P077 Clinical and functional efficacy of elexacaftor/tezacaftor/ivacaftor in people with cystic fibrosis carrying the N1303K mutation

Background: Elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) significantly improves health outcomes in people with cystic fibrosis (pwCF) carrying one or two F508del mutations. According to in vitro assays performed in FRT cells, 178 additional mutations respond to ELX/TEZ/IVA. The N1303K mutation is not included in this list of mutations. Recent in vitro data suggested that ELX/TEZ/IVA increases N1303KCFTR-activity. Based on the in vitro response, seven patients commenced treatment with ELX/TEZ/IVA. Methods: One homozygous, and six compound heterozygous N1303K/nonsense or frameshift mutation pwCF were treated off label with ELX/TEZ/IVA. Clinical data before and 8 weeks after starting treatment were prospectively collected. The response to ELX/TEZ/IVA was assessed in intestinal organoids derived from two study patients and additional two patients carrying N1303K that are not on treatment. Results: Compared to the values before commencing treatment, mean forced expiratory volume in 1 second increased by 18.4 percentage points and 25.4% relative to baseline, mean BMI increased by 0.85 Kg/m2 and mean lung clearance index decreased by 3.6 points and 22.2%. There was no significant change in sweat chloride. Nasal potential difference normalized in four patients and remained abnormal in three. Results in 3D intestinal organoids and 2D nasal epithelial cultures showed a response in CFTR channel activity. Conclusions: This report supports the previously reported in vitro data, performed in human nasal and bronchial epithelial cells and intestinal organoids, that pwCF who carry the N1303K mutation may have a significant clinical benefit by ELX/TEZ/IVA treatment. A controlled clinical trial is needed to confirm these results.