The U.S. Food and Drug Administration (FDA) has approved Kalydeco for patients ages 4 months and older with one of 38 genetic mutations. In the EU, the European Commission (EC) also approved the treatment for the same age groups. Kalydeco is available in more than 40 countries. However, the patients’ ages and mutations may vary.
How does Kalydeco work?
Mutations in the CFTR gene cause cystic fibrosis. The product of this gene is a protein channel that mucus-producing cells make. This channel has a “gate” that can open and close to control the movement of charged salts, such as chloride and sodium, in and out of cells. The level of these salts in the cell influences the movement of water. When the protein channel does not function properly, sticky mucus builds up in various organs.
There are many different types of CFTR mutations that cause cystic fibrosis. A gating mutation results in the production of a faulty CFTR protein that can cause the “gate” to be stuck closed.
Researchers designed Kalydeco to treat cystic fibrosis patients with this particular type of mutation. It works by keeping the CFTR gate open for longer at the cell surface. This eases the transport of salts and water in and out of cells to improve hydration and mucus clearance. In other words, it acts to enhance the activity of the CFTR protein.
The treatment does not increase the amount of CFTR protein that cells produce. This means that it is ineffective for the most common form of cystic fibrosis, which is caused by a mutation known as F508del and results in cells producing little or no CFTR protein.
Kalydeco was the first therapy that addresses the underlying cause of cystic fibrosis, rather than treating the disease’s symptoms.
Kalydeco in clinical trials
The FDA initially approved Kalydeco in January 2012 to treat cystic fibrosis patients, ages 6 and older, with a single type of gating mutation called G551D. This approval was based on the results of two randomized, double-blind, placebo-controlled clinical trials: STRIVE (NCT00909532) and ENVISION (NCT00909727).
In both trials, researchers treated patients with 150 mg of Kalydeco or a placebo twice a day, together with their usual therapies. The results supported Kalydeco’s safety and superiority in improving lung function as measured by FEV1. (FEV1 is the amount of air a person can forcibly exhale in one second). Improvements persisted through 48 weeks of follow-up.
Five years later, in August 2017, the FDA approved Kalydeco for cystic fibrosis patients, ages 2 and older, who have one of an additional five mutations in the CFTR gene. Those mutations result in a splicing defect, causing a moderate loss of chloride transport. Patients with these mutations experience a progressive decline in lung function and other complications.
This new approval was based on the results of the Phase 3 EXPAND study (NCT02392234), in which Kalydeco was used as a monotherapy and was generally well-tolerated.
EXPAND was an eight-week crossover study that also evaluated the effect of a combination therapy of Kalydeco with tezacaftor in people with a mutation that results in residual CFTR function and an F508del mutation. The study, which met its primary objectives, led to improvements in lung function in patients receiving the combination treatment as well as Kalydeco monotherapy. This trial also helped to support the subsequent approval of Symdeko (tezacaftor/ivacaftor).
Ongoing clinical trials
Researchers are currently investigating Kalydeco in an open-label, Phase 3 clinical trial (NCT02725567), called ARRIVAL, that launched in 2016. ARRIVAL is continuing to enroll up to 35 infants and toddlers — children from newborns to 24 months old — with cystic fibrosis and one of 10 CFTR gating mutations. More information on enrollment is available here.
The trial, expected to conclude in July 2022, is testing the treatment’s safety, pharmacokinetics (movement in the body), and pharmacodynamics (effect on the body).
Initial results from ARRIVAL were published in The Lancet Respiratory Medicine, in November 2020. Involving 19 children, ages 12-24 months who completed six months of treatment, these early results showed Kalydeco to be well-tolerated and associated with a quick and significant (almost threefold) reduction in sweat chloride. No one discontinued treatment because of safety concerns. The most common side effects included coughing, fever, increased liver enzyme levels, and a runny nose.
Based on these results, the FDA approved Kalydeco in August 2018 to treat cystic fibrosis patients, ages 12 to 24 months, with any of these 10 mutations. The EC followed with the same decision in November 2018.
Further data from the ARRIVAL study lead to the FDA expanding the use of Kalydeco to include younger children — ages 6 months to a year old, weighing 5 kg or more — in May 2019. This expansion included all 9 mutations previously approved for children under age 18. The EC also expanded the use of Kalydeco in December 2019 to include children as young as 6 months.
Following continuing results from the ARRIVAL study, the FDA in September 2020 approved Kalydeco for use in infants as young as age 4 months. The EC in November 2020 also expanded the age range to 4 months and older in Europe.
In the U.S. and Europe, Kalydeco is available as a 150 mg tablet for patients ages 6 and older. For children younger than age 6, Kalydeco is available as 25, 50, and 75 mg oral granule packets. Treatment with Kalydeco is not effective in cystic fibrosis patients who have two copies of the F508del mutation in the CFTR gene.
Ivacaftor, the active ingredient of Kalydeco, is also a part of Orkambi, a combination therapy that includes lumacaftor, Symdeko, a combination that includes tezacaftor, and Trikafta, a combination that includes tezacaftor and elexacaftor.
Headaches, upper respiratory tract infections, stomach pain, and diarrhea are some of the common side effects of Kalydeco. The medication’s label warns about the risk of elevated levels of liver enzymes, called transaminases, as well as cataracts in children.
Last updated: Nov. 10, 2020
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