Triple therapy shows safety, tolerability for older children with cystic fibrosis
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Key takeaways:
- Children aged 6 years and older receiving cystic fibrosis triple therapy tolerated the treatment well.
- Improvements at the 24-week mark continued to be seen after an additional 96 weeks of treatment.
In kids aged 6 years and older with cystic fibrosis and either F508del/minimal function or F508del/F508del genotypes, elexacaftor/tezacaftor/ivacaftor was safe and well tolerated for up to 120 weeks, according to study results.
These results, published in American Journal of Respiratory and Critical Care Medicine, also showed that improvements at the 24-week mark of elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA; Trikafta, Vertex Pharmaceuticals) treatment were sustained after 96 more weeks of the therapy.
“Treatment with ELX/TEZ/IVA remained generally safe and well tolerated in this pediatric population, with most children having [adverse events] that were mild or moderate in severity and consistent with CF disease manifestations,” Claire E. Wainwright, MBBS, MRCP, MD, professor in the Child Health Research Centre at The University of Queensland, Australia, and colleagues wrote.
In a phase 3, open-label, multicenter extension study of a prior 24-week parent study, Wainwright and colleagues assessed 64 children aged 6 years or older with CF heterozygous for F508del and a minimal function CFTR mutation (F/MF genotypes; n = 36) or homozygous for F508del (F/F genotype; n = 28) treated with ELX/TEZ/IVA to determine the safety, tolerability and efficacy of the triple therapy after an additional 96 weeks.
Researchers also evaluated absolute changes in lung function, sweat chloride concentration, lung clearance index2.5 (LCI2.5, a sensitive lung function test) and the Cystic Fibrosis Questionnaire-Revised respiratory domain score from baseline of the parent study to the end of part A of the first extension period to understand how the triple therapy worked in children of this age range. An additional 96-week extension period is planned as part B of the study.
As Healio previously reported, this triple therapy improved lung function and respiratory symptoms among children aged 6 to 11 years with the F/MF genotypes of CF at 24 weeks.
Researchers determined the dosing of the triple therapy based on whether the child weighed less than 30 kg (100 mg ELX/30 mg TEZ once a day, 75 mg IVA every 12 hours) or 30 kg or more (200 mg ELX/100 mg TEZ once a day, 150 mg IVA every 12 hours).
Primary endpoint
Over a mean treatment period of 93.9 weeks, adverse events occurred among 63 (98.4%) children; however, nearly half of these events were classified as mild (46.9%), 48.4% were moderate and all were “generally consistent with common CF disease manifestations or childhood infections,” the researchers wrote.
Cough (37.5%) was the most frequent adverse event, followed by headache (28.1%), rhinorrhea (25%), nasal congestion (21.9%), pyrexia (21.9%) and upper respiratory tract infection (20.3%).
Serious adverse events occurred in four children (6.3%), and researchers reported that one (idiopathic intracranial hypertension) may be linked to the triple therapy, whereas the serious adverse events experienced by the remaining three children were not linked to the treatment.
Notably, three adolescents stopped receiving the triple therapy. Reasons for discontinuation included moderate aggression that researchers deemed as “unlikely related” to treatment, refusal by the child and a switch to commercially available triple therapy.
Compared with 24-week data from the parent study, part A of the extension study showed decreased exposure-adjusted rates of adverse events (407.74 vs. 987.04 per 100 patient-years) and serious adverse events (4.72 vs. 8.68 events per 100 patient-years).
Secondary endpoints
When evaluating the absolute change in percent-predicted FEV1 at week 96 vs. baseline of the parent study, researchers found a mean rise of 11.2 percentage points (95% CI, 8.3-14.2). Is a post-hoc analysis, researchers found an annualized rate change in percent-predicted FEV1 of 0.51 (95% CI, –0.73 to 1.75) percentage points per year.
Patients also showed a positive change in the Cystic Fibrosis Questionnaire-Revised respiratory domain score, with an increase of 13.3 points (95% CI, 11.4-15.1).
Researchers further found reductions in sweat chloride concentration (mean absolute change, –62.3 mmol/L; 95% CI, –65.9 to –58.8) and LCI2.5 (mean absolute change, –2 units; 95% CI, –2.45 to –1.55) from baseline to week 96, both of which signal improvement.
At week 96, several growth parameters went up compared with baseline, including BMI-for-age z score (mean absolute change, 0.24; 95% CI, 0.11-0.37), weight-for-age z score (mean absolute change, 0.23; 95% CI, 0.1-0.35) and height-for-age z score (mean absolute change, 0.06; 95% CI, –0.03 to 0.16).
The estimated rate of pulmonary exacerbations was 0.04 per year based on seven instances among five children reported in the parent and extension studies, according to researchers.
“The improvements in lung function, respiratory symptoms, CFTR function and nutritional parameters seen in the 24-week pivotal trial were maintained for an additional 2 years,” Wainwright and colleagues wrote. “These results support the long-term safety profile and durable efficacy of ELX/TEZ/IVA in this pediatric population.”