Efficacy and Safety of Elexacaftor-Tezacaftor-Ivacaftor in the Treatment of Cystic Fibrosis: A Systematic Review

Kapouni, Nikoletta; Moustaki, Maria; Douros, Konstantinos; Loukou, Ioanna

doi:10.3390/children10030554

Cited by 17 publications

(16 citation statements)

References 54 publications

(98 reference statements)

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“…Although randomized controlled trials demonstrated that ELX/TEZ/IVA was safe and effective, there are limited post-approval clinical data, particularly in children over two years old (52)(53)(54)(55)(56). BMI and ppFEV 1 are useful markers of clinical response to CFTR modulator treatment in children (57).…”

Section: Discussionmentioning

confidence: 99%

Longitudinal Profiling of the Intestinal Microbiome in Children with Cystic Fibrosis Treated with Elexacaftor-Tezacaftor-Ivacaftor

Reasoner,

Bernard,

Waalkes

et al. 2023

Preprint

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The intestinal microbiome influences growth and disease progression in children with cystic fibrosis (CF). Elexacaftor-tezacaftor-ivacaftor (ELX/TEZ/IVA), the newest pharmaceutical modulator for CF, restores function of the pathogenic mutated CFTR channel. We performed a single-center longitudinal analysis of the effect of ELX/TEZ/IVA on the intestinal microbiome, intestinal inflammation, and clinical parameters in children with CF. Following ELX/TEZ/IVA, children with CF had significant improvements in BMI, ppFEV1 and required fewer antibiotics for respiratory infections. Intestinal microbiome diversity increased following ELX/TEZ/IVA coupled with a decrease in the intestinal carriage of Staphylococcus aureus, the predominant respiratory pathogen in children with CF. There was a reduced abundance of microbiome-encoded antibiotic-resistance genes. Microbial pathways for aerobic respiration were reduced after ELX/TEZ/IVA. The abundance of microbial acid tolerance genes was reduced, indicating microbial adaptation to increased CFTR function. In all, this study represents the first comprehensive analysis of the intestinal microbiome in children with CF receiving ELX/TEZ/IVA.

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Section: Discussionmentioning

confidence: 99%

Longitudinal Profiling of the Intestinal Microbiome in Children with Cystic Fibrosis Treated with Elexacaftor-Tezacaftor-Ivacaftor

Reasoner,

Bernard,

Waalkes

et al. 2023

Preprint

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“…Some of the representative data is shown below. For full details, see the systematic review of all the initial trials by Kapouni et al [8 ▪▪ ]. Sutharsan et al studied ETI versus ET in 176 pwCF at least 12 years of age.…”

Section: Impact Of Highly Effective Cftr Modulator Therapies On Bioma...mentioning

confidence: 99%

Cystic fibrosis liver disease in the post-modulator era

Narkewicz

2023

Current Opinion in Pulmonary Medicine

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Purpose of review Highly effective modulators of cystic fibrosis transmembrane conductance regulator (CFTR) function have had dramatic impact on pulmonary and nutritional outcomes in persons with cystic fibrosis (pwCF). The impact on liver disease in pwCF was not the focus of the registration trials. The purpose of this review is to assess the current literature on the impact of HEMT on liver disease, progression, regression, and safety. Recent findings Short-term studies of HEMT in pwCF have shown that there is no significant impact on the frequency of liver enzyme abnormalities. There is no evidence for significant improvement in liver enzymes over time on HEMT therapy. There is conflicting data on improvement in liver fibrosis determined by fibrosis indices (APRI and GPR) or elastography. One study showed improvement, and another showed worsening in younger (<20 years old) pwCF. There are reports of resolution or improvement in hepatic steatosis. There are rare reports of severe acute hepatitis and one report of hepatic decompensation leading to liver transplantation due to drug-induced liver disease. Summary HEMT have not been shown to have a significant impact on improving liver disease or preventing fibrosis with short-term therapy. Longer studies are needed to assess the impact of HEMT on liver disease in pwCF.

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“…To date, four drugs are available, notably LUM/IVA for patients with homozygous F508del variant and ELX/TEZ/IVA for patients with at least one F508del variant. Therefore, CFTR modulators are revolutionizing CF care with a major impact on symptoms and life expectancy, especially considering the latest and highly effective ELX/TEZ/IVA drug ( 6 , 7 ). On the other hand, the adverse effects (AEs) of CFTR modulators are relatively frequent, as evidenced in a real-world safety review ( 6 ) and in a more recent systematic review focused on ELX/TEZ/IVA in patients aged 6 years or older ( 7 ).…”

Section: Introductionmentioning

confidence: 99%

Case Report: When cystic fibrosis, elexacaftor/tezacaftor/ivacaftor therapy, and alpha1 antitrypsin deficiency get together

Kinuani,

Ezri,

Kernen

et al. 2024

Front. Pediatr.

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In the last 10 years, the care of patients with cystic fibrosis (CF) has been revolutionized with the introduction of cystic fibrosis transmembrane conductance regulator (CFTR) modulator drugs, with a major impact on symptoms and life expectancy, especially considering the newest and highly effective elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) therapy. Conversely, adverse effects are relatively frequent, with some being life-threatening, such as severe hepatitis. Clinical trials on children starting CFTR modulators have reported transaminase elevations >3× upper limit of the norm in 10%–20% of patients, whereas real-life studies have reported discontinuation rates three times higher than those observed in phase 3 trials. We report the case of a 10-year-old boy with CF who developed severe acute hepatitis 2 weeks after starting ELX/TEZ/IVA therapy. An extensive screening for potential causes led to the identification of heterozygous alpha1-antitrypsin (AAT) deficiency with genotype MZ. The Z allele of SERPINA1 gene, encoding AAT, is known as a risk factor for CF liver disease. We hypothesized that it may act as a risk factor for drug-induced liver injury from CFTR modulators, notably ELX/TEZ/IVA. Therefore, checking AAT before starting CFTR modulator therapy can be suggested, in particular for children with previous, even transient, liver disease.

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Efficacy and Safety of Elexacaftor-Tezacaftor-Ivacaftor in the Treatment of Cystic Fibrosis: A Systematic Review

Cited by 17 publications

References 54 publications

Longitudinal Profiling of the Intestinal Microbiome in Children with Cystic Fibrosis Treated with Elexacaftor-Tezacaftor-Ivacaftor

Longitudinal Profiling of the Intestinal Microbiome in Children with Cystic Fibrosis Treated with Elexacaftor-Tezacaftor-Ivacaftor

Cystic fibrosis liver disease in the post-modulator era

Case Report: When cystic fibrosis, elexacaftor/tezacaftor/ivacaftor therapy, and alpha1 antitrypsin deficiency get together

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