The FDA has expanded the approved use of ivacaftor (Kalydeco, Vertex Pharmaceuticals) for treating cystic fibrosis. The approval triples the number of rare gene mutations that the drug can now treat, expanding the indication from the treatment of 10 mutations to 33. The agency based its decision, in part, on the results of laboratory testing, which it used in conjunction with evidence from earlier human clinical trials. The approach provides a pathway for adding additional, rare mutations of the disease, based on laboratory data.
“Many rare cystic fibrosis mutations have such small patient populations that clinical trial studies are not feasible,” said Janet Woodcock, MD, director of the FDA’s Center for Drug Evaluation and Research. “This challenge led us to using an alternative approach based on precision medicine, which made it possible to identify certain gene mutations that are likely to respond to Kalydeco.”
Cystic fibrosis affects the cells that produce mucus, sweat, and digestive juices. These secreted fluids are normally thin and slippery due to the movement of sufficient ions (chloride) and water in and out of the cells. People with the progressive disease have a defective cystic fibrosis transmembrane conductance regulator (CFTR) gene that can’t regulate the movement of ions and water, causing the secretions to become sticky and thick. The secretions build up in the lungs, digestive tract, and other parts of the body leading to severe respiratory and digestive problems, as well as other complications such as infections and diabetes.
Results from an in vitro cell-based model system have been shown to reasonably predict clinical response to ivacaftor. When additional mutations responded to ivacaftor in the laboratory test, researchers were thus able to extrapolate clinical benefit demonstrated in earlier clinical trials of other mutations. This resulted in the addition of gene mutations for which the drug is now indicated.
Kalydeco, available as tablets or oral granules taken two times a day with fat-containing food, helps the protein made by the CFTR gene function better and as a result, improves lung function and other effects of cystic fibrosis, including weight gain. If the patient’s genotype is unknown, an FDA-cleared cystic fibrosis mutation test should be used to detect the presence of a CFTR mutation followed by verification with bidirectional sequencing when recommended by the mutation test instructions for use.
Cystic fibrosis is a rare disease that affects about 30,000 people in the United States. Ivacaftor is indicated for patients 2 years of age and older who have one mutation in the CFTR gene that is responsive to drug treatment based on clinical and/or in vitro (laboratory) data. The expanded indication will affect another 3% of the cystic fibrosis population, impacting approximately 900 patients. Ivacaftor serves as an example of how successful patient-focused drug development can provide greater understanding about a disease. For example, the Cystic Fibrosis Foundation maintains a 28,000-patient registry, including genetic data, which it makes available for research.
Common side effects of ivacaftor include headache; upper respiratory tract infection (common cold) including sore throat, nasal or sinus congestion, or runny nose; stomach (abdominal) pain; diarrhea; rash; nausea; and dizziness. Ivacaftor is associated with risks including elevated transaminases (various enzymes produced by the liver) and pediatric cataracts.
Source: FDA; May 17, 2017.