Effects of Elexacaftor/Tezacaftor/Ivacaftor Therapy on CFTR Function in Patients with Cystic Fibrosis and One or Two <i>F508del</i> Alleles

Graeber, Simon Y.; Vitzthum, Constanze; Pallenberg, Sophia Theres; Naehrlich, L.; Stahl, Mirjam; Rohrbach, Alexander; Drescher, Marika; Minso, Rebecca; Ringshausen, Felix C.; Rueckes-Nilges, Claudia; Klajda, Jan; Berges, Julian; Yin, Yin; Scheuermann, Heike; Hirtz, Stephanie; Sommerburg, Olaf; Dittrich, Anna-Maria; Tümmler, Burkhard; Mall, Marcus

doi:10.1164/rccm.202110-2249oc

Cited by 94 publications

(110 citation statements)

References 49 publications

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“…Indeed, it is more similar to the mean (SD) baseline SCC (85.6 (15.2)) of the F/F subjects recruited in the US observational study, treated with two-drug modulators before the switch to the TCT [18]. Changes in SCC are considered to provide a direct indicator of systemic CFTR function, and this data has been confirmed in parallel measurements of CFTR function in airway and intestinal epithelia in patients with CF and one or two F508del alleles [20]. An important endpoint in this study was the effect of the ETI treatment on healthcare utilisation.…”

Section: Discussionsupporting

confidence: 52%

Elexacaftor/Tezacaftor/Ivacaftor in Patients with Cystic Fibrosis Homozygous for the F508del Mutation and Advanced Lung Disease: A 48-Week Observational Study

Carnovale

Iacotucci

Terlizzi

et al. 2022

JCM

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Background: Elexacaftor/tezacaftor/ivacaftor (ETI) is the newest cystic fibrosis transmembrane conductance regulator (CFTR) modulator drug approved for the treatment of patients with cystic fibrosis (pwCF) aged ≥6 years with at least one copy of the F508del mutation (F) in the CFTR gene or another mutation that is responsive to treatment with ETI. This study determined the effectiveness and safety of ETI in a cohort of severely affected pwCF with an F/F genotype. Methods: Retrospective observational study in F/F pwCF treated for 48 weeks, enrolled in an ETI managed access program available to subjects with advanced lung disease (ppFEV1 < 40). Twenty-six patients from three centres were included. The main outcomes included lung function, sweat chloride concentration (SCC), nutrition, frequency of pulmonary exacerbations (PEx), CFQ-R, and safety. Results: ppFEV1 improved by 12.06 (95%CI 8.54, 15.57) from baseline after 4 weeks of treatment with ETI, 15.32 (11.3, 19.34) after 24 weeks, and 14.48 (10.64, 18.32) after 48 weeks. The increase in FEV1 was accompanied by a decrease in SCC, improvement of BMI, and noticeable reduction in PEx. An overall good safety profile was observed. Conclusions: In F/F pwCF with advanced lung disease with an F/F genotype, ETI was safe and associated with clinical improvement.

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Section: Discussionsupporting

confidence: 52%

Elexacaftor/Tezacaftor/Ivacaftor in Patients with Cystic Fibrosis Homozygous for the F508del Mutation and Advanced Lung Disease: A 48-Week Observational Study

Carnovale

Iacotucci

Terlizzi

et al. 2022

JCM

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“…Some of the patients with F508del/F508del migrated from tezacaftor/ivacaftor to ETI. The biomarkers show changes in the biomarkers in parallel with clinical change observed (Table 1 and Figures E2–E4) ( 4 ). Only weak correlations were seen between CFTR biomarker response and changes in lung function with ETI (Figure 4) ( 4 ).…”

Section: What New Insights Have These Two Papers Provided?mentioning

confidence: 80%

“…These two papers have demonstrated that ETI leads to ∼50% functional correction of the CFTR protein channels in epithelial cells across multiple organs, leading to impressive clinical impacts for patients 12 years and older with at least one copy of the F508del variant (plus a small number of other ETI-responsive variants) ( 3 , 4 ).…”

Section: What New Insights Have These Two Papers Provided?mentioning

confidence: 99%

“…The article by Graeber and colleagues ( 4 ) comes from five German CF centers and examines the effect of ETI on CFTR function in airway and intestinal epithelia, using CFTR biomarkers, SCC, nasal potential difference (NPD), and intestinal current measurement (ICM). The study included 107 patients with one or two F508del CFTR variants (55 with F508del and minimal function variant; 52 with F508del/F508del ) over a 6-month period.…”

Section: What New Insights Have These Two Papers Provided?mentioning

confidence: 99%

“…529–539 ) focused on clinical outcomes ( 3 ), and the second by Graeber and colleagues (pp. 540–549 ) on CFTR channel function across multiple epithelia (sweat duct, airway, and intestine) ( 4 ). The findings are exciting and impactful, indicating that the CFTR channel function is likely approaching 50% normal levels and we are just beginning to understand the longer-term clinical impact of this biological milestone for PwCF.…”

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confidence: 99%

See 2 more Smart Citations

Cystic Fibrosis: A Disease in Transformation, yet More Work to Be Done!

Ramsey

Bell

2022

Am J Respir Crit Care Med

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Therapeutic potential of phytochemicals for cystic fibrosis

et al. 2023

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The aim of this review was to review and discuss various phytochemicals that exhibit beneficial effects on mutated membrane channels, and hence, improve transmembrane conductance. These therapeutic phytochemicals may have the potential to decrease mortality and morbidity of CF patients. Four databases were searched using keywords. Relevant studies were identified, and related articles were separated. Google Scholar, as well as gray literature (i.e., information that is not produced by commercial publishers), were also checked for related articles to locate/identify additional studies. The relevant databases were searched a second time to ensure that recent studies were included. In conclusion, while curcumin, genistein, and resveratrol have demonstrated effectiveness in this regard, it should be emphasized that coumarins, quercetin, and other herbal medicines also have beneficial effects on transporter function, transmembrane conductivity, and overall channel activity. Additional in vitro and in vivo studies should be conducted on mutant CFTR to unequivocally define the mechanism by which phytochemicals alter transmembrane channel function/activity, since the results of the studies evaluated in this review have a high degree of heterogenicity and discrepancy. Finally, continued research be undertaken to clearly define the mechanism(s) of action and the therapeutic effects that therapeutic phytochemicals have on the symptoms observed in CF patients in an effort to reduce mortality and morbidity.

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Effects of Elexacaftor/Tezacaftor/Ivacaftor Therapy on CFTR Function in Patients with Cystic Fibrosis and One or Two F508del Alleles

Cited by 94 publications

References 49 publications

Elexacaftor/Tezacaftor/Ivacaftor in Patients with Cystic Fibrosis Homozygous for the F508del Mutation and Advanced Lung Disease: A 48-Week Observational Study

Elexacaftor/Tezacaftor/Ivacaftor in Patients with Cystic Fibrosis Homozygous for the F508del Mutation and Advanced Lung Disease: A 48-Week Observational Study

Cystic Fibrosis: A Disease in Transformation, yet More Work to Be Done!

Therapeutic potential of phytochemicals for cystic fibrosis

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