Forskolin-induced organoid swelling is associated with long-term cystic fibrosis disease progression.

RATIONALE: Cystic fibrosis (CF) is a monogenic life-shortening disease associated with highly variable individual disease progression which is difficult to predict. Here we assessed the association of forskolin-induced swelling (FIS) of patient-derived organoids with long-term CF disease progression in multiple organs and compared FIS with the golden standard biomarker sweat chloride concentration (SCC). METHODS: We retrieved 9-year longitudinal clinical data from the Dutch CF Registry of 173 people with mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Individual CFTR function was defined by FIS, measured as the relative size increase of intestinal organoids after stimulation with 0.8 µM forskolin, quantified as area under the curve (AUC). We used linear mixed-effect models and multivariable logistic regression to estimate the association of FIS with long-term forced expiratory volume in 1 s % predicted (FEV1pp) decline and development of pancreatic insufficiency, CF-related liver disease and diabetes. Within these models, FIS was compared with SCC. RESULTS: FIS was strongly associated with longitudinal changes of lung function, with an estimated difference in annual FEV1pp decline of 0.32% (95% CI 0.11-0.54%; p=0.004) per 1000-point change in AUC. Moreover, increasing FIS levels were associated with lower odds of developing pancreatic insufficiency (adjusted OR 0.18, 95% CI 0.07-0.46; p<0.001), CF-related liver disease (adjusted OR 0.18, 95% CI 0.06-0.54; p=0.002) and diabetes (adjusted OR 0.34, 95% CI 0.12-0.97; p=0.044). These associations were absent for SCC. CONCLUSION: This study exemplifies the prognostic value of a patient-derived organoid-based biomarker within a clinical setting, which is especially important for people carrying rare CFTR mutations with unclear clinical consequences.

Radiological and long-term clinical response to elexacaftor/tezacaftor/ivacaftor in people with cystic fibrosis with advanced lung disease.

INTRODUCTION: A triple combination of CFTR modulators ELE/TEZ/IVA (elexacaftor/tezacaftor/ivacaftor, Trikafta™) has been evaluated in clinical trials for people with cystic fibrosis (pwCF) and was approved to the European and US market. During registration and settling reimbursement in Europe, it could be requested on a compassionate use basis, for patients with advanced lung disease (ppFEV1 < 40). AIM: The aim of this study is to evaluate 2 years of experience with the clinical and radiological response of ELE/TEZ/IVA in pwCF in a compassionate use setting. METHODS: pwCF who started ELE/TEZ/IVA in a compassionate use setting were prospectively followed with assessment of spirometry, BMI, chest CT, CFQ-R and sweat chloride concentration (SCC) before start and after 3 months. Furthermore, spirometry, sputum cultures, and BMI were repeated after 1, 6, 12, 18, and 24 months. RESULTS: Eighteen patients were eligible for this evaluation, nine with F508del/F508del genotype (eight of whom were using dual CFTR modulators) and nine with F508del/minimal function mutation. After 3 months, mean change in SCC was -44.9 (p ≤ 0.001), together with significant improvement in CT (change in Brody score: -28.27 p ≤ 0.001) and CFQ-R results (change in respiratory domain: +18.8, p = 0.002). After 24 months, ppFEV1 change was +8.89 (p = 0.002), BMI had improved by +1.53 kg/m2 (p ≤ 0.001) and exacerbation rate declined from 5.94 in 24 months before start to 1.17 (p ≤ 0.001) in the 24 months after. CONCLUSION: pwCF with advanced lung disease experience relevant clinical benefit after 2 years of treatment with ELE/TEZ/IVA in a compassionate use setting. Structural lung damage, quality of life, exacerbation rate, and BMI improved significantly with treatment. Gain in ppFEV1 is lower compared to the phase III trials that included younger patients with moderately affected lung function.