Introduction: Highly effective CFTR modulator therapies are transforming the lives of people with CF (pwCF). Treatment responses vary and not all pwCF are eligible for drug therapy; in vitro assays could help to predict clinical benefit.

Methods: In vitro response to CFTR modulators were determined from nasal epithelial cells derived from the CFIT resource (Eckford PDW et al, JCF 2019). Briefly, changes in transepithelial CFTR-mediated chloride current were determined in patient specific nasal epithelial cultures differentiated at air/liquid interface. Baseline lung function was defined as the last clinically stable measurement prior to the start of a new CFTR modulator. The first clinically stable lung function measure (forced expiratory volume in 1 second) was taken within 3 months after the start of a new modulator.

Results: 56 paired measurements (in vitro and clinical) in 41 pwCF(18 female; 23 male) were included. The average age at the start of treatment was 20.1 years (range 5.7-46.1). Twenty-six pwCF were treated with Elexacaftor/Tezacaftor/Ivacaftor, 25 were treated with dual combination Tezacaftor/Ivacaftor and 5 with Ivacaftor alone. There was a statistically significant correlation between the Forskolin (r = -0.449 (-0.635; -0.221) and Inhibitor (0.352 (0.098; 0.563) response in vitro and the relative change in FEV1. In addition, correlations were observed for a relative change in sweat chloride over 3 months (Forskolin 0.398 (0.094; 0.634); Inhibitor ?0.446 (-0.667; -0.152))

Discussion: In vitro response to CFTR modulators correlates with clinical response in the same individuals.

Funded by Genome Canada and CF Canada