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

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

  • Lancet Respir Med. 2023 Jun;11(6):550-562. doi: 10.1016/S2213-2600(22)00504-5.
Ahmet Z Uluer 1,  Gordon MacGregor 2,  Pilar Azevedo 3,  Veronica Indihar 4,  Claire Keating 5,  Marcus A Mall 6,  Edward F McKone 7,  Bonnie W Ramsey 8,  Steven M Rowe 9,  Ronald C Rubenstein 10,  Jennifer L Taylor-Cousar 11,  Elizabeth Tullis 12,  Lael M Yonker 13,  Chenghao Chu 14,  Anna P Lam 14,  Nitin Nair 14,  Patrick R Sosnay 14,  Simon Tian 14,  Fredrick Van Goor 14,  Lakshmi Viswanathan 14,  David Waltz 14,  Linda T Wang 14,  Yingmei Xi 14,  Joanne Billings 15,  Alexander Horsley 16,  VX18-121-101,  VX18-561-101 Study Groups
Affiliations

Affiliations

  • 1 Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; Brigham & Women's Hospital CF Center, Boston, MA, USA.
  • 2 Queen Elizabeth University Hospital, Glasgow, UK.
  • 3 Hospital de Santa Maria (CHLN), Lisbon Academic Medical Center, Lisbon, Portugal.
  • 4 Department of Internal Medicine, University of Cincinnati, Cincinnati, OH, USA.
  • 5 Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA.
  • 6 Department of Pediatric Respiratory Medicine, Immunology and Critical Care Medicine, Charité-Universitätsmedizin Berlin, Berlin, Germany; Berlin Institute of Health, Charité-Universitätsmedizin Berlin, Berlin, Germany; Freie Universität Berlin, Berlin, Germany; Humboldt-Universität zu Berlin, Berlin, Germany; German Center for Lung Research, Berlin, Germany.
  • 7 St Vincent's University Hospital, Dublin, Ireland.
  • 8 Department of Pediatrics, University of Washington School of Medicine and Seattle Children's Research Institute, Seattle, WA, USA.
  • 9 Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
  • 10 Washington University School of Medicine in St Louis, St Louis, MO, USA.
  • 11 National Jewish Health, Denver, CO, USA.
  • 12 University of Toronto, Toronto, ON, Canada.
  • 13 Mass General Hospital for Children, Harvard Medical School, Boston, MA, USA.
  • 14 Vertex Pharmaceuticals Incorporated, Boston, MA, USA.
  • 15 Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, University of Minnesota, Minneapolis, MN, USA.
  • 16 Division of Infection, Immunity, and Respiratory Medicine, University of Manchester, Manchester, UK. Electronic address: alexander.horsley@manchester.ac.uk.
PMID: 36842446 DOI: 10.1016/S2213-2600(22)00504-5
Abstract

Background: Elexacaftor-tezacaftor-ivacaftor has been shown to be safe and efficacious in people with cystic fibrosis and at least one F508del allele. Our aim was to identify a novel cystic fibrosis transmembrane conductance regulator (CFTR) modulator combination capable of further increasing CFTR-mediated chloride transport, with the potential for once-daily dosing.

Methods: We conducted two phase 2 clinical trials to assess the safety and efficacy of a once-daily combination of vanzacaftor-tezacaftor-deutivacaftor in participants with cystic fibrosis who were aged 18 years or older. A phase 2 randomised, double-blind, active-controlled study (VX18-561-101; April 17, 2019, to Aug 20, 2020) was carried out to compare deutivacaftor monotherapy with ivacaftor monotherapy in participants with CFTR gating mutations, following a 4-week ivacaftor monotherapy run-in period. Participants were randomly assigned to receive either ivacaftor 150 mg every 12 h, deutivacaftor 25 mg once daily, deutivacaftor 50 mg once daily, deutivacaftor 150 mg once daily, or deutivacaftor 250 mg once daily in a 1:1:2:2:2 ratio. The primary endpoint was absolute change in ppFEV1 from baseline at week 12. A phase 2 randomised, double-blind, controlled, proof-of-concept study of vanzacaftor-tezacaftor-deutivacaftor (VX18-121-101; April 30, 2019, to Dec 10, 2019) was conducted in participants with cystic fibrosis and heterozygous for F508del and a minimal function mutation (F/MF genotypes) or homozygous for F508del (F/F genotype). Participants with F/MF genotypes were randomly assigned 1:2:2:1 to receive either 5 mg, 10 mg, or 20 mg of vanzacaftor in combination with tezacaftor-deutivacaftor or a triple placebo for 4 weeks, and participants with the F/F genotype were randomly assigned 2:1 to receive either vanzacaftor (20 mg)-tezacaftor-deutivacaftor or tezacaftor-ivacaftor active control for 4 weeks, following a 4-week tezacaftor-ivacaftor run-in period. Primary endpoints for part 1 and part 2 were safety and tolerability and absolute change in ppFEV1 from baseline to day 29. Secondary efficacy endpoints were absolute change from baseline at day 29 in sweat chloride concentrations and Cystic Fibrosis Questionnaire-Revised (CFQ-R) respiratory domain score. These clinical trials are registered with ClinicalTrials.gov, NCT03911713 and NCT03912233, and are complete.

Findings: In study VX18-561-101, participants treated with deutivacaftor 150 mg once daily (n=23) or deutivacaftor 250 mg once daily (n=24) had mean absolute changes in ppFEV1 of 3·1 percentage points (95% CI -0·8 to 7·0) and 2·7 percentage points (-1·0 to 6·5) from baseline at week 12, respectively, versus -0·8 percentage points (-6·2 to 4·7) with ivacaftor 150 mg every 12 h (n=11); the deutivacaftor safety profile was consistent with the established safety profile of ivacaftor 150 mg every 12 h. In study VX18-121-101, participants with F/MF genotypes treated with vanzacaftor (5 mg)-tezacaftor-deutivacaftor (n=9), vanzacaftor (10 mg)-tezacaftor-deutivacaftor (n=19), vanzacaftor (20 mg)-tezacaftor-deutivacaftor (n=20), and placebo (n=10) had mean changes relative to baseline at day 29 in ppFEV1 of 4·6 percentage points (-1·3 to 10·6), 14·2 percentage points (10·0 to 18·4), 9·8 percentage points (5·7 to 13·8), and 1·9 percentage points (-4·1 to 8·0), respectively, in sweat chloride concentration of -42·8 mmol/L (-51·7 to -34·0), -45·8 mmol/L (95% CI -51·9 to -39·7), -49·5 mmol/L (-55·9 to -43·1), and 2·3 mmol/L (-7·0 to 11·6), respectively, and in CFQ-R respiratory domain score of 17·6 points (3·5 to 31·6), 21·2 points (11·9 to 30·6), 29·8 points (21·0 to 38·7), and 3·3 points (-10·1 to 16·6), respectively. Participants with the F/F genotype treated with vanzacaftor (20 mg)-tezacaftor-deutivacaftor (n=18) and tezacaftor-ivacaftor (n=10) had mean changes relative to baseline (taking tezacaftor-ivacaftor) at day 29 in ppFEV1 of 15·9 percentage points (11·3 to 20·6) and -0·1 percentage points (-6·4 to 6·1), respectively, in sweat chloride concentration of -45·5 mmol/L (-49·7 to -41·3) and -2·6 mmol/L (-8·2 to 3·1), respectively, and in CFQ-R respiratory domain score of 19·4 points (95% CI 10·5 to 28·3) and -5·0 points (-16·9 to 7·0), respectively. The most common adverse events overall were cough, increased sputum, and headache. One participant in the vanzacaftor-tezacaftor-deutivacaftor group had a serious adverse event of infective pulmonary exacerbation and another participant had a serious rash event that led to treatment discontinuation. For most participants, adverse events were mild or moderate in severity.

Interpretation: Once-daily dosing with vanzacaftor-tezacaftor-deutivacaftor was safe and well tolerated and improved lung function, respiratory symptoms, and CFTR function. These results support the continued investigation of vanzacaftor-tezacaftor-deutivacaftor in phase 3 clinical trials compared with elexacaftor-tezacaftor-ivacaftor.

Funding: Vertex Pharmaceuticals.

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