Long-term tezacaftor/ivacaftor safety and efficacy in people with cystic fibrosis and an F508del-CFTR mutation: 96-week, open-label extension of the EXTEND trial.

Abstract

BACKGROUND:

Study 661-110 (EXTEND) is a phase 3, open-label, three-part rollover study designed to assess the long-term safety and efficacy of tezacaftor/ivacaftor (TEZ/IVA) in participants aged ≥12 years homozygous for F508del (F/F) or heterozygous for F508del and a residual function mutation (F/RF). TEZ/IVA was shown to be safe and efficacious for up to 120 weeks in Part A. Here we report results from Part B, which evaluated safety and efficacy for an additional 96 weeks.

METHODS:

Part B enrolled participants aged ≥12 years with CF and F/F or F/RF genotypes who completed TEZ/IVA treatment in either Study 661-110 Part A, Study 661-112 (F/F), or Study 661-114 (F/F). Participants received TEZ 100 mg/IVA 150 mg fixed-dose combination once daily (morning) and IVA 150 mg once daily (evening) for 96 weeks. Safety endpoints included adverse events (AEs) and serum liver function tests. Efficacy endpoints included absolute change from baseline in percent predicted forced expiratory volume in 1 second (ppFEV1) and pulmonary exacerbation (PEx) rate.

RESULTS:

464 participants were enrolled from Part A (n=377) and other eligible studies (n=87); 463 received ≥1 dose of TEZ/IVA. Overall, 92.2% had ≥1 AE, 0.9% had AEs leading to treatment discontinuation, and 29.4% reported serious AEs. The most common AEs, which were generally consistent with common manifestations of CF, included infective PEx of CF, cough, nasopharyngitis, hemoptysis, and headache. Lung function was maintained over 96 weeks in both genotype groups. PEx rates per year were comparable with Part A.

CONCLUSIONS:

TEZ/IVA was generally safe and well tolerated over a further 96 weeks; safety data were consistent with Part A. Improvements in ppFEV1 and PEx rates were maintained for an additional 96 weeks in Part B.

• Authors: Patrick A Flume, R Scott Harris, Hildegarde Paz-Diaz, Neil Ahluwalia, Mark Higgins, Daniel Campbell, Indrias Berhane, Judy L Shih, Gregory Sawicki
• Journal: Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society (J Cyst Fibros) Vol. 22 Issue 3 Pg. 464-470 (May 2023) ISSN: 1873-5010 [Electronic] Netherlands
• PMID: 36581484 (Publication Type: Clinical Trial, Phase III, Journal Article)
• Copyright: Copyright © 2022 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.

Chemical References

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

Topics

• Humans
• Aminophenols (therapeutic use)
• Benzodioxoles (therapeutic use)
• Chloride Channel Agonists (therapeutic use)
• Cystic Fibrosis (diagnosis, drug therapy, genetics)
• Cystic Fibrosis Transmembrane Conductance Regulator (genetics, therapeutic use)
• Mutation