Theragenomics: Ivacaftor (Kalydeco) in the CFTR mutation-based treatment of cystic fibrosis (CF)

Theragenomics: Ivacaftor (Kalydeco) in the CFTR mutation-based treatment of cystic fibrosis (CF)

Last Updated on May 19, 2017 by Joseph Gut – thasso

May 18, 2017 – Ivacaftor (Kalydeco) is a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator indicated for the treatment of cystic fibrosis (CF) in patients age 2 years and older who are carriers one of the following mutations in the CFTR gene: G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549NS549R, or R117H. In contrast, Ivacaftor (Kalydeco) is not effective, and therefore not indicated, in patients with CF who are homozygous for the F508del mutation in the CFTR gene.
What Happens During Cystic Fibrosis Testing? There is no cure for cystic fibrosis (CF). Testing can help doctors diagnosis CF and start targeted treatment. Early if ever possible.

Since it’s first approval in 2012, Ivacaftor (Kalydeco) has been a pioneering principle for theragenomic medicine, that is, the use of a medicine in a therapy guided by specific genomic/genetic knowledge about either the disease itself,  the patient as such, or both. In the present case, genetic information is used to distinguish between responders to the therapy (i.e., the  carriers of the according CTFR mutations) and the non-responders (i.e., the carriers of the CFTR F508del mutation). It is only this week that the American Food & Drug Administration today expanded the approved use of Kalydeco (ivacaftor) for treating cystic fibrosis. The approval triples the number of rare CFTR gene mutations that the drug can now treat, expanding the indication from the treatment of the above 10 CFTR gene mutations to 33 CFTR gene mutations.

According to their communication, the agency based its decision, in part, on the results of laboratory testing. In this particular case with CFTR, cellular test systems in vitro can be used to test the function (molecular phenotype) of the CFTR gene when present in the test system in the form of one of its mutations (molecular genotype). In the case of cystic fibrosis, the observed molecular phenotype translates into the clinical phenotype, that is, the patient presents with overt disease (i.e., cystic fibrosis) caused by the observed molecular phenotype. Here, the results from the in vitro cell-based model system reasonably predicted clinical response to Ivacaftor (Kalydeco). Overall, when combined with evidence from earlier human clinical trials, the approach provides a pathway for identifying (rare) CFTR mutations amenable to clinical treatment based on laboratory data without the need for extended clinical trials involving patients who are carriers of a given rare CFTR-mutation.

This is important since many of these rare CFTR mutations have such a small patient population associated with it (i.e., carriers of that given mutation) that statistically sufficiently powered clinical trial studies are simply not feasible or not sufficiently informative. In clinical practice and the setting of theragenomic medicine, if the patient’s

Cystic Fibrosis (CF). Possibly dead at 18.

genotype is unknown, an FDA-cleared CF mutation test should be used to detect the presence of a CFTR mutation followed by, if necessary, verification with bi-directional sequencing when recommended by the mutation test instructions for use, in oder to guide the cystic fibrosis (CF) therapy decisions.

Cystic fibrosis (CF) 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. Ivacaftor (Kalydeco) helps the protein made by the CFTR gene function better and as a result, improves lung function and other aspects of cystic fibrosis, including weight gain. Overall, CF is a rare disease that affects about 30,000 people in the US, and, of course, many more worldwide. The expanded indication will affect another 3 percent of the CF patient population in the US, impacting approximately 900 patients.

Ivacaftor (Kalydeco) continues to serve as an example of how successful patient-focused drug development in the precision medicine frame can provide greater understanding about a disease. For CF, the Cystic Fibrosis Foundation maintains a 28,000-patient registry, including genetic data, which it makes available for research and greatly and effectively supports these efforts.

For the diehardetly interested in theragenomic medicine, be it patient or treating physician, you find here the list of all 33 CFTR gene mutations that are responsive to Ivacaftor (Kalydeco) and are now newly included in the indication of Ivacaftor (Kalydeco):  E56K, G178R, S549R, K1060T, G1244E, P67L, E193K, G551D, A1067T, S1251N, R74W, L206W, G551S, G1069R, S1255P, D110E, R347H, D579G, R1070Q, D1270N, D110H,  R352Q, S945L, R1070W, G1349D, R117C, A455E, S977F, F1074L, R117H, S549N, F1052V, D1152H, and G1349D (see the new FDA Ivacaftor (Kalydeco) drug label here).


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Ph.D.; Professor in Pharmacology and Toxicology. Senior expert in theragenomic and personalized medicine and individualized drug safety. Senior expert in pharmaco- and toxicogenetics. Senior expert in human safety of drugs, chemicals, environmental pollutants, and dietary ingredients.

1 Comment on “Theragenomics: Ivacaftor (Kalydeco) in the CFTR mutation-based treatment of cystic fibrosis (CF)

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