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

Abstract

<b>Rationale:</b> Ivacaftor's clinical effects in the residual function mutations <i>3849 + 10kb C→T</i> and <i>D1152H</i> warrant further characterization.<b>Objectives:</b> To evaluate ivacaftor's effect in people with cystic fibrosis aged ≥6 years with <i>3849 + 10kb C→T</i> or <i>D1152H</i> 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.<b>Methods:</b> 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 index_2.5 from baseline through Week 8. Additional endpoints included lung function, patient-reported outcomes, and <i>in vitro</i> intestinal organoid-based measurements of ivacaftor-induced cystic fibrosis transmembrane conductance regulator function.<b>Results:</b> Of 38 participants, 37 completed the study. The primary endpoint was met; the Bayesian posterior probability of improvement in lung clearance index_2.5 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.<b>Conclusions:</b> In people with cystic fibrosis aged ≥6 years with a <i>3849 + 10kb C→T</i> or <i>D1152H</i> 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).