CF therapy linked to better lung function, fewer flare-ups in children

Trikafta (elexacaftor/tezacaftor/ivacaftor) was associated with improved lung function and fewer pulmonary exacerbations, or sudden worsening of lung symptoms, in children ages 6 to 11 with cystic fibrosis (CF), a real-world study found.

The treatment was also associated with improved nutritional status, fewer hospitalizations and antibiotic treatments, and reduced use of daily airway-clearance therapies. The pattern and extent of these changes differed according to the children’s genetic profile, previous CFTR modulator therapy use, and lung function at treatment initiation.

The study, “Real-world Efficacy, Safety and Heterogenicity of Efficacy of Elexacaftor-Tezacaftor-Ivacaftor in Younger Children (6-11 Years Old) with Cystic Fibrosis,” was published in Respiratory Medicine.

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Trikafta targets the underlying CFTR defect

CF is caused by genetic mutations in the CFTR gene, which reduce or prevent the normal function of the CFTR protein. This leads to the accumulation of thick, sticky mucus in the lungs and other organs, driving CF symptoms.

Trikafta, sold in Europe as Kaftrio, is an approved CFTR modulator therapy designed to improve the function of defective CFTR in people with certain CF-causing mutations.

Although Trikafta is an effective and well-established treatment for children and adults with CF, real-world data on its effectiveness and factors associated with differences in treatment response in younger children (ages 6-11) remain limited.

To learn more, a team of researchers enrolled 72 children with CF, ages 6 to 11 years, in a single-center observational study of Trikafta at a CF center in the U.S. Of these, 70 completed the one-year study and were included in the analysis. Among those 70 children, the median age was 9, and 52.9% were girls.

Nearly all (97%) had at least one copy of the F508del mutation, the most common CF-causing mutation. More than half (57%) had the mutation in both copies of the CFTR gene, meaning they were homozygous for the F508del.

Among the 65 children with baseline lung-function data, 52 (80%) had a percent predicted forced expiratory volume in one second (ppFEV1) of at least 80%, indicating relatively mild lung disease. ppFEV1 reflects how much air a person can forcefully exhale in the first second after a deep breath compared with what would be expected for someone of the same age, height, and sex.

More than half had previously been treated with other CFTR modulators, including Orkambi (ivacaftor/lumacaftor, 32.9%), Kalydeco (ivacaftor, 18.6%), and Symdeko (tezacaftor/ivacaftor, 4.3%).

Lung function and other clinical measures improved with Trikafta

Results showed that, after one month of Trikafta treatment, sweat chloride levels, a key measure of CFTR function commonly used to diagnose CF, decreased significantly from a mean of 89.7 mmol/L at baseline to 38.9 mmol/L.

Lung function, as measured by ppFEV1, significantly improved after one year of treatment, from a mean of 94% to 99%, representing a 4.8-percentage-point increase.

Larger numerical gains were seen in children who had not previously received CFTR modulators, with ppFEV1 increasing by 8.9 points. Improvements were also larger among children homozygous for the F508del mutation, who had a 7.1-point increase, and those with poorer lung function at baseline (ppFEV1 below 80%), who had an 18-point increase.

Body mass index (BMI), a ratio of height and weight that helps reflect nutritional status, also increased significantly after treatment. Larger increases were observed in children not previously treated with CFTR modulators, those homozygous for F508del mutations, and those with poorer lung function at baseline.

During the year on Trikafta, children had significantly fewer pulmonary exacerbations, hospital admissions, and courses of intravenous antibiotics than during the year before treatment.

Subgroup patterns differed by outcome. Children who had not previously received CFTR modulators or had poorer lung function at baseline had significant reductions in pulmonary exacerbations and oral or nebulized antibiotic courses, while previously treated children and those with better baseline lung function had significant reductions in hospital admissions and intravenous antibiotic courses. Children homozygous for the F508del mutation also had significant reductions in pulmonary exacerbations, hospital admissions, and intravenous antibiotic courses.

Still, there was no significant change in the proportion of children with sputum/throat cultures testing positive for bacteria that commonly cause lung infections in people with CF, including Pseudomonas aeruginosa or methicillin-resistant Staphylococcus aureus. Sputum is a mixture of saliva and mucus coughed up from the lower respiratory tract.

Some outcomes vary, while daily treatment use declines

The researchers noted that relatively few children had positive cultures at the start of the study, which may have limited their ability to detect changes over time.

The proportion of children using daily airway-clearance treatments, including the mucus-thinning medication Pulmozyme (dornase alfa), hypertonic saline (a concentrated salt solution), and a VEST device, also fell significantly after one year on Trikafta. A VEST is a wearable system that uses gentle vibrations to help loosen and clear mucus from the lungs.

The researchers cautioned that reductions in daily therapies were not guided by a standardized protocol and were based on changes reported by families, so larger studies are needed to determine Trikafta’s long-term impact on the use of these treatments.

Trikafta was generally well tolerated. Six children experienced elevated liver enzymes, which led to treatment discontinuation in one and dose reductions in five. Four children developed a skin rash that resolved on its own within days without requiring a treatment change.

“In younger [children with CF], [Trikafta] was tolerated well in most and was associated with significantly improved ppFEV1 and BMI, decreased sweat chloride and significant reduction in pulmonary exacerbations, antibiotic use and daily therapies,” the researchers wrote. “These improvements were associated with differences in [genetic profile], previous exposure to CFTR modulators and severity of underlying lung disease (ppFEV1) at baseline.”