Safety and efficacy of vanzacaftor–tezacaftor–deutivacaftor in adults with cystic fibrosis: randomised, double-blind, controlled, phase 2 trials

Azevedo, Pilar; Indihar, V.; Keating, Claire; Mall, Marcus; Ramsey, Bonnie W.; Rowe, Steven M.; Taylor‐Cousar, Jennifer L.; Tullis, Elizabeth; Chu, Chenghao; Lam, Anna; Nair, Nitin; Sosnay, Patrick R.; Tian, Simon; Goor, Fredrick Van; Viswanathan, Lakshmi; Waltz, David A.; Wang, Linda T.; Xi, Yingmei; McCoy, Karen; Billings, Joanne; Tolle, James; Quick, Bryon; Uluer, Ahmet; Rao, Adupa P.; Reyes, Santiago; Klingsberg, Ross C.; Barreto, Celeste; Ortega, Victor E.; Willey-Courand, Donna Beth; Schwarz, Carsten; Davies, Jane; Duckers, J.; Horsley, Alexander; Doe, Simon; Nash, Edward F.; Bakker, Marleen; Heijerman, H.G.M.; Meer, Renske van der; Majoor, Christof J.; Solomon, George M.; Merlo, Christian A.; Pilewski, Joseph M.; Dunitz, Jordan M.; Sheikh, Saba; Rubenstein, Ronald C.; Rosenbluth, Daniel; Liou, Theodore G.; Indihar, Maria; Pancham, Krishna; Yonker, Lael M.; Nasr, Samya Z.; Griffonnet, Jennifer; Brown, Cynthia; Sawicki, Gregory S.; Ruddy, Jennifer; DiMango, Emily; Garcia, Bryan; Braun, Andrew T.; Gifford, Alex H.; Mehdi, Naima; Ortiz, Maria Tupayachi; Jain, Raksha; Calimano, Francisco J.; Johannes, Jimmy; Daines, Cori; Fullmer, Jason J.; Mermis, Joel; Barrios, Christopher; Ly, Ngoc P.; Casserly, Brian; Eisenmann, Stephan; Hebestreit, Helge; Kiefer, Alexander; Sutharsan, Sivagurunathan; Fischer, Rainald; MacGregor, Gordon; Peckham, D.; Ledson, M.J.; Braeckel, Eva Van; Merkus, Petrus; McElvaney, Noel G.; McKone, Edward F.; Plant, Barry J.; Burr, Lucy; Smith, Daniel J.; Middleton, Peter G.; Wilson, John W.

doi:10.1016/s2213-2600(22)00504-5

Cited by 28 publications

(6 citation statements)

References 20 publications

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“…While this manuscript was in review, clinical results from a novel triple combination of CFTR modulators were published. Uluer and collaborators performed two randomized, double-blind, controlled phase 2 trials to assess the safety and efficacy of vanzacaftor–tezacaftor–deutivacaftor in PwCF aged ≥18 years old carrying F508del-CFTR in at least one allele [ 42 ]. Initially, 77 PwCF were assigned into two different groups and received 150 or 250 mg daily of deutivacaftor.…”

Section: Clinical Trials: From Monotherapy To Triple Combination Therapymentioning

confidence: 99%

“…The mean absolute change in ppFEV 1 was 4.6 points for vanzacaftor 5 mg, 14.2 points for vanzacaftor 10 mg, and 9.8 points for vanzacaftor 20 mg (added to tezacaftor and deutivacaftor triple combination). Moreover, significant improvements in SCC and the CFQ-R respiratory domain score were also reported [ 42 ]. Such effects demonstrated the potential of vanzacaftor–tezacaftor–deutivacaftor therapy to provide similar or even greater therapeutic effects than ETI therapy.…”

Section: Clinical Trials: From Monotherapy To Triple Combination Therapymentioning

confidence: 99%

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Elexacaftor-Tezacaftor-Ivacaftor: A Life-Changing Triple Combination of CFTR Modulator Drugs for Cystic Fibrosis

et al. 2023

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Cystic fibrosis (CF) is a potentially fatal monogenic disease that causes a progressive multisystemic pathology. Over the last decade, the introduction of CF transmembrane conductance regulator (CFTR) modulator drugs into clinical practice has profoundly modified the lives of many people with CF (PwCF) by targeting the fundamental cause of the disease. These drugs consist of the potentiator ivacaftor (VX-770) and the correctors lumacaftor (VX-809), tezacaftor (VX-661), and elexacaftor (VX-445). In particular, the triple combination of CFTR modulators composed of elexacaftor, tezacaftor, and ivacaftor (ETI) represents a life-changing therapy for the majority of PwCF worldwide. A growing number of clinical studies have demonstrated the safety and efficacy of ETI therapy in both short- and long-term (up to two years of follow-up to date) and its ability to significantly reduce pulmonary and gastrointestinal manifestations, sweat chloride concentration, exocrine pancreatic dysfunction, and infertility/subfertility, among other disease signs and symptoms. Nevertheless, ETI therapy-related adverse effects have also been reported, and close monitoring by a multidisciplinary healthcare team remains vital. This review aims to address and discuss the major therapeutic benefits and adverse effects reported by the clinical use of ETI therapy for PwCF.

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Section: Clinical Trials: From Monotherapy To Triple Combination Therapymentioning

confidence: 99%

Section: Clinical Trials: From Monotherapy To Triple Combination Therapymentioning

confidence: 99%

Elexacaftor-Tezacaftor-Ivacaftor: A Life-Changing Triple Combination of CFTR Modulator Drugs for Cystic Fibrosis

et al. 2023

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“…A deuterated derivative of ivacaftor, called deutivacaftor (VX-561), has a reduced rate of clearance, greater plasma concentrations at 24 h, and a longer half-life compared with ivacaftor, thereby supporting once-daily dosing ( Harbeson et al, 2017 ). Once-daily triple therapy of deutivacaftor together with tezacaftor and the novel corrector vanzacaftor is currently being examined in clinical trials ( Uluer et al, 2023 ). Assays for quantifying ELX, TEZ, IVA in human plasma and cell lysate have meanwhile been established by academic labs applying multiple reaction monitoring mass spectrometry (MRM/MS) ( Reyes-Ortega et al, 2020 ) or isotope dilution liquid chromatography tandem mass spectrometry (LC-MS/MS) ( Habler et al, 2021 ; Ryan et al, 2022 ).…”

Section: Clinical Pharmacologymentioning

confidence: 99%

Post-approval studies with the CFTR modulators Elexacaftor-Tezacaftor—Ivacaftor

Tümmler

2023

Front. Pharmacol.

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Triple combination therapy with the CFTR modulators elexacaftor (ELX), tezacaftor (TEZ) and ivacaftor (IVA) has been qualified as a game changer in cystic fibrosis (CF). We provide an overview of the body of literature on ELX/TEZ/IVA published between November 2019 and February 2023 after approval by the regulators. Recombinant ELX/TEZ/IVA-bound Phe508del CFTR exhibits a wild type conformation in vitro, but in patient’s tissue a CFTR glyoisoform is synthesized that is distinct from the wild type and Phe508del isoforms. ELX/TEZ/IVA therapy improved the quality of life of people with CF in the real-life setting irrespective of their anthropometry and lung function at baseline. ELX/TEZ/IVA improved sinonasal and abdominal disease, lung function and morphology, airway microbiology and the basic defect of impaired epithelial chloride and bicarbonate transport. Pregnancy rates were increasing in women with CF. Side effects of mental status changes deserve particular attention in the future.

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“…Apart from the approved modulators, there is ongoing development involving a novel triple combination of vanzacaftor-tezacaftor-deutivacaftor that has undergone phase 2 clinical trials in patients over 18 years. It is aimed to achieve once daily dosing for patients who have at least one copy of the F508del mutation and exceed the clinical benefit of ETI which is currently the benchmark therapy for F508del mutations ( Uluer et al, 2023 ). Undoubtedly, if it displays superior efficacy and tolerable safety profiles, clinical trials will proceed to young patients since it is hoped that HEMT treatment options can extend to younger age groups to control manifestations of CF symptoms early.…”

Section: Hemtmentioning

confidence: 99%

Ocular development after highly effective modulator treatment early in life

Zhu,

Li,

Reyes-Ortega

et al. 2023

Front. Pharmacol.

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Highly effective cystic fibrosis (CF) transmembrane conductance regulator (CFTR) modulator therapies (HEMT), including elexacaftor-tezacaftor-ivacaftor, correct the underlying molecular defect causing CF. HEMT decreases general symptom burden by improving clinical metrics and quality of life for most people with CF (PwCF) with eligible CFTR variants. This has resulted in more pregnancies in women living with CF. All HEMT are known to be able pass through the placenta and into breast milk in mothers who continue on this therapy while pregnant and breast feeding. Toxicity studies of HEMT in young rats demonstrated infant cataracts, and case reports have reported the presence of congenital cataracts in early life exposure to HEMT. This article reviews the evidence for how HEMT influences the dynamic and interdependent processes of healthy and abnormal lens development in the context of HEMT exposure during pregnancy and breastfeeding, and raises questions that remain unanswered.

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Safety and efficacy of vanzacaftor–tezacaftor–deutivacaftor in adults with cystic fibrosis: randomised, double-blind, controlled, phase 2 trials

Cited by 28 publications

References 20 publications

Elexacaftor-Tezacaftor-Ivacaftor: A Life-Changing Triple Combination of CFTR Modulator Drugs for Cystic Fibrosis

Elexacaftor-Tezacaftor-Ivacaftor: A Life-Changing Triple Combination of CFTR Modulator Drugs for Cystic Fibrosis

Post-approval studies with the CFTR modulators Elexacaftor-Tezacaftor—Ivacaftor

Ocular development after highly effective modulator treatment early in life

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