Improvements in cystic fibrosis transmembrane conductance regulator (CFTR) function and lung function in children 2 through 5 years of age were achieved over a 24-week treatment period with elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) treatment, according to study findings published in the American Journal of Respiratory and Critical Care Medicine.

The triple combination CFTR modulator regimen ELX/TEZ/IVA, a small-molecule therapy that targets the underlying cause of CF, had been found to be safe and effective in individuals at least 6 years of age with CF who have at least 1 F508del allele, the most common mutation resulting in CF.  Because CF can affect children younger than 6, researchers conducted a study (ClinicalTrials.gov Identifier: NCT04537793) to assess the pharmacokinetics, pharmacodynamics, efficacy, and safety of ELX/TEZ/IVA in children 2 through 5 years of age with CF.

The phase 3, open-label, 2-part multicenter international trial included children aged 2 through 5 years with CF and at least 1 F508del allele. These children received 1 of the following treatment regimens, depending upon their weight on day 1 of the trial: (1) for those weighing less than 14k g: elexacaftor 80 mg once daily, tezacaftor 40 mg once daily, and ivacaftor 60 mg each morning and 59.5 mg each evening; or (2) for those weighing 14 kg or more: elexacaftor 100 mg once daily, tezacaftor 50 mg once daily, and ivacaftor 75 mg every 12 hours.

The trial had 2 parts: Part A, conducted at 7 sites in the US between November 2020 and March 2021, assessed ELX/TEZ/IVA pharmacokinetics, safety, and tolerability over a 15-day treatment period; Part B, conducted at 22 sites in Europe, Australia, and North America between July 2021 and June 2022, assessed ELX/TEZ/IVA pharmacokinetics, safety, and tolerability over a 24-week treatment period. Pharmacokinetic data analysis from 18 children in Part A (children either homozygous for F508del [F/F genotype] or heterozygous for F508del and a minimal function mutation [F/MF genotypes]) verified the correctness of the dosing regimen in Part B. Researchers enrolled 75 children in Part B with at least one F508del mutation or an ELX/TEZ/IVA-responsive CFTR mutation (n=52 F/MF genotypes; n=23 F/F genotype) and dosed appropriately.

ELX/TEZ/IVA treatment in children aged 2 through 5 years was generally safe and well tolerated, led to improvements in CFTR function and lung function, and was associated with stable nutritional status over a 24-week treatment period.

The researchers noted that 98.7% (all but 1) of the children had adverse events (62.7% mild severity; 36.0% moderate severity [2 children serious severity]). Cough (61%), fever (35%), and rhinorrhea (33%) were the most frequent adverse events. Significant additional adverse events included vomiting (28%), COVID-19 (19%), nasal congestion (17%), rash (16%), and upper respiratory tract infection (15%). Elevated levels of alanine aminotransferase and/or aspartate aminotransferase greater than 3 times the upper limit of normal occurred in 6 children, greater than 5 times in 2 children, and greater than 8 times in 1 child.

Researchers found decreases from baseline through week 24 in sweat chloride concentration, -57.9mmol/L (95% CI, -61.3 to -54.6; n=69) and LCI2.5, -0.83 units (95% CI, -1.01 to -0.66; n=50). Mean body mass index (in normal range at baseline) remained stable at week 24.

Study limitations include lack of a comparator group limiting interpretation of safety and efficacy results, and parts of the study taking place during the SARS-CoV-2 pandemic probably contributing to decreased pulmonary exacerbation rates.

“ELX/TEZ/IVA treatment in children aged 2 through 5 years was generally safe and well tolerated, led to improvements in CFTR function and lung function, and was associated with stable nutritional status over a 24-week treatment period,” researchers concluded. They added “These results show that ELX/TEZ/IVA has a favorable safety profile and provides clinically meaningful benefits to people with CF as young as 2 years of age.”

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

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