Peter van Mourik

131 Comparing in vitro and in vivo effects of lumacaftor-ivacaftor assays were blinded for patient characteristics. Changes from baseline were tested by paired Student t -test and Wilcoxon signed rank test as appropriate. Pearson and Spearman correlation coefficients (r) were calculated to describe relationships between organoid FIS and changes in CFTR biomarkers and clinical outcomes. Correction for multiple comparisons was performed using the Benjamini-Hochberg procedure. RESULTS Treatment with lumacaftor-ivacaftor resulted in a clear FIS response in all organoids, albeit with substantial heterogeneity between patients (mean 939.5 ± 234.3, range 541.9 to 1397.6 area under the curve of organoid swelling). In patients, lumacaftor- ivacaftor treatment improved SCC, CFTR Cl - channel function in intestinal tissues determined by ICM as previously reported (6), whereas no treatment effects were observed in NPD, ppFEV 1 or other pulmonary function testing outcomes (Table 1) in this cohort of 21 patients. No correlation was observed between the lumacaftor-ivacaftor induced FIS in organoids versus in vivo improvement of CFTR function determined by SCC, NPD or ICM in patients (Figure 1A-C). In addition, neither FIS nor improvement in any of the other biomarkers of CFTR function correlated with improvements in ppFEV 1 in CF patients treated with lumacaftor-ivacaftor (Figure 1D). DISCUSSION This is the first study to compare effects of CFTR modulator treatment with lumacaftor-ivacaftor on organoid swelling and in vivo biomarkers of CFTR function in F508del-homozygous CF patients. Consistent with previous reports, all organoids were responsive to lumacaftor-ivacaftor in vitro and ICM improved in all individuals included in our study (Figure 1) (4, 6). However, no correlations were found between the magnitude of FIS of intestinal organoids and changes observed in ICM and other in vivo biomarkers of CFTR function (SCC, NPD) (Figure 1). We speculate that this lack of correlation likely results from the limited signal-to-noise ratios determined by the given efficacy of lumacaftor-ivacaftor in F508del-homozygous patients and the variability of the respective CFTR biomarkers. Using SCC, NPD and ICM, we previously demonstrated that lumacaftor-ivacaftor restores ~10-20% of normal CFTR function in F508del-homozygous patients in vivo (6). In comparison, previous studies that found high discriminative ability of FIS and correlations with several other biomarkers of CFTR function included patients with a spectrum of CFTR mutations including CFTR gating and residual function mutations and a broader range of responses to different CFTR modulators including highly effective modulator therapy with ivacaftor (3, 4, 5). Based on these previous studies (3, 5), sample size estimation 6