A Phase 3 Open-Label Study of Elexacaftor/Tezacaftor/Ivacaftor in Children 6 through 11 Years of Age with Cystic Fibrosis and at Least One <i>F508del</i> Allele

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Abstract

Rationale: Elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) was shown to be efficacious and safe in patients ≥12 years of age with cystic fibrosis and at least one F508del-CFTR (cystic fibrosis transmembrane conductance regulator) allele, but it has not been evaluated in children <12 years of age.

Objectives: To assess the safety, pharmacokinetics, and efficacy of ELX/TEZ/IVA in children 6 through 11 years of age with F508del–minimal function or F508del- F508del genotypes.

Methods: In this 24-week open-label phase 3 study, children ( N = 66) weighing <30 kg received 50% of the ELX/TEZ/IVA adult daily dose (ELX 100 mg once daily, TEZ 50 mg once daily, and IVA 75 mg every 12 h) whereas children weighing ⩾30 kg received the full adult daily dose (ELX 200 mg once daily, TEZ 100 mg once daily, and IVA 150 mg every 12 h).

Measurements and Main Results: The primary endpoint was safety and tolerability. The safety and pharmacokinetic profiles of ELX/TEZ/IVA were generally consistent with those observed in older patients. The most commonly reported adverse events included cough, headache, and pyrexia; in most of the children who had adverse events, these were mild or moderate in severity. Through Week 24, ELX/TEZ/IVA treatment improved the percentage of predicted FEV ₁ (10.2 percentage points; 95% confidence interval [CI], 7.9 to 12.6), Cystic Fibrosis Questionnaire–Revised respiratory domain score (7.0 points; 95% CI, 4.7 to 9.2), lung clearance index _2.5 (−1.71 units; 95% CI, −2.11 to −1.30), and sweat chloride (−60.9 mmol/L; 95% CI, −63.7 to −58.2); body mass index-for-age z-score increased over the 24-week treatment period when compared with the pretreatment baseline.

Conclusions: Our results show ELX/TEZ/IVA is safe and efficacious in children 6 through 11 years of age with at least one F508del-CFTR allele, supporting its use in this patient population.

Clinical trial registered with www.clinicaltrials.gov (NCT03691779).

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Most cited references 29

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Elexacaftor–Tezacaftor–Ivacaftor for Cystic Fibrosis with a Single Phe508del Allele

Peter G. Middleton, Marcus Mall, Pavel Drevinek … (2019)

Cystic fibrosis is caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) protein, and nearly 90% of patients have at least one copy of the Phe508del CFTR mutation. In a phase 2 trial involving patients who were heterozygous for the Phe508del CFTR mutation and a minimal-function mutation (Phe508del-minimal function genotype), the next-generation CFTR corrector elexacaftor, in combination with tezacaftor and ivacaftor, improved Phe508del CFTR function and clinical outcomes.

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Cystic fibrosis.

J. Elborn (2016)

Cystic fibrosis is a common life-limiting autosomal recessive genetic disorder, with highest prevalence in Europe, North America, and Australia. The disease is caused by mutation of a gene that encodes a chloride-conducting transmembrane channel called the cystic fibrosis transmembrane conductance regulator (CFTR), which regulates anion transport and mucociliary clearance in the airways. Functional failure of CFTR results in mucus retention and chronic infection and subsequently in local airway inflammation that is harmful to the lungs. CFTR dysfunction mainly affects epithelial cells, although there is evidence of a role in immune cells. Cystic fibrosis affects several body systems, and morbidity and mortality is mostly caused by bronchiectasis, small airways obstruction, and progressive respiratory impairment. Important comorbidities caused by epithelial cell dysfunction occur in the pancreas (malabsorption), liver (biliary cirrhosis), sweat glands (heat shock), and vas deferens (infertility). The development and delivery of drugs that improve the clearance of mucus from the lungs and treat the consequent infection, in combination with correction of pancreatic insufficiency and undernutrition by multidisciplinary teams, have resulted in remarkable improvements in quality of life and clinical outcomes in patients with cystic fibrosis, with median life expectancy now older than 40 years. Innovative and transformational therapies that target the basic defect in cystic fibrosis have recently been developed and are effective in improving lung function and reducing pulmonary exacerbations. Further small molecule and gene-based therapies are being developed to restore CFTR function; these therapies promise to be disease modifying and to improve the lives of people with cystic fibrosis.

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Efficacy and safety of the elexacaftor plus tezacaftor plus ivacaftor combination regimen in people with cystic fibrosis homozygous for the F508del mutation: a double-blind, randomised, phase 3 trial

Harry Heijerman, Edward McKone, Damian G. Downey … (2019)

Cystic fibrosis transmembrane conductance regulator (CFTR) modulators correct the basic defect caused by CFTR mutations. Improvements in health outcomes have been achieved using the combination of a CFTR corrector and potentiator in people with CF (pwCF) homozygous for F508del . The addition of elexacaftor (ELX; VX-445), a next-generation CFTR corrector, to tezacaftor/ivacaftor (TEZ/IVA) further improved F508del-CFTR function and clinical outcomes in a phase 2 study in pwCF homozygous for F508del . A phase 3, multi-centre, randomised, double-blind, active-controlled trial of ELX in triple combination with TEZ/IVA (ELX/TEZ/IVA) in pwCF homozygous for F508del was conducted. Eligible participants were aged ≥12 years with stable disease and percent predicted forced expiratory volume in 1 second (ppFEV 1 ) of 40 to 90, inclusive. After a four-week TEZ/IVA run-in, participants were randomised 1:1 to four weeks of ELX/TEZ/IVA versus TEZ/IVA alone. The primary endpoint was absolute change from baseline (measured at the end of the TEZ/IVA run-in) in ppFEV 1 at week 4. Key secondary endpoints were absolute change in sweat chloride and CF Questionnaire–Revised respiratory domain (CFQ-R RD) score. ClinicalTrials.gov , number NCT03525548 . Between August and December 2018, 113 participants were enrolled. Following the run-in, 107 participants were randomised and completed the 4-week treatment period. The ELX/TEZ/IVA group had improvements in ppFEV 1 (10·0 percentage points, 95% CI 7·4 to 12·6, p<0·0001), sweat chloride concentration (−45·1 mmol/L, 95% CI −50·1 to −40·1, p<0·0001), and CFQ-R RD score (17·4 points, 95% CI 11·8 to 23·0, p<0·0001) compared with the TEZ/IVA group. ELX/TEZ/IVA was well tolerated, with no discontinuations. Most adverse events were mild or moderate; serious adverse events occurred in 4% (n=2) of participants receiving ELX/TEZ/IVA and 2% (n=1) receiving TEZ/IVA. ELX/TEZ/IVA provided clinically robust benefit vs TEZ/IVA alone with a favourable safety profile and demonstrates the potential to lead to transformative improvements in the lives of pwCF homozygous for F508del .

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Author and article information

Journal

Journal ID (nlm-ta): Am J Respir Crit Care Med

Journal ID (iso-abbrev): Am J Respir Crit Care Med

Journal ID (publisher-id): ajrccm

Title: American Journal of Respiratory and Critical Care Medicine

Publisher: American Thoracic Society

ISSN (Print): 1073-449X

ISSN (Electronic): 1535-4970

Publication date (Electronic, pub): 15 June 2021

Publication date (Electronic, collection): June 2021

Publication date PMC-release: 15 June 2021

Volume: 203

Issue: 12

Pages: 1522-1532

Affiliations

[ ¹ ]Department of Pediatrics, University of Colorado Anschutz Medical Campus and Children’s Hospital Colorado, Aurora, Colorado;

[ ² ]Department of Medicine and

[ ³ ]Department of Pediatrics, National Jewish Health, Denver, Colorado;

[ ⁴ ]National Heart and Lung Institute, Imperial College London, National Institute for Health Research Imperial Biomedical Research Centre and Royal Brompton and Harefield National Health Service Foundation Trust, London, United Kingdom;

[ ⁵ ]University of Washington/Seattle Children’s Hospital, Seattle, Washington;

[ ⁶ ]Department of Pediatric Pulmonology, Immunology and Intensive Care Medicine, Charité–Universitätsmedizin Berlin, Berlin, Germany;

[ ⁷ ]Berlin Institute of Health, Berlin, Germany;

[ ⁸ ]German Center for Lung Research, Berlin, Germany;

[ ⁹ ]St. Vincent’s University Hospital and University College, Dublin, Ireland;

[ ¹⁰ ]Children’s Health Ireland and Royal College of Surgeons in Ireland University of Medicine and Health Sciences, Dublin, Ireland;

[ ¹¹ ]British Columbia Children’s Hospital, Vancouver, British Columbia, Canada;

[ ¹² ]University of Alabama at Birmingham, Birmingham, Alabama;

[ ¹³ ]St. Michael’s Hospital, Toronto, Ontario, Canada;

[ ¹⁴ ]Vertex Pharmaceuticals Incorporated, Boston, Massachusetts;

[ ¹⁵ ]University of Queensland, Brisbane, Queensland, Australia;

[ ¹⁶ ]Ann and Robert H. Lurie Children’s Hospital of Chicago, Chicago, Illinois; and

[ ¹⁷ ]Northwestern University Feinberg School of Medicine, Chicago, Illinois

Author notes

Correspondence and requests for reprints should be addressed to Susanna A. McColley, M.D., Ann and Robert H. Lurie Children’s Hospital of Chicago, 303 E Superior Street #205, Chicago, IL 60611. E-mail: smccolley@ 123456luriechildrens.org .

[*]

These authors contributed equally to this work.

[‡]

B.W.R. is Associate Editor of AJRCCM. Her participation complies with American Thoracic Society requirements for recusal from review and decisions for authored works.

[§]

These authors contributed equally to this work.

Author information

Marcus A. Mall http://orcid.org/0000-0002-4057-2199

Paul McNally http://orcid.org/0000-0001-7102-1712

Steven M. Rowe http://orcid.org/0000-0001-9045-0133

Article

Publisher-manuscript ID: 202102-0509OC

DOI: 10.1164/rccm.202102-0509OC

PMC ID: 8483230

PubMed ID: 33734030

SO-VID: 860009da-227d-481b-b55d-b4101dbb63a2

License:

This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 ( https://creativecommons.org/licenses/by-nc-nd/4.0/). For commercial usage and reprints, please contact Diane Gern ( dgern@ 123456thoracic.org ).

History

Date received : 25 February 2021

Date accepted : 18 March 2021

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Figures: 5, Tables: 3, References: 30, Pages: 45

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A Phase 3 Open-Label Study of Elexacaftor/Tezacaftor/Ivacaftor in Children 6 through 11 Years of Age with Cystic Fibrosis and at Least One F508del Allele

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Elexacaftor–Tezacaftor–Ivacaftor for Cystic Fibrosis with a Single Phe508del Allele

Cystic fibrosis.

Efficacy and safety of the elexacaftor plus tezacaftor plus ivacaftor combination regimen in people with cystic fibrosis homozygous for the F508del mutation: a double-blind, randomised, phase 3 trial

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Cited by 68

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