P287 Characterisation of CFTR mutations in people with cystic fibrosis and severe liver disease who are not eligible for CFTR modulators

CFTR modulators (CFTR-Ms) have had a dramatic impact on CF outcomes in patients with genotype eligible for such treatment. However, data in those with CF-liver disease (CFLD) are limited. CFTR-Ms may improve CFLD natural history and reduce/prevent its progression, but this will take time to demonstrate. Meanwhile there remains an unmet need for patients with genotypes not eligible for CFTR-Ms, particularly those with evolving cirrhosis and portal hypertension, which are associated with poorer prognosis. Our aim was therefore to quantify this unmet need in a large cohort of well characterised patients with CF. Follow-up analysis of genetic eligibility for elexacaftor/tezacaftor/ivacaftor (ETI), and ivacaftor (IVA) monotherapy was performed on data from a retrospective international study on liver-related outcomes (Colombo C et al, J Cyst Fibros 2022;21:220–6): 1591 patients enrolled in 11 centres were followed from birth up to a median age of 15 years and 171 cases of severe CFLD were observed. Based on CFTR mutations, 13% (N = 184/1420) of children without CFLD and 11% (N = 19/171) of those with severe CFLD were not eligible for either ETI or IVA therapy. Among the 19 non-eligible patients with severe CFLD, we identified 20 variants (17 CF-causing); 13 (65%) resulted in a truncated protein due to a stop codon or ins/del mutation, leading to complete loss of the CFTR function, and were present on both alleles in 7/19 patients. A substantial proportion of patients not eligible for current CFTR-Ms develops advanced CFLD. Even if CFTR-Ms prove effective mitigating its development, there remains an unmet therapy need for ineligible patients.