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

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).

Keywords: crossover studies; rectal organoids; residual function mutations.

Figures

Figure 1.
Figure 1.
Study design. D = day; q12h = every 12 hours; W = week.
Figure 2.
Figure 2.
Least squares mean change from baseline by visit through Week 8 in (A) lung clearance index at 2.5% of initial tracer gas concentration, (B) sweat chloride concentration, and (C) percentage predicted forced expiratory volume in 1 second. BL = baseline; CI = confidence interval; LCI2.5 = lung clearance index at 2.5% of initial tracer gas concentration; LS = least squares; ppFEV1 = percentage predicted forced expiratory volume in 1 second.
Figure 3.
Figure 3.
Dose–response curve of mean background-corrected area under the curve of organoid swelling versus forskolin concentration by VX-770 dose for (A) 3849 + 10kb C→T (n = 16) and (B) D1152H mutations (n = 9). Each point represents the average background-corrected area under the curve of organoid swelling at corresponding forskolin and VX-770 concentrations. AUC = area under the curve; SE = standard error.

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