27 research outputs found
EâH Bond Activation Reactions (E = H, C, Si, Ge) at Ruthenium: Terminal Phosphides, Silylenes, and Germylenes
Safety and efficacy of vanzacaftorâtezacaftorâdeutivacaftor in adults with cystic fibrosis: randomised, double-blind, controlled, phase 2 trials
Background
Elexacaftorâtezacaftorâivacaftor 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 vanzacaftorâtezacaftorâdeutivacaftor 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 vanzacaftorâtezacaftorâdeutivacaftor (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 tezacaftorâdeutivacaftor 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)âtezacaftorâdeutivacaftor or tezacaftorâivacaftor active control for 4 weeks, following a 4-week tezacaftorâivacaftor 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 â0·8 to 7·0) and 2·7 percentage points (â1·0 to 6·5) from baseline at week 12, respectively, versus â0·8 percentage points (â6·2 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)âtezacaftorâdeutivacaftor (n=9), vanzacaftor (10 mg)âtezacaftorâdeutivacaftor (n=19), vanzacaftor (20 mg)âtezacaftorâdeutivacaftor (n=20), and placebo (n=10) had mean changes relative to baseline at day 29 in ppFEV1 of 4·6 percentage points (â1·3 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 (â4·1 to 8·0), respectively, in sweat chloride concentration of â42·8 mmol/L (â51·7 to â34·0), â45·8 mmol/L (95% CI â51·9 to â39·7), â49·5 mmol/L (â55·9 to â43·1), and 2·3 mmol/L (â7·0 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 (â10·1 to 16·6), respectively. Participants with the F/F genotype treated with vanzacaftor (20 mg)âtezacaftorâdeutivacaftor (n=18) and tezacaftorâivacaftor (n=10) had mean changes relative to baseline (taking tezacaftorâivacaftor) at day 29 in ppFEV1 of 15·9 percentage points (11·3 to 20·6) and â0·1 percentage points (â6·4 to 6·1), respectively, in sweat chloride concentration of â45·5 mmol/L (â49·7 to â41·3) and â2·6 mmol/L (â8·2 to 3·1), respectively, and in CFQ-R respiratory domain score of 19·4 points (95% CI 10·5 to 28·3) and â5·0 points (â16·9 to 7·0), respectively. The most common adverse events overall were cough, increased sputum, and headache. One participant in the vanzacaftorâtezacaftorâdeutivacaftor 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 vanzacaftorâtezacaftorâdeutivacaftor was safe and well tolerated and improved lung function, respiratory symptoms, and CFTR function. These results support the continued investigation of vanzacaftorâtezacaftorâdeutivacaftor in phase 3 clinical trials compared with elexacaftorâtezacaftorâivacaftor.
Funding
Vertex Pharmaceuticals