Relationship between theratyping in nasal epithelial cells and clinical outcomes in people with cystic fibrosis.

BACKGROUND: In people with cystic fibrosis (pwCF), human nasal epithelial cell (HNEC) cultures can be used to assess response to CF transmembrane conductance regulator (CFTR) modulators. However, thresholds of in vitro responses that predict clinical benefit remain poorly understood. In this study we describe the concordance between in vitro response in HNECs and clinical outcomes in pwCF harbouring the F508del variant, treated with either lumacaftor/ivacaftor, tezacaftor/ivacaftor or elexacaftor/tezacaftor/ivacaftor.

METHODS: Response of HNECs to CFTR modulators was assessed by CFTR-mediated chloride current stimulated by forskolin or inhibited by CFTRinh-172 in both pwCF and healthy controls. Clinical response was defined as change in forced expiratory volume in 1 s (FEV1), lung clearance index (LCI), sweat chloride or respiratory domain of the Cystic Fibrosis Questionnaire-Revised (CFQ-R) between baseline and within 3 months after the start of modulator treatment.

RESULTS: In 58 unique in vitro-clinical pairs, in vitro measures of functional rescue correlated with changes in FEV1, LCI and sweat chloride, but not CFQ-R. The concordance between in vitro response and clinical outcomes was highest when a composite outcome was used. For example, an in vitro response of 10% of healthy controls had positive and negative predictive values of 90.5% and 100%, respectively, for a clinical response in either FEV1, LCI or sweat chloride.

CONCLUSIONS: We identified thresholds of nasal epithelial cell theratype response in pwCF to predict clinical benefit from CFTR modulator therapy. The utility of this therapy testing platform to predict a clinical response improves when multiple clinical outcome measures are combined.