Breakthrough drug Kalydeco targets faulty protein to treat rare form of cystic fibrosis . A drug that targets the underlying cause of a rare form of cystic fibrosis (CF), the first medication of its kind, was recently approved by the U.S Food and Drug Administration.
On Jan. 31, the FDA approved the twice-daily pill Kalydeco (ivacaftor) for the treatment of a rare form of CF in patients ages six years and older who have the specific G551D mutation in the Cystic Fibrosis Transmembrane Regulator (CFTR) gene. The drug targets that defective CFTR protein, the underlying cause of their disease.
“Kalydeco is the first available treatment that targets the defective CFTR protein, which is the underlying cause of cystic fibrosis,” says Janet Woodcock, M.D., FDA’s Center for Drug Evaluation and Research director, in a news release. “This is a breakthrough therapy for the cystic fibrosis community because current therapies only treat the symptoms of this genetic disease.”
A serious genetic disorder affecting the lungs and other organs, cystic fibrosis eventually leads to an early death. Afflicting about 30,000 people in the United States, it’s the most common fatal genetic disease among Caucasians.
Aggressive treatments addressing the disease’s symptoms have helped stretch the average lifespan for CF patients over the years. But most still don’t live beyond their 30s and 40s.
Target: one specific protein in one specific CF mutation
About four percent of those with CF, or some 1,200 people, are believed to have the G551D mutation. This mutation involves a protein called CFTR that regulates the transport of ions like chloride, as well as water, in the body.
Defective transport of chloride and water causes thick mucus to builds up in the lungs, digestive tract and other parts of the body — leading to severe respiratory and digestive problems, and complications like infections and diabetes.
Kalydeco is only effective in people with the rare form of CF involving the G551D mutation. It isn’t effective in patients with the more common form of cystic fibrosis, in which patients have a CFTR gene that bears two copies of the F508 mutation.
To determine whether it’s the G551D mutation that’s causing the CF, an FDA-cleared CF mutation test should be used.
In patients with the G551D mutation, Kalydeco, taken twice a day with fatty food, helps the protein made by the CFTR gene function better. This improves lung function and helps induce weight gain—a desirable issue in CF patients who often lose a lot of weight.
Right now, Kalydeco has been approved for use only in patients six years old and older. But Vertex is planning to study the drug’s effectiveness in younger children. The drug maker is also looking at how to treat cystic-fibrosis patients with different mutations, as well as probing how effective the drug will be when combined with other medications.
Fast-track approval for orphan drug
To gain approval, Vertex enrolled 213 patients in two 48-week, placebo-controlled clinical studies—one for patients 12 years old and above and the other study for patients ages six years to 11 years.
Both studies, used to evaluate the safety and efficacy of Kalydeco in CF patients with the G551D mutation, showed that treatment with Kalydeco brought significant and sustained improvement in lung function.
This was enough for the FDA to approve Kalydeco ahead of schedule. The CF pill was approved under the agency’s priority six-month review program, offered for drugs that pose significant treatment advances over available therapies. Normally, the FDA takes 10 months to approve a drug and the drug’s prescription user fee goal date is April 18, 2012.
The CF medication is designated as an “orphan drug” meant for disease as affecting fewer than 200,000 people in the U.S.
High liver enzymes in the blood have been reported in patients receiving Kalydeco, so doctors will have to do blood tests on people taking Kalydeco to check their liver function. Tests will be done before taking the drug, every three months during the first year of taking Kalydeco, and every year while you are taking Kalydeco.
Kalydeco’s most common side effects include upper respiratory tract infection, headache, stomachache, rash, diarrhea, and dizziness.
Targeting the right mechanism
“Kalydeco is an excellent example of the promise of personalized medicine—targeted drugs that treat patients with a specific genetic makeup,” says FDA Commissioner Dr. Margaret A. Hamburg in a news release.
While the gene responsible for cystic fibrosis was identified in 1989, progress in drug development comes only now, more than 20 years after.
Pinpointing the gene was only the first step. Scientists had to come up with a hypothesis as to how the defective gene actually causes the disease, then devise a way to address the problem.
A substance made by tissues, mucus lines some organs and body cavities, such as the lungs and nose. Normally a slippery, watery substance, it keeps the linings of certain organs moist and prevents them from drying out or getting infected.
But in people with CF, thick and sticky mucus builds up in their lungs and blocks their airways. Mucus buildup also makes it easy for bacteria to grow, leading to serious and repeated lung infections that can damage the lungs over time. In fact, respiratory failure is the most common cause of death in people who have CF.
The thick, sticky mucus also block ducts in the pancreas, stopping digestive enzymes produced in this organ from reaching the small intestine. Because these enzymes help break down food, without them, the intestines can’t fully absorb fats and proteins. Since nutrients end up passing through the body without being used, patients suffer from vitamin deficiency and malnutrition.
CF also causes sweat to become very salty—and patients end up losing large amounts of salt. This upsets the balance of minerals in the blood, causing dehydration, increased heart rate, fatigue, weakness, decreased blood pressure, heat stroke and—rarely–death.
Some scientists believe that the CFTR gene makes the channels that carry chloride in cells up to airways, where it’s needed to clear mucus that builds up. Mutations in this gene impede the flow of chloride, causing the mucus to accumulate and impeding the hair-like cilia from beating back and forth to clear out the mucus.
When attempts to use gene therapy to replace the mutated gene didn’t work, researchers turned to drugs to help chloride to reach the airways.
Other drug makers have experimental therapies at various stages in the development pipeline.
Model for future medicines
“Kalydeco presents an excellent example of the future of personalized medicine,” says Dr. Stephen P. Spielberg, FDA’s Deputy Commissioner for Medical and Tobacco in a video on the breakthrough the FDA’s website.
“It’s also a part of a revolution of how we will treat patients in the future using increasingly targeted, personalized treatment,” he says.
“This medicine represents the skillful application of basic genetic science: Understanding at the molecular level why the protein doesn’t work properly. Then discovering and developing a medicine specifically targeted to improve the function of that protein…” he enthuses. “And then, to do a clinical trial using a genetic test to select the right patients to participate in that trial.”
“The success of this trial hopefully will lead to more the development of new medicines to address the more common genetic mutations that cause CF and also serve as a model for the development of medicines for other conditions,” he concludes.
Kalydeco do’s and don’ts
DO know the medicines you take.
DO tell your doctor about all the medicines you take.
DO ask your doctor or pharmacist for a list of these medicines if you are not sure.
DO keep a list of them to show your doctor and pharmacist when you get a new medicine.
DON’t take Kalydeco if you take certain medicines or herbal supplements such as:
• the antibiotics rifampin (Rifamate, Rifater) or rifabutin (Mycobutin)
• seizure medications such as phenobarbital, carbamazepine (Tegretol, Carbatrol, Equetro) or phenytoin (Dilantin, Phenytek)
• St. John’s Wort
DO talk to your doctor before taking Kalydeco, if you take any of the medicines or supplements listed above.
DO tell your doctor what medications you are taking, including prescription and nonprescription medicines, vitamins and herbal supplements. Kalydeco may affect the way other medicines work, and other medicines may affect how Kalydeco works. The dose of Kalydeco may need to be adjusted when taken with certain medications.
DO take special care to tell your doctor if you take:
• antifungal medications such as ketoconazole (e.g., Nizoral), itraconazole (e.g., Sporanox), posaconazole (e.g., Noxafil), voriconazole (e.g., Vfend), or fluconazole (e.g., Diflucan)
• antibiotics such as telithromycin (e.g., Ketek), clarithromycin (e.g., Biaxin), or erythromycin (e.g., Ery-Tab)
DO tell your doctor if you:
• have kidney or liver problems
• eat grapefruit or Seville oranges or drink grapefruit juice
• are pregnant or plan to become pregnant. It isn’t known if Kalydeco will harm your unborn baby. You and your doctor should decide if you will take Kalydeco while you are pregnant.
• are breastfeeding or plan to breastfeed. It isn’t known if Kalydeco passes into your breast milk. You and your doctor should decide if you will take Kalydeco while you are breastfeeding.
When taking Kalydeco
DO take Kalydeco exactly as your doctor tells you to take it.
DO take Kalydeco with fatty food—always. Examples of fat-containing food include butter, peanut butter, eggs, cheese, pizza, etc.
DO take your doses of Kalydeco 12 hours apart.
DON’T drive a car, use machinery or do anything that needs you to be alert until you know how Kalydeco affects you. Kalydeco can cause dizziness in some people who take it.
DON’T eat food containing grapefruit or Seville oranges while you are taking Kalydeco.
Serious side effects
High liver enzymes in the blood have been reported in patients receiving Kalydeco.
Your doctor will do blood tests to check your liver:
• before you start Kalydeco
• every 3 months during your first year of taking Kalydeco
• every year while you are taking Kalydeco
DO call your doctor right away if you have any of the following symptoms of liver problems:
• pain or discomfort in the upper right stomach (abdominal) area
• yellowing of your skin or the white part of your eyes
• loss of appetite
• nausea or vomiting
• dark, amber-colored urine
Common side effects of Kalydeco include:
• upper respiratory tract infection (common cold), including:
• sore throat
• nasal or sinus congestion
• runny nose
• stomach (abdominal) pain
DO tell your doctor if you have any side effect that bothers you or that doesn’t go away.
These are not all the possible side effects of Kalydeco. For more information, ask your doctor or pharmacist.
DO call your doctor for medical advice about side effects.
DO report side effects to FDA at 1 800-FDA-1088, if you wish.