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

Authors :
Ahmet Z Uluer
Gordon MacGregor
Pilar Azevedo
Veronica Indihar
Claire Keating
Marcus A Mall
Edward F McKone
Bonnie W Ramsey
Steven M Rowe
Ronald C Rubenstein
Jennifer L Taylor-Cousar
Elizabeth Tullis
Lael M Yonker
Chenghao Chu
Anna P Lam
Nitin Nair
Patrick R Sosnay
Simon Tian
Fredrick Van Goor
Lakshmi Viswanathan
David Waltz
Linda T Wang
Yingmei Xi
Joanne Billings
Alexander Horsley
Edward F. Nash
Marleen Bakker
Renske van der Meer
Petrus Merkus
Christof Majoor
Karen McCoy
Krishna Pancham
James Tolle
Bryon Quick
Ahmet Uluer
Emily DiMango
Adupa Rao
Santiago Reyes
Ross Klingsberg
Celeste Barreto
Victor Ortega
Donna Willey-Courand
Carsten Schwarz
Sivagurunathan Sutharsan
Rainald Fischer
Jane Davies
Jamie Duckers
Simon Doe
Harry Heijerman
George M. Solomon
Christian Merlo
Jennifer Griffonnet
Joseph Pilewski
Jordan Dunitz
Saba Sheikh
Ronald C. Rubenstein
Daniel B. Rosenbluth
Theodore Liou
Maria Indihar
Lael Yonker
Samya Nasr
Cynthia D. Brown
Gregory S. Sawicki
Jennifer Ruddy
Bryan Garcia
Andrew Braun
Alex H. Gifford
Nighat Mehdi
Maria Tupayachi Ortiz
Raksha Jain
Francisco J. Calimano
Jimmy Johannes
Cori L. Daines
Jason Fullmer
Joel Mermis
Christopher Barrios
Ngoc Ly
Brian P. Casserly
Stephan Eisenmann
Helge Hebestreit
Alexander Kiefer
Daniel Peckham
Martin Ledson
Eva Van Braeckel
Noel Gerard McElvaney
Edward McKone
Barry Plant
Lucy Burr
Daniel J. Smith
Peter Middleton
John Wilson
VU University medical center
Source :
The Lancet Respiratory Medicine, 11(6), 550-562. Elsevier Limited, VX18-121-101 & VX18-561-101 Study Groups 2023, ' Safety and efficacy of vanzacaftor–tezacaftor–deutivacaftor in adults with cystic fibrosis : randomised, double-blind, controlled, phase 2 trials ', The Lancet Respiratory Medicine, vol. 11, no. 6, pp. 550-562 . https://doi.org/10.1016/S2213-2600(22)00504-5, LANCET RESPIRATORY MEDICINE
Publication Year :
2023

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.

Details

Language :
English
ISSN :
03911713 and 22132600
Database :
OpenAIRE
Journal :
The Lancet Respiratory Medicine, 11(6), 550-562. Elsevier Limited, VX18-121-101 & VX18-561-101 Study Groups 2023, ' Safety and efficacy of vanzacaftor–tezacaftor–deutivacaftor in adults with cystic fibrosis : randomised, double-blind, controlled, phase 2 trials ', The Lancet Respiratory Medicine, vol. 11, no. 6, pp. 550-562 . https://doi.org/10.1016/S2213-2600(22)00504-5, LANCET RESPIRATORY MEDICINE
Accession number :
edsair.doi.dedup.....72b19fd4ef9823a3f92122d18b15dec4
Full Text :
https://doi.org/10.1016/S2213-2600(22)00504-5