Cystic fibrosis triple therapy improves lung function, early airway disease in children
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Elexacaftor/tezacaftor/ivacaftor safely improved lung function and respiratory symptoms among children aged 6 to 11 years with the F508del/minimal function genotypes of cystic fibrosis, according to study results.
Elexacaftor/tezacaftor/ivacaftor (Trikafta, Vertex Pharmaceuticals) showed the ability to improve early airway disease and change the treatment trajectory for this group of patients, according to the researchers.
“Treatment with elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) resulted in significant improvements in [lung clearance index2.5] as well as robust improvements in [percent predicted] FEV1, [Cystic Fibrosis Questionnaire-Revised] respiratory domain score and sweat chloride concentration compared with placebo,” Marcus A. Mall, MD, director of the department of pediatric respiratory medicine, immunology and critical care medicine at Charité – Universitätsmedizin Berlin, and colleagues wrote in the study, published in American Journal of Respiratory and Critical Care Medicine. “Safety data were consistent with the established safety profile for ELX/TEZ/IVA, with no new safety concerns observed.”
In a phase 3b, randomized, placebo-controlled study, Mall and colleagues analyzed 121 children with cystic fibrosis aged 6 to 11 years who were heterozygous for F508del and who harbored a minimal function CFTR mutation (F/MF genotypes) to conduct additional analyses on the efficacy and safety of ELX/TEZ/IVA in this patient population. In order to be included in this study, children needed to have a lung clearance index2.5 (LCI2.5) greater than or equal to 7.5, which researchers wrote may signal small airway disease.
As Healio previously reported, the FDA approved this triple therapy for children aged 6 to 11 years with cystic fibrosis who have a F508del mutation in the CFTR gene or a mutation in the CFTR gene that is responsive to the therapy.
Treatment efficacy
For 24 weeks, 60 children (mean age, 9.1 years; 58.3% girls) received ELX/TEZ/IVA, with one child discontinuing due to rash, and 61 children (mean age, 9.2 years; 57.4% girls) received placebo. Weight at screening determined the child’s daily dose of the triple combination therapy.
Difference in absolute changes in LCI2.5 between the groups served as the study’s primary endpoint. Secondary outcomes included absolute changes in sweat chloride concentration, percent predicted FEV1 and Cystic Fibrosis Questionnaire-Revised respiratory domain scores.
Researchers found a greater mean decrease in LCI2.5 among those treated with ELX/TEZ/IVA (–2.29 units; 95% CI, –2.6 to –1.97) than those treated with placebo (–0.02 units; 95% CI, –0.29 to 0.34), for a between-group difference of –2.26 units (95% CI, –2.71 to –1.81; P < .0001).
Additionally, children receiving triple therapy had greater mean changes in sweat chloride concentration (between-group difference, –51.2 mmol/L; 95% CI, –55.3 to –47.1) and percent predicted FEV1 (between-group difference, 11 percentage points; 95% CI, 6.9-15.1; P < .0001 for both).
Researchers also observed a higher mean increase in Cystic Fibrosis Questionnaire-Revised respiratory domain score for the triple therapy group (between-group treatment difference, 5.5; 95% CI, 1-10; P = .0174).
Treatment safety, implications
Overall, 57 children (93.4%) in the placebo group experienced an adverse event compared with 48 children (80%) in the ELX/TEZ/IVA group. Researchers reported that most of these events were mild/moderate and commonly in accordance with manifestations of cystic fibrosis; however, nine children (14.8%) in the placebo group and four children (6.7%) in the triple therapy group had a serious adverse event.
Children receiving the triple therapy frequently experienced headache (30%) and cough (23.3%), meanwhile children receiving the placebo frequently experienced cough (42.6%), abdominal pain (27.9%), infective pulmonary exacerbation of cystic fibrosis (26.2%), headache (19.7%) and oropharyngeal pain (19.7%).
“These results demonstrate the ability of ELX/TEZ/IVA treatment to ameliorate early airway disease in cystic fibrosis and alter the natural trajectory of cystic fibrosis disease in children,” Mall and colleagues wrote.
This study by Mall and colleagues adds to the literature indicating that the CFTR modulator therapy of ELX/TEZ/IVA for children aged 6 to 11 years has sufficient evidence to back up its benefits, according to an accompanying editorial by Jordana E. Hoppe, MD, MSCS, pediatric pulmonologist at the Breathing Institute of the Children’s Hospital Colorado, and colleagues.
“The availability of ELX/TEZ/IVA in younger populations is exciting and offers hope that disease progression can be slowed or even prevented,” Hoppe and colleagues wrote. “Given the substantial benefit demonstrated with ELX/TEZ/IVA, it is unlikely that another placebo-controlled trial will be conducted in this age group.
“As these are lifelong medications, information about adverse effects and relative benefit compared with prior standard-of-care therapies is critical for families and clinicians deciding to start therapies,” they added. “Mall and colleagues have made a substantial contribution to this understanding, with implications for studies in even younger children where clinical impact on early disease manifestations such as pancreatic insufficiency may take on added importance.”