Ivacaftor in People with Cystic Fibrosis and a <i>3849+10kb C</i> → <i>T</i> or <i>D1152H</i> Residual Function Mutation
Eitan Kerem, Malena Cohen‐Cymberknoh, Reuven Tsabari, Michael Wilschanski, Joel Reiter, David Shoseyov, Alex Gileles‐Hillel, Thea Pugatsch, Jane C. Davies, Christopher Short, Clare Saunders, Cynthia DeSouza, James C. Sullivan, Jamie R. Doyle, Keval Chandarana, Nils Kinnman
Abstract
Abstract Rationale Ivacaftor’s clinical effects in the residual function mutations 3849 + 10kb C→T and D1152H warrant further characterization. Objectives To evaluate ivacaftor’s effect in people with cystic fibrosis aged ≥6 years with 3849 + 10kb C→T or D1152H residual function mutations and to explore the correlation between ivacaftor-induced organoid-based cystic fibrosis transmembrane conductance regulator function measurements and clinical response to ivacaftor. Methods Participants were randomized (1:1) in this placebo-controlled crossover study; each treatment sequence included two 8-week treatments with an 8-week washout period. The primary endpoint was absolute change in lung clearance index2.5 from baseline through Week 8. Additional endpoints included lung function, patient-reported outcomes, and in vitro intestinal organoid–based measurements of ivacaftor-induced cystic fibrosis transmembrane conductance regulator function. Results Of 38 participants, 37 completed the study. The primary endpoint was met; the Bayesian posterior probability of improvement in lung clearance index2.5 with ivacaftor versus placebo was &gt;99%. Additional endpoints improved with ivacaftor. Safety findings were consistent with ivacaftor’s known safety profile. Dose-dependent swelling was observed in 23 of 25 viable organoid cultures with ivacaftor treatment. Correlations between ivacaftor-induced organoid swelling and clinical endpoints were negligible to low. Conclusions In people with cystic fibrosis aged ≥6 years with a 3849 + 10kb C→T or D1152H mutation, ivacaftor treatment improved clinical endpoints compared with placebo; however, there was no correlation between organoid swelling and change in clinical endpoints. The organoid assay may assist in identification of ivacaftor-responsive mutations but in this study did not predict magnitude of clinical benefit for individual people with cystic fibrosis with these two mutations. Clinical trial registered with ClinicalTrials.gov (NCT03068312).