Zemanick ET, Ramsey B, Sands D, McKone EF, Fajac I, Taylor-Cousar JL, Mall MA, Konstan MW, Nair N, Zhu J, Arteaga-Solis E, Van Goor F, McGarry L, Prieto-Centurion V, Sosnay PR, Bozic C, Waltz D, and Mayer-Hamblett N
Background: Highly effective CFTR modulators improve CFTR function and lead to dramatic improvements in health outcomes in many people with cystic fibrosis (pwCF). The relationship between measures of CFTR function, such as sweat chloride concentration, and clinical outcomes in pwCF treated with CFTR modulators is poorly defined. We conducted analyses to better understand the relationships between sweat chloride and CFTR function in vitro, and between sweat chloride and clinical outcomes following CFTR modulator treatment., Methods: Mean sweat chloride values in healthy people, CF carriers, and pwCF treated with CFTR modulators at different doses were compared to chloride transport in corresponding human bronchial epithelial (HBE) cells. A pooled analysis of phase 3 CFTR modulator studies was performed to evaluate the relationship between attained values of sweat chloride and improvements in lung function, body mass index (BMI), patient reported outcomes, pulmonary exacerbations, and lung function change over time., Results: Sweat chloride concentrations in vivo correlated strongly with CFTR-dependent chloride current in HBE cells in vitro. Sweat chloride values of <30 mmol/L and ≥30 to <60 mmol/L in pwCF following CFTR modulator treatment were associated with better clinical outcomes than sweat chloride ≥60 to <80 mmol/L and ≥80 mmol/L., Conclusions: In pwCF treated with CFTR modulators, lower sweat chloride levels (reflecting greater CFTR function) are associated with better clinical outcomes. These results support the therapeutic strategy of further restoring CFTR function towards normal, as reflected in lowering sweat chloride to below the diagnostic threshold for CF (<60 mmol/L) and to normal (<30 mmol/L), with CFTR modulators., Competing Interests: Declaration of competing interest EZ reports grants and personal consulting fees from the Cystic Fibrosis Foundation and Vertex Pharmaceuticals (Vertex). BM reports grants from Vertex, Cystic Medicines, and Sionna Therapeutics, and serves on an advisory board for Vertex. DS reports honoraria from Vertex for an educational event and she is president of the Polish Cystic Fibrosis Society. EM reports grants and lecture honoraria from Vertex, and advisory board participation with Vertex, Janssen, Insmed, and CF Storm. IF reports grants from AbbVie, Bayer, Boehringer Ingelheim, Insmed, GSK, Vertex, and Zambon, consulting fees from AbbVie, Boehringer Ingelheim, Kither Biotech, and Vertex, and a leadership role with the European Cystic Fibrosis Society. JT-C reports institutional grants for research trial conduct from Vertex, Eloxx and 4DMT; personal consulting fees from Vertex, Insmed, and 4DMT; personal speaker fees from Vertex; personal fees for chairing DMC for AbbVie; leadership or committee roles in CFF, ATS, JCF, Emily's Entourage, and NIH. MM reports personal consulting fees from Abbvie, Antabio, Arrowhead, Boehringer Ingelheim, Enterprise Therapeutics, Kither Biotec, Prieris, Recode, Santhera, Splisense, and Vertex, honoraria for lectures from Vertex, and participation in advisory boards from Abbvie, Antabio, Arrowhead, Boehringer Ingelheim, Enterprise Therapeutics, Kither Biotec, and Pari. MK reports personal consulting fees from AbbVie, AzurRx, Cystetic Medicines, EnBiotix, First Wave Biopharma, Insmed, Laurent Pharmaceuticals, Mylan, and PBM BC Holdings; board participation for AbbVie, CFF, First Wave Biopharma, Insmed, Laurent Pharmaceuticals, Sionna, and Vertex; and committee membership for the Cystic Fibrosis Foundation. NN, JZ, EA-S, FVG, LM, VP-C, PS, CB, and DW are employees of Vertex and own stock or stock options in the company. NM-HD reports consulting fees from Enterprise Therapeutics and received honoraria for NIH data safety monitoring board participation., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)