New Drug Targets Underlying Cause of Cystic
WEDNESDAY, Nov. 2 (HealthDay News) -- A new drug that targets a
faulty protein that causes cystic fibrosis led to improved lung
function and fewer symptoms in people with the lung disease,
The drug -- ivacaftor -- 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
"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
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
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
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.
"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.
Foundation has more on the disease.
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