhalable antibiotics, but Vertex’s drug is the first FDA-approved therapy that works by altering an underlying disease-related protein.
Ramsey has had an instrumental role in developing this drug since its infancy. As the executive director of the Cystic Fibrosis Foundation’s Therapeutic Development Network, back in 2000 she began collaborating with the drug’s original developer, San Diego-based Aurora Biosciences (later acquired by Vertex.)
Ramsey was the lead investigator of a pivotal study of 161 patients, known as Strive, which yielded results in February that laid the foundation for yesterday’s FDA approval. The study showed that patients age 12 and older on the twice-daily pill from Vertex had about a 10.6 percent absolute improvement in their ability to force out air from their lungs in one second—compared with a placebo. The effect held up over the full 48-week course of the study. Researchers also saw significant improvements in being able to gain weight, while also reducing cough, sputum production, and the incidence of pulmonary exacerbations. Side effects included headache, and upper respiratory tract infections, researchers said, although more patients dropped out of the placebo group than the drug group. A second study verified the effect in younger patients, age six and above.
What excites scientists is that the drug has a compelling foundation in biology. It is designed to help the protein made by the CFTR gene function better. These are instances in which the CFTR-made protein gets to the surface of the cell, but is not properly activated, so it can’t properly transport water and salt across the cell membrane. By helping improve that cellular process, Vertex showed it could have an impact on the disease.
There are a number of efforts underway to expand the usage of Kalydeco to more patients. That was a big focus of my conversation yesterday with Ramsey, and something she wanted to get across to patients. “What’s most important for the patients to know is that we’re not going to be satisfied until we take care of the other 95 percent,” Ramsey says.
One study, being led by Margaret Rosenfeld at Seattle Children’s, is looking at how patients with the G551D mutation do on the new Vertex drug when they are as young as ages two through five. This study required some extra effort upfront, Ramsey says, because children that young need a liquid formulation instead of pill form, and they can’t perform the standard lung function test used in older children. So researchers will examine progress based on the amount of sweat chloride that can be observed on the surface of the skin, as well as other quality of life measures in kids ages two through five, Ramsey says. It’s an important study, Ramsey says, because CF is a lifelong disease and “you want to start this drug as early as possible,” before some long-term damage from symptoms starts to accrue.
Vertex has also done extensive work on cell lines in the petri dish that show its new compound can work against other types of mutations, Ramsey says. The problem is that there are thought to be as many as 1,500 to 2,000 different mutations found in cystic fibrosis, and many of these are so rare that it’s not feasible to run a large, controlled clinical trial in these distinct subpopulations, Ramsey says. Vertex is working with the FDA, she says, to find a way to test the new drug in well-defined genetic populations.
One thing Vertex does know, unfortunately, is that the new drug doesn’t work on its own for cystic fibrosis patients with the most common mutation, known as Delta F508. About 70 percent of CF patients have that mutation. The hope in this patient group, however, is that Vertex may be able to combine Kalydeco with one of its other experimental drugs, VX-809 or VX-661. Those drugs help traffic the CFTR protein up to the surface of the cell, where Kalydeco can do its job of helping water and salt get across the membrane, Ramsey says.
Researchers have already seen some preliminary results, in which Kalydeco and VX-809 can reduce the amount of sweat chloride on the skin in these patients. Elevated amounts of sweat chloride on the skin are an indicator that the CFTR protein isn’t working right. However, the magnitude of sweat chloride reduction seen with Kalydeco and VX-809 in Delta F508 patients hasn’t been as dramatic as what researchers have seen with Kalydeco alone for G551D patients, Ramsey says. It’s possible that the reduced effect still might be enough to achieve a meaningful improvement in lung function for the Delta F508 patients, she adds.
The newly approved drug comes with a high price of $294,000 a year, per patient, for a lifelong therapy. Still, Ramsey says she doesn’t expect any significant pushback from insurers, because a well-validated genetic test provides a definitive yes/no answer on who should get the drug, and the clinical trial data shows such a convincing benefit for patients on the drug. There is likely to be a stampede among patients to get the new treatment, because the vast majority of CF patients already know their genotype, and the CF Foundation is working to help make sure all eligible patients can get access to the new medicine. “It’s possible insurers will ask to get a second genotype done to verify the mutation. But the data is clean and clear. They’d be hard pressed to not approve [reimbursement claims],” she says.
Some competition has picked up in the field recently because of Vertex’s success, Ramsey says. South Plainfield, NJ-based PTC Therapeutics, for one, is testing a drug for a Class 1 mutation that leads to a faulty RNA transcription of the CFTR protein. That drug is supposed to yield meaningful clinical results this year, Ramsey says, although she’s not involved in development of that one.
Other companies, which Ramsey describes only as “major companies,” have shown increasing interest in CF recently. But “Vertex is way ahead,” not just with Kalydeco, but also with VX-809 and VX-661, Ramsey says.
Over the course of more than 30 years treating CF patients, Ramsey has seen life expectancy soar from about age 18 to 39, through a variety of methods. No one knows yet whether Kalydeco or some of the other genetic-based treatments in development will extend lifespan, but based on the data seen so far, Ramsey says it’s possible that life expectancy could see a significant boost.
“If lung function improvement that we’ve seen is sustained, then I’d assume it will have an impact,” Ramsey says. “For a major of patients, this drug doesn’t change their lives today. But they should know there are other drugs in the pipeline that will eventually be used with Kalydeco, which can offer a benefit.”
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