Efficacy and safety of using Elexacaftor/Tezacaftor/Ivacaftor in the treatment of children with cystic fibrosis: real-world evidence from Brazil

Martins, Guilherme da Silva; Rambo, Carolina; Spessatto, Gabriela; Saab, Maitê Milagres; João, Bruno Hernandes David; Fajardo, Aline Didoni; Primon, Juliana Gonçalves; Picciani, Thalita Gonçalves; Cunha, Roberta Corrêa da; Chong-Neto, Herberto José; Massignan, Carlos Roberto Lebarbenchon; Silva-Filho, Luiz Vicente Ribeiro Ferreira da; Riedi, Carlos Antônio; Rosário Filho, Nelson Augusto; Chong-Silva, Débora Carla

doi:10.1016/j.jped.2025.05.007

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Original article • J. Pediatr. (Rio J.) 101 (5) • 2025 • https://doi.org/10.1016/j.jped.2025.05.007 linkcopy

Efficacy and safety of using Elexacaftor/Tezacaftor/Ivacaftor in the treatment of children with cystic fibrosis: real-world evidence from Brazil

Authorship SCIMAGO INSTITUTIONS RANKINGS

Abstract

Objective Cystic fibrosis (CF) treatment has evolved significantly with the development of CFTR modulators, particularly elexacaftor/tezacaftor/ivacaftor (ETI). This study aimed to evaluate in a real-life context, the efficacy, safety and tolerability of ETI in children and adolescents with CF at a national reference center in Brazil.

Methods A cohort of 39 patients (mean age: 11.7 years) who had been using ETI for at least three months were evaluated. Anthropometric data, pulmonary function, sweat chloride concentration, pulmonary exacerbations, antibiotic use, and liver function were assessed over a follow-up period of up to 17 months.

Results Significant improvements were observed in weight Z-score at three months (p = 0.046) and six months (p = 0.018), as well as absolute weight gain (p < 0.001). Height showed absolute growth, but no significant changes in Z-scores. Sweat chloride concentration decreased by 52.8 mmol/L (p < 0.001). Pulmonary exacerbations and antibiotic use significantly declined (p < 0.001 for both). Despite limitations in spirometry data collection, FEV1 values showed a median increase of 6 percentage points. Oropharyngeal swab cultures for Pseudomonas aeruginosa positivity dropped from 43.6 % to 5.1 %. Safety assessments showed a transient rise in alkaline phosphatase (p = 0.011), but no significant hepatotoxicity. The most common adverse events were increased respiratory secretions (25.6 %) and abdominal pain (15.4 %). One temporary treatment suspension and one dose reduction occurred, but no patient required permanent discontinuation.

Conclusions ETI demonstrated effectiveness in improving weight gain, reducing pulmonary exacerbations, and significantly lowering sweat chloride concentration. The treatment was well-tolerated, with a favorable safety profile. These findings align with existing literature, supporting ETI's role as a transformative therapy in pediatric CF management.

Keywords
Children; Cystic fibrosis; Cystic fibrosis transmembrane conductance regulator; Elexacaftor; Ivacaftor; Tezacaftor

Variable	Classification	n	%
Age (years)	Mean ± SDS (minimum-maximum)	11.7 + 2.8 (7-18.5)
Biological sex	Female	17	43.6 %
Biological sex	Male	22	56.4 %
CFTR variants
CFTR variants	F/F (p.Phe508del / p.Phe508del/)	19	48.7 %
Second variants	F/non-F (p.Phe508del / second variant)
	p.Gly542*	4	10.2 %
	p.Ser4*	3	7.69 %
	p.Arg1162*	3	7.69 %
	p.Tyr1092*	2	5.12 %
	p.Arg117Cys	1	2.51 %
	p.Arg347Pro	1	2.51 %
	p.Ala455Glu	1	2.51 %
	p.Ile506del	1	2.51 %
	p.Ala561Glu	1	2.51 %
	pThr1179llefs*17	1	2.51 %
	Deletion of exons 2 and 3 (ENST00000003084)	1	2.51 %
	non-F / non-F (p.Gly85Glu/p.Gly542*)	1	2.51 %
Duration of use of ETI (months)	Median (minimum-maximum)	9 (3-17)
Another CFTR modulator before ETI (Lumacaftor/ Ivacaftor)	Yes	12	30.81 %

Variable	Time compared to ETI use	Mean ± SDS	Median (min-max)	Difference compared to baseline	p valuea
Weight Z-score	Baseline (n = 31)	−0.71 ± 1.69	−0.59 (−6.6; 1.99)
	Month 3	−0.55 ± 1.59	−0.21 (−5.81; 1.92)	0.16	0.046
	Baseline (n = 27)	−0.78 ± 1.26	−0.59 (−3.53; 1.40)
	Month 6	−0.52 ± 1.20	−0.21 (−3.04; 1.43)	0.26	0.018
Weight (kg)	Baseline (n = 31)	33.7 ± 13.5	30 (15.8; 72)
	Month 3	36.4 ± 13.9	33 (16.9; 73)	2.7	<0.001
	Baseline (n = 27)	34.7 ± 13,0	33 (17.7; 72)
	Month 6	38.4 ± 13.3	36 (18.9; 74)	3.7	<0.001
Height Z-score	Baseline (n = 31)	−0.57 ± 1.24	−0.83 (−3.64; 1.61)
	Month 3	−0.62 ± 1.38	−0.50 (−4.92; 1.98)	−0.06	0.661
	Baseline (n = 27)	−0.56 ± 1.10	−0.77 (−2.87; 1.18)
	Month 6	−0.47 ± 1.06	−0.48 (−2.34; 1.46)	0.09	0.437
Height (cm)	Baseline (n = 31)	138.0 ± 17.0	138 (108.5; 168)
	Month 3	140.1 ± 16.59	141 (111; 171)	2.1	<0.001
	Baseline (n = 27)	141.0 ± 15.8	145 (112; 168)
	Month 6	144.6 ± 15.3	149 (113; 172)	3.6	<0.001
SCC (mmol/L)	Baseline (n = 19)	93.2 ± 14.4	93 (66; 128)
	After ETI	40.4 ± 17.5	40 (15; 69)	52.8	<0.001

Variable	Time compared to ETI use	Mean ± SDS	Median (min-max)	Difference compared to baseline	p valuea
FEV1 (%)	Baseline (n = 10)	76.3 ± 20.7	75.5 (38-114)
	After ETI	75.8 ± 27.2	81.5 (11-105)	- 0.5	0.192
Pulmonary exacerbations (Pex)	Baseline (n = 38)	1.3 ± 1.6b	1 (0-6)
	After ETI	0.4 ± 0.7b	0 (0-3)	- 0.9	<0.001
Antibiotic use	Baseline (n = 38)	1.5 ± 2.1b	1 (0-10)
	After ETI	0.5 ± 1.0b	0 (0-4)	- 1.0	<0.001

Variable	Time compared to ETI use	Mean ± SDS	Median (min-max)	Difference compared to baseline	p valuea
AST	Baseline (n = 26)	29.6 ± 8.6	30 (17; 49)
	After ETI	33.8 ± 14.4	29 (19; 72)	4.2	0.082
ALT	Baseline (n = 25)	30.8 ± 18.8	23 (11; 81)
	After ETI	36.8 ± 33.3	28.5 (13.7; 168)	6.0	0.520
GGT	Baseline (n = 23)	23.8 ± 14.1	20 (9; 71)
	After ETI	25.3 ± 24.6	19 (8.8; 132)	1.5	0.884
ALP	Baseline (n = 21)	250.2 ± 88.5	257 (60; 395)
	After ETI	317.7 ± 120.8	319 (93; 494)	67.5	0.011
Albumin	Baseline (n = 16)	4.5 ± 0.3	4.5 (4.1; 5.1)
	After ETI	4.5 ± 0.3	4.5 (4; 4.8)	0	0.970

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[1] Cm, centimeters; ETI, elexacaftor/tezacaftor/ivacaftor; kg, kilograms; SCC, sweat chloride concentration; SDS, standard deviation score.

[2] p values in bold: results with statistical significance.

[TFN1] ^a
Paired Student's T-test, p < 0.05.