Approved CF med can also lessen airway inflammation, study finds
Still, individualized treatment approaches urged for patients
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Use of Trikafta, an approved oral medication for cystic fibrosis (CF), can reduce airway inflammation — known to exacerbate symptoms — in people with the genetic disease, a new study demonstrates.
However, after a year of treatment, CF patients on Trikafta still show differences in airway inflammation compared with what’s seen in people without CF, the researchers noted.
The findings suggest that individualized treatment approaches may be needed to fully normalize airway inflammation in people with CF, according to the team.
The study, “CFTR modulator therapy reshapes airway inflammation in cystic fibrosis: Insights from proteomics and machine learning,” was published in the Journal of Cystic Fibrosis.
CF is caused by mutations in the gene that encodes CFTR, a protein that’s vital for normal mucus production. Lacking functional CFTR protein, people with CF produce abnormally thick and sticky mucus that builds up in the lungs and other organs to drive most disease symptoms.
Inflammation broadly refers to activation of the immune system, which normally fights infections. In CF, the buildup of mucus in the lungs — paired with the high risk of respiratory infections — often leads to chronic inflammation in the airways.
Trikafta eases inflammation, but does not normalize ‘airway biology’
CFTR modulators are a class of therapies that work to improve the functionality of defective CFTR protein in people with CF caused by certain mutations. Trikafta contains a combination of three such modulators — elexacaftor, tezacaftor, and ivacaftor — and is widely approved to treat patients with eligible mutations.
Clinical trials have demonstrated that Trikafta treatment can help normalize mucus production and improve lung function in eligible CF patients. However, not much is known about how Trikafta affects airway inflammation.
To learn more, scientists in Sweden analyzed samples of sputum, or phlegm coughed up from the lungs, collected from 30 people with CF. Sputum samples were taken at three timepoints: before starting Trikafta, after three months of treatment, and after 9-12 months of use. For comparison, sputum samples from seven people without CF were also analyzed.
Airway inflammation in CF typically is characterized by increased activity of neutrophils, a specific type of immune cell. The researchers found that neutrophil activity tended to decrease among the CF patients after starting Trikafta.
Another feature of airway inflammation in CF is a disruption of the balance between two types of enzymes: proteases and anti-proteases. Proteases are enzymes that act to break down damaged proteins — a process that’s important for wound healing — while anti-proteases stop proteases from acting in ways that could be damaging to healthy tissues.
In CF, there is often too much protease activity and not enough anti-protease activity. But the researchers found that levels of key anti-proteases increased following Trikafta treatment.
Levels of other immune-related proteins, such as interleukin-1beta, interleukin-8, and TNFalpha, were also altered after starting Trikafta. That broadly indicates a shift toward less inflammation following treatment, according to the scientists.
However, the researchers noted that, even with all these changes, individuals with CF on Trikafta still showed evidence of abnormal inflammation relative to what was seen in people without the condition.
The team concluded that Trikafta treatment “leads to reduced neutrophilic inflammation, improved protease/anti-protease balance, and a significant remodelling of the airway [proteins] in [people with] CF.” Still, “despite these improvements, [inflammatory protein] profiles remain distinct from those of healthy controls, highlighting persistent airway inflammation and the need for individualized therapeutic approaches,” the scientists wrote.
Overall, use of the therapy for a year showed benefits in easing inflammation, “but does not fully normalise airway biology,” the team wrote.
Trikafta is sold by Vertex Pharmaceuticals, which was not involved with this study.
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