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

Vincenzo Carnovale,Laura Salvadori,Michele D’Andria,Angela Pepe,Giovanni Marsicovetere,Vito Terlizzi,Serena Buonaurio,Carmela Colangelo,Assunta Celardo,Nicola Ferrara,Paola Iacotucci,Donatello Salvatore,Lorenza Ferrillo,Giovanni Taccetti,Michela Francalanci

doi:10.3390/jcm11041021

Abstract

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.

Highlights

The combinations of the cystic fibrosis transmembrane conductance regulator (CFTR) correctors lumacaftor and tezacaftor with the potentiator ivacaftor were the first CFTR modulator drugs approved for the treatment of patients with cystic fibrosis (CF) homozygous for the common F508del mutation
The secondary outcomes were the absolute change from baseline in sweat chloride concentration (SCC) and in body mass index (BMI) and the number of pulmonary exacerbations (PEx) through the 48 weeks of treatment
All patients included in this report had pancreatic insufficiency; CF-related diabetes (CFRD) affected 11 (42.3%) patients

Summary

Introduction

The combinations of the cystic fibrosis transmembrane conductance regulator (CFTR) correctors lumacaftor and tezacaftor with the potentiator ivacaftor were the first CFTR modulator drugs approved for the treatment of patients with cystic fibrosis (CF) homozygous for the common F508del mutation. Recent randomised clinical trials showed that treatment with a triple combination of CFTR modulators, two correctors (elexacaftor-tezacaftor), and the potentiator ivacaftor, resulted in quick and sustained improvements of lung function and nutritional status and reduced the rate of PEx patients carrying at least one F508del mutation [8,9,10]. The RCT involving patients homozygous for the F508del mutation showed these encouraging results comparing the triple combination treatment (TCT) with the double treatment tezacaftor-ivacaftor and not with a placebo [8] These results have led to the approval of elexacaftor-tezacaftor-ivacaftor (ETI) by the US Food and Drug Administration and the European Medicines Agency for patients with eligible CFTR genotypes and aged 6 years and older. Conclusions: In F/F pwCF with advanced lung disease with an F/F genotype, ETI was safe and associated with clinical improvement

Objectives

Methods

Discussion

Conclusion