Gitte Berkers1, Renske van der Meer2, Harry Heijerman3, Jeffrey M Beekman4, Sylvia F Boj5, Robert G J Vries5, Peter van Mourik1, Jamie R Doyle6, Paul Audhya6, Zheng Jason Yuan6, Nils Kinnman6, C Kors van der Ent7. 1. Department of Pediatric Pulmonology, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, the Netherlands. 2. HagaZiekenhuis, The Hague, the Netherlands. 3. Department of Pulmonology, University Medical Center Utrecht, Utrecht, the Netherlands. 4. Department of Pediatric Pulmonology, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, the Netherlands; Regenerative Medicine Center Utrecht, University Medical Center Utrecht, Utrecht, the Netherlands. 5. Foundation Hubrecht Organoid Technology, Utrecht, the Netherlands. 6. Vertex Pharmaceuticals Incorporated, Boston, MA, USA. 7. Department of Pediatric Pulmonology, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, the Netherlands. Electronic address: k.vanderent@umcutrecht.nl.
Abstract
BACKGROUND: Previous in vitro organoid data showed A455E-CFTR, a rare CFTR mutation with 4.1% prevalence in the Netherlands, responds to lumacaftor/ivacaftor (LUM/IVA). We explored LUM/IVA's clinical efficacy in people with CF and ≥1 A455E-CFTR mutation. METHODS: Participants aged ≥12 years were randomized to 1 of 2 treatment sequences (LUM/IVA→placebo or placebo→LUM/IVA) with an 8-week washout period between. Primary endpoint was absolute change in ppFEV1 from study baseline through 8 weeks. Additional endpoints were change in sweat chloride concentration (SwCl) and CFQ-R respiratory domain score. Correlations between organoid-based measurements and clinical endpoints were investigated. RESULTS: Twenty participants were randomized at 2 sites in the Netherlands. Mean absolute change in ppFEV1 from study baseline through Week 8 showed a treatment difference of 0.1 percentage points (95% CI, -2.5 to 2.7; P = 0.928) between LUM/IVA (within-group mean change, 2.7) and placebo (within-group mean change, 2.6). The mean absolute change in SwCl concentration from study baseline through Week 8 showed a treatment difference of -7.8 mmol/L between LUM/IVA and placebo (P = 0.004), while the absolute change in CFQ-R respiratory domain score showed a treatment difference of 3.5 between LUM/IVA and placebo (P = 0.469). The in vitro organoid-based assay demonstrated a concentration-dependent swelling increase with LUM/IVA. Exploratory correlation analyses between organoid swelling and ppFEV1 and SwCl outcomes showed correlation coefficients of 0.49 and -0.11, respectively. CONCLUSIONS: In this exploratory study, LUM/IVA elicited an in vitro response in organoid swelling and in vivo response in SwCl in participants with CF and ≥1 A455E-CFTR mutation. The primary endpoint (ppFEV1) did not show a statistically significant difference between LUM/IVA and placebo; correlations between in vitro and in vivo responses were not established (NCT03061331).
BACKGROUND: Previous in vitro organoid data showed A455E-CFTR, a rare CFTR mutation with 4.1% prevalence in the Netherlands, responds to lumacaftor/ivacaftor (LUM/IVA). We explored LUM/IVA's clinical efficacy in people with CF and ≥1 A455E-CFTR mutation. METHODS: Participants aged ≥12 years were randomized to 1 of 2 treatment sequences (LUM/IVA→placebo or placebo→LUM/IVA) with an 8-week washout period between. Primary endpoint was absolute change in ppFEV1 from study baseline through 8 weeks. Additional endpoints were change in sweat chloride concentration (SwCl) and CFQ-R respiratory domain score. Correlations between organoid-based measurements and clinical endpoints were investigated. RESULTS: Twenty participants were randomized at 2 sites in the Netherlands. Mean absolute change in ppFEV1 from study baseline through Week 8 showed a treatment difference of 0.1 percentage points (95% CI, -2.5 to 2.7; P = 0.928) between LUM/IVA (within-group mean change, 2.7) and placebo (within-group mean change, 2.6). The mean absolute change in SwCl concentration from study baseline through Week 8 showed a treatment difference of -7.8 mmol/L between LUM/IVA and placebo (P = 0.004), while the absolute change in CFQ-R respiratory domain score showed a treatment difference of 3.5 between LUM/IVA and placebo (P = 0.469). The in vitro organoid-based assay demonstrated a concentration-dependent swelling increase with LUM/IVA. Exploratory correlation analyses between organoid swelling and ppFEV1 and SwCl outcomes showed correlation coefficients of 0.49 and -0.11, respectively. CONCLUSIONS: In this exploratory study, LUM/IVA elicited an in vitro response in organoid swelling and in vivo response in SwCl in participants with CF and ≥1 A455E-CFTR mutation. The primary endpoint (ppFEV1) did not show a statistically significant difference between LUM/IVA and placebo; correlations between in vitro and in vivo responses were not established (NCT03061331).
Authors: Danya Muilwijk; Eyleen de Poel; Peter van Mourik; Sylvia W F Suen; Annelotte M Vonk; Jesse E Brunsveld; Evelien Kruisselbrink; Hugo Oppelaar; Marne C Hagemeijer; Gitte Berkers; Karin M de Winter-de Groot; Sabine Heida-Michel; Stephan R Jans; Hannah van Panhuis; Menno M van der Eerden; Renske van der Meer; Jolt Roukema; Edward Dompeling; Els J M Weersink; Gerard H Koppelman; Robert Vries; Domenique D Zomer-van Ommen; Marinus J C Eijkemans; Cornelis K van der Ent; Jeffrey M Beekman Journal: Eur Respir J Date: 2022-08-18 Impact factor: 33.795
Authors: Danya Muilwijk; Marlou Bierlaagh; Peter van Mourik; Jasmijn Kraaijkamp; Renske van der Meer; Rutger van den Bor; Harry Heijerman; René Eijkemans; Jeffrey Beekman; Kors van der Ent Journal: J Pers Med Date: 2021-12-16