A Phase 3, open-label, 96-week trial to study the safety, tolerability, and efficacy of tezacaftor/ivacaftor in children ≥ 6 years of age homozygous for F508del or heterozygous for F508del and a residual function CFTR variant

Abstract

Background: Two previous Phase 3 studies ("parent studies") showed that tezacaftor/ivacaftor was generally safe and efficacious for up to 24 weeks in children 6 through 11 years of age with cystic fibrosis (CF) and F508del/F508del (F/F) or F508del/residual function (F/RF) genotypes. We assessed the safety and efficacy of tezacaftor/ivacaftor in an open-label, 96-week extension study.

Methods: This was a Phase 3, 2-part, multicenter, open-label, extension study in children 6 through 11 years of age at treatment initiation (Study VX17-661-116; NCT03537651). The primary endpoint was safety and tolerability. Secondary endpoints were absolute change from baseline in lung clearance index2.5 (LCI2.5), sweat chloride (SwCl) concentration, Cystic Fibrosis Questionnaire-Revised (CFQ-R) respiratory domain score, and body mass index (BMI).

Results: One-hundred thirty children enrolled and received ≥ 1 dose of tezacaftor/ivacaftor; 109 completed treatment. Most (n = 129) had ≥ 1 treatment-emergent adverse event (TEAE), the majority of which were mild or moderate in severity and generally consistent with common manifestations of CF. Exposure-adjusted TEAE rates were similar to or lower than those in the parent studies. Five (3.8%) had TEAEs leading to treatment discontinuation. Efficacy results from the parent studies were maintained, with improvements in lung function, SwCl concentration, CFQ‑R respiratory domain score, and BMI observed from parent study baseline to Week 96.

Conclusions: Tezacaftor/ivacaftor is generally safe and well tolerated, and treatment effects are maintained for up to 120 weeks. These results support long-term use of tezacaftor/ivacaftor in children ≥ 6 years of age with CF and F/F or F/RF genotypes.

Keywords: Cystic fibrosis; Ivacaftor; Tezacaftor.

Conflict of interest statement

Declaration of Competing Interest All authors received nonfinancial support (assistance with manuscript preparation) from ArticulateScience LLC, which received funding from Vertex Pharmaceuticals Incorporated. Additional disclosures are as follows: GSS reports consulting fees and serving on an advisory board for Vertex Pharmaceuticals. JM reports support for attending the NACFC meeting from the CF Foundation (care center award), outside the submitted work. LN reports grants from the German Center for Lung Research, Vertex Pharmaceuticals, and Boehringer Ingelheim, serving on a steering committee for CF STORM, serving as a medical lead for the German Cystic Fibrosis registry, and serving as a pharmacovigilance study manager for the European Cystic Fibrosis Society (ECFS), outside the submitted work. CS reports grants from the Cystic Fibrosis Foundation, Cystic Fibrosis Ireland, Cystic Fibrosis Trust, and Engineering and Physical Sciences Research Council (EPSRC), personal fees from Vertex Pharmaceuticals, outside the submitted work; in addition, CS is an employee of Royal Brompton Hospital, which received remuneration from Vertex Pharmaceuticals and Boehringer Ingelheim for services provided by the European Cystic Fibrosis Clinical Trials Network's Central Over-reading Centre during sponsored clinical trials. ISG reports grants, serving on advisory boards, and travel support from Vertex Pharmaceuticals, outside the submitted work. CEW reports grants, honorarium to support attending meetings, and serving on advisory boards and steering committees for Vertex Pharmaceuticals, outside the submitted work; in addition, CEW is Deputy Editor for Thorax and Associate Editor for Respirology. NA, RSH, HPD, and JLS are employees of Vertex Pharmaceuticals and may own stock or stock options in the company. DC was an employee of Vertex Pharmaceuticals at the time of the study and is a current employee of Biohaven Pharmaceuticals. JCD reports clinical trial leadership and/or advisory board and speaking roles for Vertex Pharmaceuticals, Boehringer Ingelheim, Eloxx, AlgiPharma, AbbVie, Arcturus, and Enterprise Therapeutics, grants from the Cystic Fibrosis Foundation, Cystic Fibrosis Ireland, Cystic Fibrosis Trust, EPSRC, and European Cystic Fibrosis Society; in addition, JCD is Deputy Editor for the Journal of Cystic Fibrosis. MC has nothing further to disclose.

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