CFTR modulator therapy with elexacaftor/tezacaftor/ivacaftor (ETI) has been approved for people with CF and at least one F508del allele in Europe. In the US, the ETI label has been expanded to 177 rare CFTR mutations responsive in Fischer rat thyroid cells, including G85E, but not N1303K. However, knowledge on the effect of ETI on G85E or N1303K CFTR function remains limited. In vitro effects of ETI were measured in primary human nasal epithelial cultures (pHNECs) of a G85E homozygous patient and an N1303K homozygous patient. Effects of ETI therapy in vivo in these patients were assessed using clinical outcomes, including multiple breath washout and lung MRI, and the CFTR biomarkers sweat chloride concentration (SCC), nasal potential difference (NPD) and intestinal current measurement (ICM), before and after initiation of ETI. ETI increased CFTR-mediated chloride transport in G85E/G85E and N1303K/N1303K pHNECs. In the G85E/G85E and the N1303K/N1303K patient, we observed an improvement in lung function, SCC, and CFTR function in the respiratory and rectal epithelium after initiation of ETI. The approach of combining preclinical in vitro testing with subsequent in vivo verification can facilitate access to CFTR modulator therapy and enhance precision medicine for patients carrying rare CFTR mutations.

Introduction: Multiple-breath washout (MBW) has been shown to be a sensitive outcome measure to detect lung function impairment and response to therapy in patients with cystic fibrosis (CF), but MBW data in patients with bronchiectasis of other etiologies remain limited. Methods: To determine the feasibility and sensitivity of MBW versus spirometry to detect lung function impairment in children and adults with bronchiectasis, we performed both measurements in 231 patients with bronchiectasis (age range: 0.2 – 79.3 years), including 128 patients with CF, 60 with primary ciliary dyskinesia, 33 with non-CF-bronchiectasis, 10 with postinfectious bronchiolitis obliterans and, in addition, 168 healthy controls and 76 patients with asthma as disease controls. Results: Success rate of MBW in all 475 participants was 96.0 %. The FEV1 z-score was reduced (p < 0.0001) and the lung clearance index (LCI2.5) was elevated (p < 0.0001) in patients with bronchiectasis compared to all other groups. Overall groups LCI2.5 correlated strongly with FEV1 z-score (r = - 0.742, p < 0.0001). 33 % of patients with bronchiectasis had a normal FEV1 z-score but elevated LCI2.5 versus 2 % of patients that had a reduced FEV1 z-score but normal LCI2.5 (p < 0.0001). LCI2.5 was a superior parameter to detect lung function impairment in bronchiectasis than FEV1 z-score (AUC: 0.913 vs. 0.778). Conclusion: Our data show that MBW is feasible and more sensitive than spirometry to detect lung function impairment in children and adults with bronchiectasis. This supports further development of LCI2.5 for diagnostic monitoring and as outcome measure in clinical trials.