Ivacaftor in People with Cystic Fibrosis and a 3849+10kb C→T or D1152H Residual Function Mutation

• DOI: 10.1513/annalsats.202006-659oc
• Publication Date: 2020-10-23T13:36:43Z
• Authors: Eitan Kerem; Malena Cohen-Cymb...; 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
• Keywords: Cross-Over Studies; Cystic Fibrosis; Respiratory System; rectal organoids; 610; Cystic Fibrosis Transmembrane Conductance Regulator; 1103 Clinical Sciences; Bayes Theorem; Quinolones; Aminophenols; crossover studies; 3. Good health; 03 medical and health sciences; 0302 clinical medicine; Forced Expiratory Volume; Mutation; Humans; residual function mutations; Original Research

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 >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).