Improvement of abdominal symptoms in people with Cystic Fibrosis during therapy with Elexacaftor/Tezacaftor/Ivacaftor brings gastrointestinal involvement into the paediatric pulmonologistʼs focus

Background

Over the past decades, care of patients with Cystic fibrosis (CF) focused on the involvement of their airway system as up to 90% of people with CF (pwCF) died prematurely from respiratory failure. Only recently, CF-Transmembrane Conductance Regulator (CFTR)-modulating therapies have become available for the majority of pwCF, targeting the underlying defect, i. e. correcting the deficiency or absence of CF transmembrane conductance regulator (CFTR) channels on the apical surface of epithelia. Highly effective CFTR-modulating therapy (HEMT) with ivacaftor, primarily approved for the rare gating mutations and recently the new triple modulator elexacaftor/tezacaftor/ivacaftor (ETI), approved for pwCF carrying the most frequent CFTR mutation F508del, has changed the face of the disease. ETI achieved the highest effects on pulmonary function with percentage of predicted FEV1-increases of 12–15 points (Middleton et al., N Engl J Med 2019; 7; 381(19):1809–1819, Zemanick et al., Am J Respir Crit Care Med 2021; 15; 203 (12): 1 522–1532). However, as pulmonary manifestations improve, extra-pulmonary involvement is receiving increasing clinical and scientific attention (Rowbotham et al., Thorax 2023; 78 (8): 840–843).

Whereas nowadays paediatric and adult pulmonologists are heading most of the CF centres, some decades ago, CF centres were frequently directed by paediatric gastroenterologists. For long, nutritional deficiencies and failure to thrive had been predominant reasons for premature death in pwCF, mostly occurring before reaching school-age. Effective supplementation of pancreatic enzymes then substantially improved the course of the disease in the majority of pwCF who suffer from exocrine pancreatic insufficiency. Unlike previous treatment options, such as pancreatic enzyme replacement therapies, which directly target only the nutritional status, ETI effects result to reach most of the organs involved in CF. Accordingly, most approval studies for CFTR modulators, also found a significant stabilisation of body weight/Body Mass Index, whilst having FEV1 as the primary outcome parameter (Grasemann H et al., N Engl J Med 2023; 2; 389 (18): 1693–1707).

Publication History

Article published online:
06 May 2025