is the first to halt the underlying processes that cause the inherited disease, which causes thick, sticky mucus to build up in the lungs and the pancreas and can lead to life-threatening infections, experts said.
"It has a huge significance for the whole cystic fibrosis community," said study author Dr. Bonnie Ramsey, director of the Center for Clinical and Translational Research at Seattle Children's Hospital and a professor at the University of Washington School of Medicine. "It's the first time we have developed a therapy directed at the abnormal proteins and showing that it can be corrected."
Only 4 percent to 5 percent of cystic fibrosis patients have the particular genetic variant that the drug is being studied to treat, but for them, the results could mean a significant improvement in their health, said Robert Beall, president and CEO of the Cystic Fibrosis Foundation.
"We're talking about adding decades to these people's lives, that's how profound this drug is," Beall said.
But Beall and other experts say the drug may end up helping people with other cystic fibrosis genetic variants, including the most common one, D508, one copy of which is present in more than 90 percent of people with cystic fibrosis.
Though ivacaftor (previously known as VX-770) on its own didn't work all that well in these patients, a trial looking at using ivacaftor in conjunction with another drug is currently under way. Results of that trial are expected in the fall of 2012, said Beall, whose organization has provided funding for VX-770 research.
In the study reported in the Nov. 3 issue of the New England Journal of Medicine, 161 patients aged 12 and older were randomly divided into two groups. One received the drug every 12 hours and the other received a placebo. All patients had at least one copy of the G551D mutation.
Researchers could tell the drug was working two weeks after people started taking it and the concentration of chloride in their sweat dropped, for some to levels seen in people without the disease. Very salty sweat is a telltale sign of the disease.
Patients also showed improved lung function, as measured by FEV1, or how much air they could blow out in one second.
"It's not surprising you would see an effect in two weeks. By changing the hydration of the mucus, you can clear it out better and open up the airways," Ramsey said. "We saw the improvement across all illness severities … That was very encouraging. We had been very worried once you had the lung damage or the infections you wouldn't be able to reverse it. That's not saying the lungs would return to normal, but there was more reversibility than we thought there would be."
Patients also experienced an average relative change in their lung function of 17 percent. Relative change means relative to where they started. The absolute change was about a 10 percent improvement.
At 48 weeks, patients on the drug were 55 percent less likely to have experienced an exacerbation, or an infection that left them ill and unable to work or hospitalized.
Patients on the drug also gained an average of 7 pounds, a huge feat for someone with cystic fibrosis, experts said. The weight gain brought people who were nutritionally deficient and underweight closer to a normal body weight, Ramsey said.
The results stayed consistent through 48 weeks, and there were few side effects, according to the study.
Best of all, patients reported feeling better, Beall said. "We had a lot of people call us and say it was incredible how much better they feel."
Cystic fibrosis is a progressive, inherited disease caused by a defect in the CF gene, which produces the CFTR (cystic fibrosis transmembrane conductance regulator) protein, which is important in the transport of salt and fluids in the cells of the lungs and digestive tract.
In healthy cells, when chloride moves out of cells, water follows, keeping the mucus around the cell hydrated.
In people with the faulty CFTR protein, the chloride channels don't work properly. Chloride and water in the cells of the lungs stay trapped inside the cell, causing the mucus to become thick, sticky and dehydrated.
Overtime, the abnormal mucus builds up in the lungs and in the pancreas, which helps to break down and absorb food. Patients with cystic fibrosis have both breathing problems and problems with maintaining weight.
In the lungs, the accumulation of the mucus leaves people prone to serious, hard-to-treat and recurrent infections. Overtime, the repeated infections destroy the lungs.
Though improving with inhaled antibiotics and other treatments, the average life expectancy for a person with cystic fibrosis is about 39, according to the Cystic Fibrosis Foundation.
Ivacaftor is believed to work by opening up the chloride channels, allowing the water to exit the cell and the mucus to become better hydrated. For people with the more common variant, D508, ivacaftor will likely open the channels, but only if the protein is properly transported to the surface of the cell. That's where a second drug would come in, experts explained.
Vertex Pharmaceuticals, the company developing the drug, has applied for expedited U.S. Food and Drug Administration approval. If the FDA grants the company's request, that would shorten the review time to six months from the usual 10, and would mean the FDA would make a decision by April, according to Dawn Kalmar, director of product communications for Vertex.
The drug will be marketed under the brand name Kalydeco.
Dr. Pamela Davis, dean of Case Western Reserve University School of Medicine, in Cleveland, said the drug holds great promise for cystic fibrosis sufferers.
All her life, Lindsay Shipp knew that she was dying. As a baby, she would cry after eating, and salt collected on her forehead. The diagnosis was cystic fibrosis, an incurable genetic disease that, at the time, meant a life expectancy of 18 years.
The disease, which affects 30,000 people in the United States, hinders the movement of salt in the body. Because of this, the pancreas fails soon after birth, patients cannot properly digest food, and their airways fill with mucus, leaving them vulnerable to lung infections and other problems. The current average life expectancy is now 37.
"The exciting thing about this is a drug that interacts directly with the defective protein and changes its function," Davis said. "Admittedly this protein is only found in about 5 percent of the patients with CF but it does appear to restore normal function."
Though more testing is needed, it might be possible to give the drug to babies to head off the disease before it begins to damage the lungs, she added.
Millions of Americans carry a defective CF gene, but do not have any symptoms. To be symptomatic, a person with CF must inherit two defective CF genes -- one from each parent. About 30,000 people have CF, according to the Cystic Fibrosis Foundation.
I had this race-against-time mentality where I did everything I could possibly do in a day," said Shipp, now 27 and working part time in San Diego as a bookkeeper and at an Apple store. "I never let a moment go to waste."
Shipp starred in her high school musicals and dreamed of auditioning on Broadway, until her lungs got so bad that she gave up singing and dancing.
But since she started taking an experimental drug as part of a closely watched clinical trial, her outlook has changed. The drug, called ivacaftor, cleared her lungs and allowed her to add a healthy 15 pounds to her 5-foot, 100-pound frame. On the day in February of last year when a regular checkup revealed her lungs were functioning at 96% — bringing her to essentially the same level as a healthy person — Shipp collapsed on a bench outside the hospital and sobbed with relief. "I realized I would have a full life at that moment," she said.
The trial results, published in Thursday's edition of the New England Journal of Medicine, showed that ivacaftor reduced the incidence of pulmonary exacerbations — sudden, serious flare-ups that can send patients to the hospital and cause irreversible lung damage — by 55% compared with a placebo. The study of 161 patients also found that patients who took the drug saw their lung function improve 10.4% and gained nearly 6 pounds over 48 weeks.
"This is exciting work," said Michael Welsh, a pulmonary physician at the University of Iowa who was not involved in the study. "I think that it is very promising for the people who have this particular mutation, and it may turn out to have broader significance."
Ivacaftor affects a genetic mutation in 4% to 5% of cystic fibrosis patients that prevents a protein called CFTR from allowing enough chloride ions to exit a certain type of cell. Chloride, when coupled with sodium to make salt, helps regulate the flow of water in the body. When that channel doesn't work, the lungs dry up and the once-protective mucus grows thick and immovable, providing an ideal breeding ground for bacteria.
This salt imbalance affects the pancreas and digestive tract, so patients are often small and malnourished. The sweat glands don't work properly either, leading to overly salty skin.
The drug helps that chloride gateway stay open, restoring the salt balance in the body. It is the first therapy that fixes the basic problem that causes the disease, not just the symptoms, said study coauthor Michael Konstan, a pediatric pulmonologist at Case Western Reserve University School of Medicine in Cleveland.
"The goal is if you would give a therapy like this before [the lungs deteriorate], you can prevent lung disease from developing," Konstan said.
The drug can't yet help the vast majority of cystic fibrosis sufferers: About 90% of them have a mutation in which the protein, once manufactured inside the cell, never even makes it to the cell surface where it is supposed to act as a chloride channel. Researchers are trying to develop drugs that would help bring that protein to the surface. Once a patient is on such a drug, ivacaftor could then pick up the process from there.
"It's creating such a sense of hope and optimism for all the cystic fibrosis patients because this approach will work," said Robert Beall, president and chief executive of the Bethesda, Md.-based Cystic Fibrosis Foundation, which has spent millions funding such research.
cystic fibrosis dating
Although therapies to fight the disease seemed to be around the corner when the CFTR gene was discovered in 1989, it took more than two decades to develop a treatment based on the genetic defect.
"This timeline suggests that much of the promise of the Human Genome Project has yet to be fulfilled and that realizing the therapeutic benefits will take persistence and determination," Dr. Pamela Davis of Case Western wrote in an editorial accompanying the study. "Society cannot allow support for research and development to be compromised in the current rush to cut the federal budget."
If all goes smoothly, ivacaftor may be approved by the Food and Drug Administration in 2012, said study lead author Bonnie Ramsey, a pediatric pulmonologist at Seattle Children's Hospital. The study was partially funded by ivacaftor's maker, Vertex Pharmaceuticals Inc. of Cambridge, Mass., which plans to market it under the name Kalydeco.
cystic fibrosis symptoms
The drug is not an absolute cure. It cannot rid the body of bacterial infections that stick around even after mucus has been cleared from the lungs. But perhaps, if given to patients that were young enough — say, newborns — it could allow them to live an essentially normal life.
As for Lindsay Shipp, who will be singing at the Cystic Fibrosis Conference in Anaheim this week — a downtempo cover of Katy Perry's "Firework" and "Thank You for the Music," from the musical "Mamma Mia!" — the girl who once gave up her dreams of Broadway now thinks she might fly to New York and audition.
"It has a huge significance for the whole cystic fibrosis community," said study author Dr. Bonnie Ramsey, director of the Center for Clinical and Translational Research at Seattle Children's Hospital and a professor at the University of Washington School of Medicine. "It's the first time we have developed a therapy directed at the abnormal proteins and showing that it can be corrected."
Only 4 percent to 5 percent of cystic fibrosis patients have the particular genetic variant that the drug is being studied to treat, but for them, the results could mean a significant improvement in their health, said Robert Beall, president and CEO of the Cystic Fibrosis Foundation.
"We're talking about adding decades to these people's lives, that's how profound this drug is," Beall said.
But Beall and other experts say the drug may end up helping people with other cystic fibrosis genetic variants, including the most common one, D508, one copy of which is present in more than 90 percent of people with cystic fibrosis.
Though ivacaftor (previously known as VX-770) on its own didn't work all that well in these patients, a trial looking at using ivacaftor in conjunction with another drug is currently under way. Results of that trial are expected in the fall of 2012, said Beall, whose organization has provided funding for VX-770 research.
In the study reported in the Nov. 3 issue of the New England Journal of Medicine, 161 patients aged 12 and older were randomly divided into two groups. One received the drug every 12 hours and the other received a placebo. All patients had at least one copy of the G551D mutation.
Researchers could tell the drug was working two weeks after people started taking it and the concentration of chloride in their sweat dropped, for some to levels seen in people without the disease. Very salty sweat is a telltale sign of the disease.
Patients also showed improved lung function, as measured by FEV1, or how much air they could blow out in one second.
"It's not surprising you would see an effect in two weeks. By changing the hydration of the mucus, you can clear it out better and open up the airways," Ramsey said. "We saw the improvement across all illness severities … That was very encouraging. We had been very worried once you had the lung damage or the infections you wouldn't be able to reverse it. That's not saying the lungs would return to normal, but there was more reversibility than we thought there would be."
Patients also experienced an average relative change in their lung function of 17 percent. Relative change means relative to where they started. The absolute change was about a 10 percent improvement.
At 48 weeks, patients on the drug were 55 percent less likely to have experienced an exacerbation, or an infection that left them ill and unable to work or hospitalized.
Patients on the drug also gained an average of 7 pounds, a huge feat for someone with cystic fibrosis, experts said. The weight gain brought people who were nutritionally deficient and underweight closer to a normal body weight, Ramsey said.
The results stayed consistent through 48 weeks, and there were few side effects, according to the study.
Best of all, patients reported feeling better, Beall said. "We had a lot of people call us and say it was incredible how much better they feel."
Cystic fibrosis is a progressive, inherited disease caused by a defect in the CF gene, which produces the CFTR (cystic fibrosis transmembrane conductance regulator) protein, which is important in the transport of salt and fluids in the cells of the lungs and digestive tract.
In healthy cells, when chloride moves out of cells, water follows, keeping the mucus around the cell hydrated.
In people with the faulty CFTR protein, the chloride channels don't work properly. Chloride and water in the cells of the lungs stay trapped inside the cell, causing the mucus to become thick, sticky and dehydrated.
Overtime, the abnormal mucus builds up in the lungs and in the pancreas, which helps to break down and absorb food. Patients with cystic fibrosis have both breathing problems and problems with maintaining weight.
In the lungs, the accumulation of the mucus leaves people prone to serious, hard-to-treat and recurrent infections. Overtime, the repeated infections destroy the lungs.
Though improving with inhaled antibiotics and other treatments, the average life expectancy for a person with cystic fibrosis is about 39, according to the Cystic Fibrosis Foundation.
Ivacaftor is believed to work by opening up the chloride channels, allowing the water to exit the cell and the mucus to become better hydrated. For people with the more common variant, D508, ivacaftor will likely open the channels, but only if the protein is properly transported to the surface of the cell. That's where a second drug would come in, experts explained.
Vertex Pharmaceuticals, the company developing the drug, has applied for expedited U.S. Food and Drug Administration approval. If the FDA grants the company's request, that would shorten the review time to six months from the usual 10, and would mean the FDA would make a decision by April, according to Dawn Kalmar, director of product communications for Vertex.
The drug will be marketed under the brand name Kalydeco.
Dr. Pamela Davis, dean of Case Western Reserve University School of Medicine, in Cleveland, said the drug holds great promise for cystic fibrosis sufferers.
All her life, Lindsay Shipp knew that she was dying. As a baby, she would cry after eating, and salt collected on her forehead. The diagnosis was cystic fibrosis, an incurable genetic disease that, at the time, meant a life expectancy of 18 years.
The disease, which affects 30,000 people in the United States, hinders the movement of salt in the body. Because of this, the pancreas fails soon after birth, patients cannot properly digest food, and their airways fill with mucus, leaving them vulnerable to lung infections and other problems. The current average life expectancy is now 37.
"The exciting thing about this is a drug that interacts directly with the defective protein and changes its function," Davis said. "Admittedly this protein is only found in about 5 percent of the patients with CF but it does appear to restore normal function."
Though more testing is needed, it might be possible to give the drug to babies to head off the disease before it begins to damage the lungs, she added.
Millions of Americans carry a defective CF gene, but do not have any symptoms. To be symptomatic, a person with CF must inherit two defective CF genes -- one from each parent. About 30,000 people have CF, according to the Cystic Fibrosis Foundation.
I had this race-against-time mentality where I did everything I could possibly do in a day," said Shipp, now 27 and working part time in San Diego as a bookkeeper and at an Apple store. "I never let a moment go to waste."
Shipp starred in her high school musicals and dreamed of auditioning on Broadway, until her lungs got so bad that she gave up singing and dancing.
But since she started taking an experimental drug as part of a closely watched clinical trial, her outlook has changed. The drug, called ivacaftor, cleared her lungs and allowed her to add a healthy 15 pounds to her 5-foot, 100-pound frame. On the day in February of last year when a regular checkup revealed her lungs were functioning at 96% — bringing her to essentially the same level as a healthy person — Shipp collapsed on a bench outside the hospital and sobbed with relief. "I realized I would have a full life at that moment," she said.
The trial results, published in Thursday's edition of the New England Journal of Medicine, showed that ivacaftor reduced the incidence of pulmonary exacerbations — sudden, serious flare-ups that can send patients to the hospital and cause irreversible lung damage — by 55% compared with a placebo. The study of 161 patients also found that patients who took the drug saw their lung function improve 10.4% and gained nearly 6 pounds over 48 weeks.
"This is exciting work," said Michael Welsh, a pulmonary physician at the University of Iowa who was not involved in the study. "I think that it is very promising for the people who have this particular mutation, and it may turn out to have broader significance."
Ivacaftor affects a genetic mutation in 4% to 5% of cystic fibrosis patients that prevents a protein called CFTR from allowing enough chloride ions to exit a certain type of cell. Chloride, when coupled with sodium to make salt, helps regulate the flow of water in the body. When that channel doesn't work, the lungs dry up and the once-protective mucus grows thick and immovable, providing an ideal breeding ground for bacteria.
This salt imbalance affects the pancreas and digestive tract, so patients are often small and malnourished. The sweat glands don't work properly either, leading to overly salty skin.
The drug helps that chloride gateway stay open, restoring the salt balance in the body. It is the first therapy that fixes the basic problem that causes the disease, not just the symptoms, said study coauthor Michael Konstan, a pediatric pulmonologist at Case Western Reserve University School of Medicine in Cleveland.
"The goal is if you would give a therapy like this before [the lungs deteriorate], you can prevent lung disease from developing," Konstan said.
The drug can't yet help the vast majority of cystic fibrosis sufferers: About 90% of them have a mutation in which the protein, once manufactured inside the cell, never even makes it to the cell surface where it is supposed to act as a chloride channel. Researchers are trying to develop drugs that would help bring that protein to the surface. Once a patient is on such a drug, ivacaftor could then pick up the process from there.
"It's creating such a sense of hope and optimism for all the cystic fibrosis patients because this approach will work," said Robert Beall, president and chief executive of the Bethesda, Md.-based Cystic Fibrosis Foundation, which has spent millions funding such research.
cystic fibrosis dating
Although therapies to fight the disease seemed to be around the corner when the CFTR gene was discovered in 1989, it took more than two decades to develop a treatment based on the genetic defect.
"This timeline suggests that much of the promise of the Human Genome Project has yet to be fulfilled and that realizing the therapeutic benefits will take persistence and determination," Dr. Pamela Davis of Case Western wrote in an editorial accompanying the study. "Society cannot allow support for research and development to be compromised in the current rush to cut the federal budget."
If all goes smoothly, ivacaftor may be approved by the Food and Drug Administration in 2012, said study lead author Bonnie Ramsey, a pediatric pulmonologist at Seattle Children's Hospital. The study was partially funded by ivacaftor's maker, Vertex Pharmaceuticals Inc. of Cambridge, Mass., which plans to market it under the name Kalydeco.
cystic fibrosis symptoms
The drug is not an absolute cure. It cannot rid the body of bacterial infections that stick around even after mucus has been cleared from the lungs. But perhaps, if given to patients that were young enough — say, newborns — it could allow them to live an essentially normal life.
As for Lindsay Shipp, who will be singing at the Cystic Fibrosis Conference in Anaheim this week — a downtempo cover of Katy Perry's "Firework" and "Thank You for the Music," from the musical "Mamma Mia!" — the girl who once gave up her dreams of Broadway now thinks she might fly to New York and audition.
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