Sisters Thrive on Experimental Cystic Fibrosis Drug

Experimental drug has potential to lengthen lives by targeting gene defect.

Nov. 2, 2011— -- An experimental drug called ivacaftor has transformed life for two Massachusetts sisters born with cystic fibrosis, a genetic disease that frequently interrupted their schoolwork and extracurricular activities by turning simple colds and viruses into potentially life-threatening lung infections that slowly reduced their ability to breathe freely.

Laura Cheevers, now 13, and her sister Cate, 10, were born with a gene defect that clogged their lungs with thick, sticky mucus, leaving them vulnerable to bacterial growth, infection and inflammation. Cystic fibrosis affects mucus membranes elsewhere in their bodies, including their digestive systems, where it interferes with absorption of nutrients, forcing them to consume thousands of daily calories to keep from losing weight. Both were in and out of the hospital and tired easily from an incurable, progressive disorder, which their parents knew could cut short their lives.

But today both are thriving, thanks to an international team of scientists and the Cystic Fibrosis Foundation, which spent years jointly developing what is shaping up to be the first treatment successfully targeting the basic defect underlying their disease. Although the twice-daily pill only helps CF patients with one particular genetic mutation, about 5 percent, experts expect the research to help them target the other mutations responsible for the disease. Both girls participated in double-blind clinical trials comparing ivacaftor pills to dummy pills among young adults and children. Neither the patients, nor their doctors, knew for sure for 48 weeks if they were getting the medication -- or the placebo.

However, the family and Cate had their suspicions. They noticed that Cate began improving within a month of beginning the study of ivacaftor in children 6 to 11. She stopped coughing, began growing like a weed, and her first lung tests showed "almost a 30 percent bump, which blew all of us away," said her mother, Kim Cheevers. Laura, who was in a similar study of the drug in children and adults ages 12 and older, stayed "pretty much the same as before. She ended up worsening over the winter."

Then, on April 1, everyone in the two trials began getting the medication for sure, and the results have been nothing short of stunning for the sisters from North Andover, Mass.

Laura, who typically "strains to gain a pound a year," has gained about 8 pounds, said Kim Cheevers, a pediatric intensive care nurse at Massachusetts General Hospital in Boston. "She is not coughing at night anymore. When she does get sick --and this week we all have this horrendous cold and cough -- her mucus isn't that thick, thick sticky mucus. Everything is watery; it's easier for her to clear." More remarkable still, "she hasn't been on a course of antibiotics since she's been on the drug. In the past, every other month she'd be on something."

Cate, a soccer goal-tender and defender, said she feels relieved now that both she and her sister are getting the medication. "I'm more comfortable now that I know, for definitely, that I am on the study drug, that I'm not on a placebo." It's also easier to see her sister benefiting now, too. "During the trial, when we didn't know that I was on the study drug – if any of us was on the study drug --she would be coughing a lot more. I would feel bad because I wouldn't be coughing," Cate said in an interview on the way to practice. When Laura would have a special line inserted in her upper arm to deliver antibiotics directly into a vein, "I'd just be there watching," she said.

Both Sisters Now Thriving On Experimental Medication

Laura and Cate are now six months into extensions of the ivacaftor clinical studies, which will provide them with the medication for eight years, their mother said. "We're on it until it gets FDA approval."

Vertex Pharmaceuticals, of Cambridge, Mass., developed the drug in collaboration with a non-profit drug research affiliate of the Cystic Fibrosis Foundation. On Oct. 19, Vertex asked the FDA for a priority review of the drug, which can be granted to medications considered major treatment advances. Vertex also requested similar expedited consideration from the European Medicines Agency, the regulatory body for the European Union.

The trial in which Laura enrolled found that ivacaftor improved lung function, helped with normal growth and weight gain, and reduced infections with few side effects, according to a report in today's issue of the New England Journal of Medicine. Improvements for those getting the drug began as early as two weeks and lasted for the duration of the study. At the 24-week mark, participants receiving the drug scored 10.6 percentage points better on a test of their ability to push air out of their lungs than those getting a placebo. By the end of the 48 weeks, those getting the drug had gained, on average, almost six pounds more than those getting a dummy pill. Furthermore, the rate of serious side effects was worse among placebo recipients than those getting ivacaftor, suggesting it's safe as well.

"I've been doing research in Seattle 30 years and this is a really dramatic finding," said lead author Dr. Bonnie W. Ramsey, who holds an endowed chair in cystic fibrosis at the University of Washington School of Medicine and directs the Center for Clinical and Translational Research at Seattle Children's Research Institute. "This is the first time that there has been a drug treating the basic defect, the abnormal protein [of cystic fibrosis]. The changes that have been observed, not only lung function, but reduction in number of respiratory flares, symptoms, weight gain, those have all been dramatic changes."

The drug's experimental success represents "a triumph resulting from the discovery of the cystic fibrosis gene in 1989," Dr. Pamela Davis, of Case Western Reserve University School of Medicine in Cleveland, wrote in an accompanying editorial. However, critical questions remain, such as whether the drug will be safe for infants and younger children and if it can be used preventively, before lung disease develops, she wrote.

Up until now, most drugs given for cystic fibrosis treated only its complications, such as chronic lung inflammation and frequent infections, and helped patients clear the clogged mucus better. These drugs helped push median survival in the last four decades from 11 years to what the Cystic Fibrosis Foundation says is now 37 years.

The disorder results from mutations in the gene for the protein that controls the balance of salt and water in the body's mucus membranes. Ivacaftor, also called Kalydeco, restores the normal balance of salt and water among the 5 percent of CF patients with the G551D mutation, one of hundreds that affect the CFTR (cystic fibrosis transmembrane conductance regulator) gene. About 30,000 Americans have cystic fibrosis.

Ivacaftor, although only helpful to that sub-group of patients, still has great potential, said Dr. Ronald Crystal, chairman of the Department of Genetic Medicine at NewYork-Presbyterian Hospital/Weill Cornell Medical College, and chief of pulmonary and critical care medicine. "I would predict for the subset of individuals who have this mutation, that it will prolong their lives."

He said the drug turns a bad protein into a good protein, "taking something that's dysfunctional and making it functional. It's making a silk purse out of a sow's ear." The techniques used to search for the drug have other applications, said Crystal, who was not involved with the study. "This will give further encouragement to pharmaceutical companies to develop drugs for these chronic genetic disorders."

Results from a study of ivacaftor in children ages 6 to 11 (in which Cate participated), as well as use of the drug in combination with VX-809, another drug in the CF pipeline, are being presented this week at the 25th Annual North American Cystic Fibrosis Conference in Anaheim, Calif.