Using Trikafta may shield CF patients from lung damage: Study
Beyond lung function gains, long-term treatment seen to curb inflammation
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Treatment with Trikafta (elexacaftor/tezacaftor/ivacaftor) may do more than improve the function of a faulty protein in people with cystic fibrosis (CF). According to a new study from Italy, the triple-combination therapy may also help reduce chronic inflammation, known to contribute to long-term lung damage in those with CF.
The data showed that, in addition to its well-established benefits for lung function and nutritional status, Trikafta lowered several markers of inflammation in CF patients with advanced lung disease.
The researchers noted that these effects may be partly lessened by Trikafta’s ability to lower activation of proteins in the JAK/STAT signaling pathway, which is known to mediate inflammatory responses.
Still, “long-term [Trikafta] treatment confirms clinical benefits and exerts measurable immunomodulatory effects, partially via inhibition of JAK/STAT signaling,” the team wrote, noting that “these findings support [Trikafta’s] broader impact” beyond its well-documented lung function gains.
Per the team, “further studies are warranted to explore long-term immunological outcomes, especially in younger patients initiating early therapy.”
The study, “Modulation of immune responses by elexacaftor/tezacaftor/ivacaftor therapy in cystic fibrosis: data from a compassionate use program,” was published in the journal Respiratory Research.
CF is caused by mutations in the CFTR gene, which makes a protein of the same name that controls the movement of certain salt molecules and water in and out of cells. When CFTR doesn’t work properly, thick, sticky mucus builds up in the lungs — where it leads to shortness of breath and frequent respiratory infections — and in the digestive tract, limiting nutrient absorption.
Chronic inflammation helps drive lung disease in those with CF
Lung disease in people with CF is also driven by a chronic inflammatory state. Even in the absence of infection, airway immune cells continuously release inflammatory molecules, creating a cycle of immune activation that contributes to progressive lung damage.
Trikafta, marketed by Vertex Pharmaceuticals, is a CFTR modulator approved in the U.S. for use in patients 2 and older who carry at least one copy of F508del or another CF-causing mutation responsive to treatment.
Clinical trials and real-world studies have shown that Trikafta improves lung function and nutritional status while also reducing pulmonary exacerbations, or flare-ups of lung symptoms. Such exacerbations are often triggered by infections and typically require antibiotic treatment.
However, the researchers wrote, “despite these clinical advances, it remains unclear whether [Trikafta] therapy can effectively modulate the chronic inflammatory state characteristic of CF.”
To investigate this further, a team of scientists in Italy followed 49 adults with CF who began treatment with Trikafta through a compassionate-use program — a pathway that allows patients to access promising therapies before they are fully approved — between October 2019 and June 2021.
The participants, who had a mean age of 36.3, were monitored for 24 months, or about two years. Most had advanced lung disease.
Consistent with previous studies, Trikafta led to significant improvements in lung function and nutritional status. Treatment also significantly reduced the amount of chloride in sweat — typically high in people with CF — and the number of intravenous, or into-the-vein, antibiotic treatments needed. These benefits were sustained throughout the follow-up period.
Blood tests also showed signs of reduced inflammation. Levels of C-reactive protein, a marker of inflammation, dropped significantly after one year and remained near normal at two years. Total white blood cell counts declined as well, particularly monocytes and lymphocytes, immune cells often elevated in chronic inflammatory conditions.
These results support a partial but sustained anti-inflammatory effect [of Trikafta in people with CF].
Trikafta also lowered levels of six proinflammatory molecules found at higher levels in blood samples of people with CF compared with healthy individuals of similar age.
“These results support a partial but sustained anti-inflammatory effect” of Trikafta in people with CF, the researchers wrote.
Trikafta shows anti-inflammatory effects in 2 cell types
The team then examined signaling pathways in blood immune cells collected from three patients, both before and three months after starting treatment. They found Trikafta reduced activation of STAT5 and STAT2, proteins involved in the JAK/STAT pathway.
Treatment also reduced levels of three proinflammatory molecules regulated by STAT5, which were among the six previously found to be strongly lowered in patients’ blood samples after starting Trikafta.
The researchers noted that three of four patients who showed clear drops in STAT2 and STAT5 activity in blood immune cells after treatment with Trikafta also experienced marked improvements in lung function.
Trikafta’s anti-inflammatory effects were not limited to blood immune cells. In airway cell models carrying the CF-causing F508del mutation, Trikafta lowered STAT5 activation to levels closer to those seen in healthy airway cells, the researchers noted.
In these same CF airway cells, ruxolitinib — a drug that blocks JAK/STAT signaling — reduced levels of STAT5-regulated proinflammatory molecules in a pattern similar to that seen in patients’ blood immune cells after treatment with Trikafta, strengthening evidence that this pathway plays an important role in CF-related inflammation.
“Collectively, these findings identify STAT5 as a previously unrecognized driver of CF inflammation and support the development of adjunct therapies that combine CFTR modulation with anti-inflammatory targeted strategies to curb extra-pulmonary complications and long-term decline in [people with CF],” the researchers wrote.
