Abstract / Summary
The clinical response to elexacaftor/tezacaftor/ivacaftor (ETI) in people with cystic fibrosis carrying the rare cystic fibrosis transmembrane conductance regulator (CFTR) variant W1282R has not been well characterized. We retrospectively analyzed 12 people with cystic fibrosis treated with ETI for 3–36 months in addition to ongoing standard CF therapy. Baseline lung function was generally preserved in patients with available spirometry (median percent predicted forced expiratory volume in 1 s (ppFEV1), 110%; interquartile range (IQR), 93–123), limiting the potential for further improvement in ppFEV1; no statistically significant change in ppFEV1 was detected during ETI therapy (p = 0.328). Paired data for ppFEV1, body mass index (BMI), and sweat conductivity were available for 8, 12, and 9 patients, respectively. CFTR function was assessed by intestinal current measurement (ICM; n = 4) and patient-derived intestinal organoids (n = 2). Functional testing demonstrated markedly reduced baseline CFTR activity. In the patient with paired ICM measurements before and during ETI therapy, restoration of CFTR-mediated chloride transport was observed, whereas ETI significantly increased forskolin-induced swelling (FIS) in both patient-derived organoid cultures (p < 0.001 for each culture). BMI did not change significantly during ETI therapy (p = 0.269). Sweat conductivity showed a statistically significant overall reduction (median change, −3 mmol/L; p = 0.031); however, marked reductions were observed in only two of nine patients. Interpretation is limited by the small retrospective cohort and incomplete availability of paired clinical and functional data. These findings indicate that functional responsiveness of W1282R-CFTR to ETI may not be accompanied by consistent improvement across the clinical outcomes assessed.