Ivacaftor essential component of CF treatment Trikafta, study finds
Part of triple-combination therapy, it plays role in restoring mucus clearance
Ivacaftor, a component of the triple-combination therapy Trikafta, is essential to restore mucus clearance in people with cystic fibrosis (CF), a study reports.
The study was launched after previous work using CF airway cells suggested that long-term exposure to ivacaftor limited the restoration of CFTR, the protein that’s faulty or absent in CF patients. However, researchers demonstrated that different cell culture conditions profoundly affected Trikafta-mediated CFTR restoration.
“These findings have important implications for the use of patient-derived airway models for future development of novel CFTR modulators, as well as personalized medicine approaches for patients with CF,” scientists concluded.
The study, “The potentiator ivacaftor is essential for pharmacological restoration of F508del-CFTR function and mucociliary clearance in cystic fibrosis,” was published in JCI Insight.
CFTR helps maintain balance of salt, water on body surfaces
CFTR is a channel protein that regulates the flow of chloride ions across cell membranes and helps maintain the balance of salt and water on many body surfaces. In CF, genetic mutations disrupt the production or function of the CFTR protein, which alters salt-water balance and leads to the buildup of thick, sticky mucus in various organs.
CFTR modulators are a class of medications designed to correct faulty CFTR, and are classified as either correctors or potentiators. Correctors help correct CFTR production defects so that more protein reaches the cell surface, while potentiators help keep the channel protein open, allowing the flow of more chloride ions.
Apart from the potentiator ivacaftor, sold on its own as Kalydeco, all other approved CFTR modulators are combinations of correctors and potentiators.
Trikafta, marked as Kaftrio in Europe, is a triple-combination of tezacaftor, elexacaftor, and ivacaftor. In the U.S., it’s approved for CF patients with at least one F508del mutation, the most common CF-causing genetic defect, or another CFTR gene mutation that’s responsive based on clinical and/or lab test data. Both clinical trials and real-world studies demonstrate the triple combination’s ability to improve patients’ lung function.
However, previous studies using CF airway cell lines indicate that long-term treatment with the potentiator ivacaftor can destabilize the CFTR protein with F508del, thus limiting the restoration of chloride channel function.
Scientists in Germany study effects of ivacaftor
To investigate further, scientists in Germany examined the acute versus chronic effects of ivacaftor, as part of triple-combination therapy, in rescuing the function of the F508del-CFTR chloride channel.
The team started with CF bronchial epithelial cells, or those that line the airways, grown in a medium called UNC-ALI. Cells were treated with the correctors elexacaftor and tezacaftor (ET) alone or with ET plus the potentiator ivacaftor (ETI), like in Trikafta.
Acute treatment with ET and ETI rescued CFTR function compared with controls, as determined by chloride secretion. The researchers then confirmed that long-term ETI treatment decreased CFTR activity by about 40% and reduced the amount of mature CFTR protein at the cell surface by about 30%, in comparison with ET.
The scientists performed similar experiments with CF-derived nasal cells grown on an air-liquid interface using the UNC-ALI medium and a different medium called PneumaCult. Consistent with the first experiments, long-term exposure to ivacaftor limited CFTR rescue by ETI when grown in the UNC-ALI medium. When cells were grown in the PneumaCult medium, however, both ET and ETI successfully rescued the activity of F508del-CFTR.
These findings, which demonstrate that ETI rescue of CFTR depends on the cell context and the growth media, “have important implications for preclinical testing of CFTR modulators in patient-derived primary airway culture models for CF drug development,” the team wrote.
The researchers then compared the impact of ET and ETI on mucus properties and clearance using CF-derived nasal cells grown in the PneumaCult medium. Treatment with ETI, but not ET, significantly restored the mucus layer on cell surfaces and enhanced mucus clearance compared with controls. When added to the ET-treated cells, ivacaftor boosted mucus clearance to match the level found in ETI-treated cultures.
Although a previous study showed that the corrector elexacaftor in Trikafta also has potentiator properties, these data suggest that “the potentiator potency of elexacaftor is substantially lower than that of ivacaftor,” the researchers wrote.
To confirm these results in people, nasal chloride secretion was measured in nine healthy individuals and 27 CF patients carrying at least one F508del mutation before and after ETI therapy. As expected, chloride flow was significantly reduced in CF patients compared with healthy individuals before ETI. However, chloride flow was partially restored in CF patients on ETI therapy to about 50% of the normal values.
“These results demonstrate that ivacaftor as a component of ETI therapy is essential to restore mucociliary clearance and suggest that this effect is facilitated by its constitutive activation of F508del channels,” the scientists wrote.
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