Elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) was generally safe and well tolerated among children with cystic fibrosis (CF) aged 6 to 11 years old who have at least 1 F508del allele, researchers reported in the American Journal of Respiratory and Critical Care Medicine.

The investigators sought to assess long-term safety and efficacy of ELX/TEZ/IVA in children aged 6 to 11 years with cystic fibrosis heterozygous for F508del and a minimal function CF transmembrane conductance regulator (CFTR) mutation (F/MF genotypes) or homozygous for F508del (F/F genotype).

The study authors reported results of part A of a 2-part, multicenter, open-label, phase 3 extension study of ELX/TEZ/IVA (study 445-107; ClinicalTrials.gov Identifier: NCT04183790), a 96-week study of children who had completed the 24-week parent study (study 445-106 part B). Part A of this extension study evaluated the safety, tolerability, efficacy, and pharmacodynamics of ELX/TEZ/IVA during the 96-week treatment period. The dosing for participants in part A was based on weight: children weighing less than 30 kg received ELX 100 mg once daily/TEZ 50 mg once daily/IVA 75 mg every 12 hours, and children weighing 30 kg or more received ELX 200 mg once daily/TEZ 100 mg once daily/IVA 150 mg every 12 hours (adult dose).

The primary endpoint in part A was safety and tolerability based on adverse events (AEs), clinical laboratory values, electrocardiograms, vital signs, pulse oximetry, and ophthalmologic examinations.

Part A was conducted from February 17, 2020, to May 24, 2022, at 21 sites in the US, Australia, Canada, United Kingdom, and Ireland. A total of 64 children (mean [SD] age, 9.3 [1.8] years; 61% female) were enrolled and received at least 1 dose of ELX/TEZ/IVA.

Treatment with ELX/TEZ/IVA remained generally safe and well tolerated in this pediatric population, with most children having AEs that were mild or moderate in severity and consistent with CF disease manifestations.

Of the cohort, 63 children (98.4%) had at least 1 AE in the 96 weeks, which were mild (46.9%) or moderate (48.4%) in severity. The overall exposure-adjusted rates of AEs and serious AEs in this analysis (407.74 and 4.72 events per 100 patient-years, respectively) were lower compared with the parent study (987.04 and 8.68 events per 100 patient-years).

Cough (37.5%), headache (28.1%), and rhinorrhea (25.0%) were the most commonly reported AEs. Serious AEs occurred in 4 children (6.3%) and included idiopathic intracranial hypertension; constipation; pyrexia; and constipation, anaphylactic reaction, and hematuria traumatic (n=1) that were not considered drug related and all were resolved.

ELX/TEZ/IVA treatment over the 96 weeks led to maintenance of the improvements in key clinical outcomes that were observed in the 24-week parent study, the study authors reported. The mean absolute change from baseline in the parent study to week 96 in percent predicted forced expiratory volume in 1 second (ppFEV1) was 11.2 percentage points (95% CI, 8.3-14.2), as well as -62.3 mmol/L (95% CI, -65.9 to -58.8) in sweat chloride concentration, and 13.3 points in Cystic Fibrosis Questionnaire-Revised (CFQ-R) respiratory domain score (95% CI, 11.4-15.1).

The estimated rate of pulmonary exacerbations per year was 0.04. The post hoc analysis of the annualized rate of ppFEV1 change was 0.51 percentage points per year (95% CI, -0.73 to 1.75).

Limitations include lack of a comparator group and the study’s overlap with the SARS-CoV-2 pandemic. Notably, social distancing measures and mask use during the pandemic were associated with a decreased incidence of pulmonary exacerbations in patients with CF, which may have partially affected some of the results, including CFQ-R respiratory domain score.

“Treatment with ELX/TEZ/IVA remained generally safe and well tolerated in this pediatric population, with most children having AEs that were mild or moderate in severity and consistent with CF disease manifestations,” the study authors concluded. “The improvements in lung function, respiratory symptoms, and CFTR function seen in the parent study were maintained through an additional 96 weeks of ELX/TEZ/IVA treatment,” the researchers noted.

Disclosure: This research was funded by Vertex Pharmaceuticals. Some of the study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures.

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