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Multicenter Study
. 2021 Mar;20(2):250-256.
doi: 10.1016/j.jcf.2020.11.002. Epub 2020 Dec 6.

Safety and efficacy of the cystic fibrosis transmembrane conductance regulator potentiator icenticaftor (QBW251)

Shamsah Kazani  1 , David J Rowlands  1 , Ivan Bottoli  2 , Julie Milojevic  3 , Jose Alcantara  1 , Ieuan Jones  1 , Kenneth Kulmatycki  1 , Surendra Machineni  4 , Lidia Mostovy  1 , Ian Nicholls  3 , Jerry A Nick  5 , Steven M Rowe  6 , Nicholas J Simmonds  7 , Raju Vegesna  8 , Jeroen Verheijen  1 , Henry Danahay  9 , Martin Gosling  10 , Phaninatha Sarma Ayalavajjala  4 , Mohammed Salman  4 , Robert Strieter  1
Affiliations
Multicenter Study

Safety and efficacy of the cystic fibrosis transmembrane conductance regulator potentiator icenticaftor (QBW251)

Shamsah Kazani et al. J Cyst Fibros. 2021 Mar.

Abstract

Background: This is the first-in-human study of icenticaftor, an oral potentiator of the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) channel. Restoration of CFTR activity has shown significant clinical benefits, but more studies are needed to address all CFTR mutations.

Methods: Safety, pharmacodynamics/pharmacokinetics of icenticaftor were evaluated in a randomized, double-blind, placebo-controlled study in healthy volunteers. Efficacy was assessed in adult CF patients with ≥1 pre-specified CFTR Class III or IV mutation (150 and 450 mg bid), or homozygous for F508del mutation (450 mg bid). Primary efficacy endpoint was change from baseline in lung clearance index (LCI2.5). Secondary endpoints included %predicted FEV1 and sweat chloride level.

Results: Class IV mutations were present in 22 patients, Class III in 2 (both S549N), and 25 were homozygous for F508del. Icenticaftor was well-tolerated in healthy and CF subjects with no unexpected events or discontinuations in the CF groups. The most frequent study-drug related adverse events in CF patients were nausea (12.2%), headache (10.2%), and fatigue (6.1%). Icenticaftor 450 mg bid for 14 days showed significant improvements in all endpoints versus placebo in patients with Class III and IV mutations; mean %predicted FEV1 increased by 6.46%, LCI2.5 decreased by 1.13 points and sweat chloride decreased by 8.36 mmol/L. No significant efficacy was observed in patients homozygous for a single F508del.

Conclusions: Icenticaftor was safe and well-tolerated in healthy volunteers and CF patients, and demonstrated clinically meaningful changes in lung function and sweat chloride level in CF patients with Class III and IV CFTR mutations. ClinicalTrials.gov: NCT02190604.

Keywords: Cystic fibrosis; Cystic fibrosis questionnaire; Homozygous F508del mutation; Icenticaftor; Lung clearance index.

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Conflict of interest statement

Declaration of Competing Interest IB, JM, BS, DR, IJ, KK, SM, LM, IMN, RV, JV, PSA, MSI are employees of Novartis. SK, JA, HD, MG and RS are past employees of Novartis. SMR reports grants, personal fees and non-financial support from Novartis, during the conduct of the study; grants, personal fees, non-financial support and other from Vertex Pharmaceuticals Inc., grants and personal fees from Bayer, grants from Translate Bio, non-financial support from Proteostasis, grants, personal fees and non-financial support from Galapagos/Abbvie, grants and personal fees from Synedgen/Synspira, grants from Eloxx, grants and personal fees from Celtaxsys, grants from Ionis, grants, personal fees and other from Renovion, outside the submitted work; in addition, SMR has a patent regarding the use of CFTR-directed therapies for diseases of mucus in which CFTR is not dysfunctional issued. NJS reports personal fees from Vertex, personal fees from Chiesi, personal fees from Raptor, personal fees from Pulmocide, personal fees from Novartis Pharmaceuticals Corporation, personal fees from Roche, personal fees from Teva, personal fees from Mylan, personal fees from Gilead, personal fees from Zambon, outside the submitted work. All other authors declare no competing interests.

Figures

Fig. 1.
Fig. 1.. Overall study overview and patient disposition.
† Healthy volunteers were randomized in to (3:1 ratio) for 14 days to icenticaftor (n = 6) or placebo (n = 2); ‡ Following completion of dosing, 5 out of 6 subjects received an additional dose for preliminary evaluation of effect of food on icenticaftor pharmacokinetics. Hence, the total number subjects remains 64; §icenticaftor was administered to patients with cystic fibrosis (Class III and IV or F508del/F508del mutation) for 14 days; icenticaftor 150 mg bid (n = 6), Placebo (n = 2); icenticaftor 450 mg bid(n = 12), Placebo (n = 4); icenticaftor 450 mg bid (F508del/F508del mutation, n = 19), Placebo (n = 6); The planned enrolment in icenticaftor 450 mg bid was 32 patients who were homozygous for the F508del mutation; however, study enrolment was discontinued in this cohort based on results of interim analysis of 16 of 25 enrolled patients which suggested futility bid, twice daily; DMC, data monitoring committee, MAD, multiple ascending dose; MES, multi-dose efficacy study; od, once daily; SAD, single ascending dose.
Fig. 2.
Fig. 2.
Arithmetic mean (SD) change from baseline for PD endpoints (LCI2.5, FEV1 % of predicted, sweat chloride mmol/L and respiratory domain score of the CFQ-R) at Day 14 or 15 by time point, groups and treatment in MES. bid, twice daily; CFQ-R, cystic fibrosis questionnaire-revised; FEV1, forced expiratory volume in one second; LCI, lung clearance index; MAD, multiple ascending dose; MES, multi-dose efficacy study; PD, pharmacodynamics; SAD, single ascending dose; SD, standard deviation.
See this image and copyright information in PMC

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