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

Gregory S Sawicki; Mark Chilvers; John McNamara; Lutz Naehrlich; Clare Saunders; Isabelle Sermet-Gaudelus; Claire E Wainwright; Neil Ahluwalia; Daniel Campbell; R Scott Harris; Hildegarde Paz-Diaz; Judy L Shih; Jane C Davies

doi:10.1016/j.jcf.2022.02.003

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

J Cyst Fibros. 2022 Jul;21(4):675-683. doi: 10.1016/j.jcf.2022.02.003. Epub 2022 Feb 18.

Authors

Affiliations

¹ Boston Children's Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA, USA. Electronic address: [email protected].
² BC Children's Hospital, 4500 Oak Street, Vancouver, BC V6H 3N1, Canada.
³ Children's Hospital & Clinics of Minnesota, 2525 Chicago Avenue, Minneapolis, MN, USA.
⁴ Universities of Giessen and Marburg Lung Center, German Center of Lung Research (DZL), Justus-Liebig-Universität Giessen, Giessen, Germany and Department of Pediatrics, Justus-Liebig-Universität Giessen, Ludwigstrasse 23, 35390 Giessen, Germany.
⁵ National Heart and Lung Institute, Imperial College London, Manresa Road, London SW3 6LR UK; Royal Brompton & Harefield Hospitals, Guy's & St Thomas' NHS Trust, Sydney Street, London SW3 6NP, UK.
⁶ INSERM U 1151 Institut Necker Enfants Malades, 156 rue de Vaugirard, Paris, France; Centre de Référence Maladies Rares, Mucoviscidose et Maladies Apparentées, Hôpital Necker Enfants Maladies, 149 rue de Sévres, Paris, France; Université de Paris, 85 boulevard Saint-Germain, Paris, France; European Reference Network Lung, Universitätsklinikum Frankfurt, Theodor-Stern-Kai 7, Frankfurt am Main, Germany.
⁷ Queensland Children's Hospital, 501 Stanley Street, Queensland, Australia; Centre for Children's Health Research, University of Queensland, 62 Graham Street, Queensland, Australia.
⁸ Vertex Pharmaceuticals Incorporated, 50 Northern Avenue, Boston, MA, USA.
⁹ formerly of Vertex Pharmaceuticals Incorporated, 50 Northern Avenue, Boston, MA, USA; Biohaven Pharmaceuticals, New Haven, CT, USA.
¹⁰ National Heart and Lung Institute, Imperial College London, Manresa Road, London SW3 6LR UK; Royal Brompton & Harefield Hospitals, Guy's & St Thomas' NHS Trust, Sydney Street, London SW3 6NP, UK; ECFS LCI Core Facility, London, UK.

PMID: 35190292
DOI: 10.1016/j.jcf.2022.02.003

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 index_2.5 (LCI_2.5), 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.

Publication types

Clinical Trial, Phase III
Multicenter Study
Research Support, Non-U.S. Gov't

MeSH terms

Aminophenols
Benzodioxoles
Child
Chloride Channel Agonists* / therapeutic use
Cystic Fibrosis Transmembrane Conductance Regulator / genetics
Cystic Fibrosis* / diagnosis
Cystic Fibrosis* / drug therapy
Cystic Fibrosis* / genetics
Disease Progression
Homozygote
Humans
Indoles
Mutation
Quinolones

Substances

Aminophenols
Benzodioxoles
CFTR protein, human
Chloride Channel Agonists
Indoles
Quinolones
tezacaftor
Cystic Fibrosis Transmembrane Conductance Regulator
ivacaftor

Associated data

ClinicalTrials.gov/NCT03537651