Having two Trikafta-responsive mutations boosts CF drug’s effects
Study: These children more likely to have sweat chloride levels in normal range
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Children with cystic fibrosis who carry two Trikafta-responsive mutations are significantly more likely to reach normal or near-normal sweat chloride levels, suggesting stronger restoration of CFTR protein function than children with one responsive and one nonresponsive mutation, according to a real-world study.
While this biochemical benefit ultimately did not translate into significantly better lung function, improved growth measures, or fewer lung exacerbations requiring treatment with antibiotics over two years, researchers believe this may be due to the inclusion of a population diagnosed and treated at a young age, whose lung function and nutritional status were largely preserved at treatment initiation.
“In such individuals, the potential for significant improvement in traditional clinical endpoints … is limited by a ceiling effect,” researchers wrote in the study, “Genotype-dependent biochemical response to elexacaftor/tezacaftor/ivacaftor in children with cystic fibrosis: A 24-month real-world study,” which was published in the journal Respiratory Medicine.
Trikafta considered most effective CFTR modulator to date
CF is caused by mutations in the CFTR gene, which provides instructions for making the CFTR protein that helps move chloride and water in and out of cells. When this protein is missing or does not work properly, mucus becomes thick and sticky, leading to problems such as poor mucus clearance in the lungs, recurrent respiratory infections, pancreatic insufficiency, poor growth, and progressive lung damage.
CFTR modulators are medications designed to boost the activity of the defective CFTR protein in people with certain mutations. Trikafta, which contains a combination of three such modulators (elexacaftor, tezacaftor, and ivacaftor), is considered the most effective of these treatments to date. However, Trikafta requires that some CFTR protein be produced, meaning it is not expected to work for mutations that prevent protein production altogether.
Everyone inherits two copies of the CFTR gene, one from each biological parent, and CF develops when both copies carry disease-causing mutations. However, clinicians still have limited information about how well Trikafta works in children with one versus two CFTR mutations predicted to respond to the medication.
Groups differed most in sweat chloride concentration
To learn more, a team led by researchers in Italy aimed to compare real-world responses to Trikafta across these two patient groups, using standard measures such as sweat chloride levels, body mass index (a measure of body fat based on weight and height), and lung function.
The analysis included 80 children with CF, ages 6 to 18 years, who were treated with Trikafta at a CF center in Florence. All had at least one copy of the F508del mutation, the most common CFTR mutation. In addition, 53 had another CFTR mutation classified as responsive to the therapy, while 27 had one nonresponsive mutation.
The clearest difference between the groups was seen in sweat chloride concentration, a marker of CFTR protein function. Before treatment, both groups had similar sweat chloride concentrations, and less than 5% in each group had normal or near-normal chloride levels in sweat (below 30 milimoles/L).
But over the follow-up period, children with two Trikafta-responsive mutations always had significantly lower sweat chloride levels, and were more likely to reach near-normal sweat chloride levels than those with only one responsive mutation.
At the first follow-up, 3 to 6 months after starting treatment, 45.3% of those with two responsive mutations reached levels below 30 milimoles/L, compared with 3.7% of those with one responsive mutation — a difference that remained significant through up to two years of follow-up.
These findings highlight the importance of [genetic mutations] in predicting modulator response and support the use of SCC [sweat chloride concentration] as a sensitive endpoint for tracking CFTR modulation in children.
Other clinical outcomes, such as body mass index and lung function, did not differ significantly between the groups. The rate of lung exacerbations requiring antibiotics also showed no differences between groups.
The findings suggest that sweat chloride concentration “remains the most direct in vivo measure of CFTR function and is highly sensitive to modulator effects,” the researchers wrote. “It is likely that biochemical correction achieved in the 2 responsive variants group reflects greater CFTR restoration, which may confer long-term clinical benefits, such as the preservation of lung function over decades that would not be captured in short-term follow-up.”
A multivariate analysis, which accounted for multiple factors, confirmed that having two responsive CFTR mutations was independently associated with lower sweat chloride levels after Trikafta treatment.
After adjusting for age, sex, and initial sweat chloride levels, children with two responsive mutations had an average sweat chloride concentration about 30% lower than those with one responsive mutation. They also had markedly lower odds of having elevated sweat chloride levels.
Overall, “these findings highlight the importance of [genetic mutations] in predicting modulator response and support the use of SCC [sweat chloride concentration] as a sensitive endpoint for tracking CFTR modulation in children,” the researchers concluded.
