ETI Improves Outcomes in Children With CF, Most in F508del Homozygotes

Elexacaftor-tezacaftor-ivacaftor (ETI) (Trikafta; Vertex Pharmaceuticals Inc) therapy, used to treat people with cystic fibrosis, first approved in late 2019, was found to be effective and safe in most young children aged 6 to 11 years and to improve clinical outcomes, according to real-world data.^1,2

Although ETI was approved 7 years ago and expanded to children aged 6 to 11 years in 2021 and to those aged 2 to 5 years in 2023, real-world data on its safety, efficacy, and overall impact on clinical outcomes in younger children remained limited.^1,3,4 In the first study, children aged 6 to 11 years on ETI therapy showed improvements in pulmonary exacerbations, hospital admissions, antibiotic courses, and the number of children receiving daily chest therapy, dornase alfa, and hypertonic saline when compared with the year before treatment.¹ The findings were presented at the CHEST 2026 Annual Meeting of the American College of Chest Physicians, held October 18 to 21, 2026, in Phoenix, Arizona.^1,2

Real-World ETI Use Tied to Better Lung Function, BMI in Children

The 1-year prospective observational study included 70 children with cystic fibrosis. The median (IQR) age was 9.0 (6.4-10.0) years, and 40 (57%) were homozygous for F508del, the most common mutation in cystic fibrosis.^1,5 F508del is considered a processing mutation that removes a single amino acid from the cystic fibrosis transmembrane conductance regulator (CFTR) protein, which is essential for the protein to maintain its 3-D shape. When that amino acid is missing, the cell disposes of the protein because it is the incorrect shape.⁵

Children with cystic fibrosis treated with ETI in the cohort experienced significant increases in mean (SD) percent predicted forced expiratory volume in 1 second (ppFEV1), from 94 (14) to 99 (13) (95% CI, 1.8-7.8; P= .002), and mean (SD) BMI, from 17.0 (3.0) to 17.7 (3.3) (95% CI, 0.29-1.1; P< .001), at 1 year.¹

ETI therapy was stopped in 1 child because of persistently elevated liver function tests (LFTs) and was interrupted in another 5 children for elevated LFTs. Among them, 2 had their dose decreased by half for 1 to 2 months and then resumed. Another 3 had to continue with half the dose throughout the study. Four children had rashes that resolved without any change in therapy.¹

Researchers concluded that ETI therapy was effective and, in most children, safe, but that LFTs need to be monitored. They suggested that starting ETI therapy early decreases morbidity and that controlling the disease early may reduce long-term disease progression.¹

Children Homozygous for F508del See Greatest Gains From ETI

Within the same 70-child cohort, researchers also examined heterogeneity in ETI efficacy across cystic fibrosis genotypes, specifically comparing children who were homozygous with those who were heterozygous for F508del.²

Of the 70 children, 37 (52.9%) were female, and 65 (93%) were White. The median (IQR) age was 9.0 (6.5-10.0) years. Forty (57%) were homozygous for F508del. In the heterozygous group, 16 had minimal function variants (F/MF), 5 had residual function variants (F/RF), and 7 had gating function variants (F/GF).² Across the total cohort, mean (SD) sweat chloride, a measure of CFTR function, decreased from 89.6 (19.1) mmol/L at baseline to 39.6 (18.6) mmol/L after 1 month of ETI therapy (P < .001).^2,3

For the entire cohort, mean ppFEV1 increased from 94 (14) to 99 (13) during 1 year of ETI therapy (95% CI, 1.8-7.8; P= .002), an absolute difference of +4.8. However, improvement was noted only among those homozygous for F508del, whose ppFEV1 changed from 92 (14) to 99 (13) (95% CI, 3.3-11; P < .001), a difference of +7.1 compared with +1.6 among the heterozygous group.²

Additionally, mean BMI significantly increased from 17.02 (2.96) to 17.70 (3.34) (95% CI, 0.29-1.1; P < .001), an absolute difference of 0.68. Similarly, improvement was noted only among those homozygous for F508del, with an absolute difference of 0.8 (P= .005) compared with 0.53 among the heterozygous group.²

Similar to the first study, the analysis showed significant decreases in the median number of cystic fibrosis pulmonary exacerbations, intravenous antibiotic courses, hospital admissions, and oral and/or nebulized antibiotic use when comparing 1 year before starting ETI therapy vs 1 year on ETI therapy (P < .001 for all). Significant improvement in all these parameters was also seen in the homozygous group.²

Daily therapy use also declined. At baseline, 61 (87%) children were using daily dornase alfa, which fell to 29 (41%) at 1 year; the number requiring daily chest therapy (vest) fell from 68 (97%) to 59 (84%); and the number requiring hypertonic saline fell from 34 (49%) to 21 (30%) (P < .001 for all). Genotype had no significant impact on the change in daily chest therapy, but the decrease in hypertonic saline use was significant among children homozygous for F508del, and the decrease in daily dornase alfa use was significant in both the homozygous and heterozygous groups.²

"ETI therapy was associated with improved clinical outcomes in younger children, and there was significant heterogenicity favoring those homozygous for dF508 compared to the heterozygous group," the study authors concluded. They added that this variability in response should be kept in mind in the development of future CFTR modulators.²

References

1. Sheikh SI, Holtzlander M, Eisner M, et al. Real-world efficacy and safety of elexacaftor-tezacaftor-ivacaftor (ETI) in younger children with cystic fibrosis. Presented at: CHEST 2026 Annual Meeting; October 18-21, 2026; Phoenix, AZ. doi:10.1016/j.chest.2026.07.183

2. Sheikh SI, Eisner M, Holtzlander M, et al. Impact of genotype on real-world heterogeneity on efficacy of elexacaftor-tezacaftor-ivacaftor (ETI) in younger children (6-11 years old) with cystic fibrosis. Presented at: CHEST 2026 Annual Meeting; October 18-21, 2026; Phoenix, AZ. doi:10.1016/j.chest.2026.07.184

3. Vertex announces US FDA approval for TRIKAFTA (elexacaftor/tezacaftor/ivacaftor and ivacaftor) in children with cystic fibrosis ages 2 through 5 with certain mutations. News release. Vertex Pharmaceuticals. April 26, 2023. Accessed October 20, 2026. https://news.vrtx.com/news-releases/news-release-details/vertex-announces-us-fda-approval-trikaftar-0

4. Vertex announces US FDA approval for TRIKAFTA (elexacaftor/tezacaftor/ivacaftor and ivacaftor) in children with cystic fibrosis ages 6 through 11 with certain mutations. News release. Vertex Pharmaceuticals. June 9, 2021. Accessed October 20, 2026. https://news.vrtx.com/node/28476

5. Types of CFTR mutations. Cystic Fibrosis Foundation. Accessed October 20, 2026. https://www.cff.org/research-clinical-trials/types-cftr-mutations