Elsevier

The Lancet

Volume 394, Issue 10212, 23–29 November 2019, Pages 1940-1948
The Lancet

Articles
Efficacy and safety of the elexacaftor plus tezacaftor plus ivacaftor combination regimen in people with cystic fibrosis homozygous for the F508del mutation: a double-blind, randomised, phase 3 trial

https://doi.org/10.1016/S0140-6736(19)32597-8Get rights and content

Summary

Background

Cystic fibrosis transmembrane conductance regulator (CFTR) modulators correct the basic defect caused by CFTR mutations. Improvements in health outcomes have been achieved with the combination of a CFTR corrector and potentiator in people with cystic fibrosis homozygous for the F508del mutation. The addition of elexacaftor (VX-445), a next-generation CFTR corrector, to tezacaftor plus ivacaftor further improved F508del-CFTR function and clinical outcomes in a phase 2 study in people with cystic fibrosis homozygous for the F508del mutation.

Methods

This phase 3, multicentre, randomised, double-blind, active-controlled trial of elexacaftor in combination with tezacaftor plus ivacaftor was done at 44 sites in four countries. Eligible participants were those with cystic fibrosis homozygous for the F508del mutation, aged 12 years or older with stable disease, and with a percentage predicted forced expiratory volume in 1 s (ppFEV1) of 40–90%, inclusive. After a 4-week tezacaftor plus ivacaftor run-in period, participants were randomly assigned (1:1) to 4 weeks of elexacaftor 200 mg orally once daily plus tezacaftor 100 mg orally once daily plus ivacaftor 150 mg orally every 12 h versus tezacaftor 100 mg orally once daily plus ivacaftor 150 mg orally every 12 h alone. The primary outcome was the absolute change from baseline (measured at the end of the tezacaftor plus ivacaftor run-in) in ppFEV1 at week 4. Key secondary outcomes were absolute change in sweat chloride and Cystic Fibrosis Questionnaire-Revised respiratory domain (CFQ-R RD) score. This study is registered with ClinicalTrials.gov, NCT03525548.

Findings

Between Aug 3 and Dec 28, 2018, 113 participants were enrolled. Following the run-in, 107 participants were randomly assigned (55 in the elexacaftor plus tezacaftor plus ivacaftor group and 52 in the tezacaftor plus ivacaftor group) and completed the 4-week treatment period. The elexacaftor plus tezacaftor plus ivacaftor group had improvements in the primary outcome of ppFEV1 (least squares mean [LSM] treatment difference of 10·0 percentage points [95% CI 7·4 to 12·6], p<0·0001) and the key secondary outcomes of sweat chloride concentration (LSM treatment difference −45·1 mmol/L [95% CI −50·1 to −40·1], p<0·0001), and CFQ-R RD score (LSM treatment difference 17·4 points [95% CI 11·8 to 23·0], p<0·0001) compared with the tezacaftor plus ivacaftor group. The triple combination regimen was well tolerated, with no discontinuations. Most adverse events were mild or moderate; serious adverse events occurred in two (4%) participants receiving elexacaftor plus tezacaftor plus ivacaftor and in one (2%) receiving tezacaftor plus ivacaftor.

Interpretation

Elexacaftor plus tezacaftor plus ivacaftor provided clinically robust benefit compared with tezacaftor plus ivacaftor alone, with a favourable safety profile, and shows the potential to lead to transformative improvements in the lives of people with cystic fibrosis who are homozygous for the F508del mutation.

Funding

Vertex Pharmaceuticals.

Introduction

Cystic fibrosis is an autosomal recessive disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which encodes the CFTR protein, an anion transporter responsible for conductance of chloride and bicarbonate across epithelial surfaces in the airway, gastrointestinal and reproductive tracts, pancreas, and sweat glands.1 An absence or reduction in the quantity or function of CFTR, or both, results in abnormal mucus secretions and multiorgan dysfunction, including pancreatic insufficiency and airway infection and obstruction.1, 2 Chronic airway infection leads to progressive lung damage and eventually respiratory failure and premature death, with a median age at death of approximately 31 years.3, 4, 5

Although more than 2000 variants of the CFTR gene are known to exist,6 the most prevalent disease-causing CFTR mutation worldwide is F508del.4, 5 Up to 90% of all people with cystic fibrosis have at least one copy of this mutation, and almost 50% of people with cystic fibrosis are homozygous for F508del.3, 4, 5

Research in context

Evidence before this study

F508del, the most common defective form of the cystic fibrosis transmembrane conductance regulator protein (F508del-CFTR), can be corrected with currently available dual modulator combinations. Treatment of people with cystic fibrosis homozygous for the F508del mutation with these dual combinations has resulted in clinical improvements, but these improvements are lower in magnitude than those observed in the small subset of people with cystic fibrosis with genotypes highly responsive to available modulators. In a phase 2 study, addition of a next-generation CFTR corrector, elexacaftor (VX-445), to the existing CFTR modulator dual combination of tezacaftor plus ivacaftor provided further benefit to this group of people with cystic fibrosis. The phase 2, double-blind, active-comparator study of elexacaftor plus tezacaftor plus ivacaftor in a small number of people with cystic fibrosis homozygous for the F508del mutation who were already receiving tezacaftor plus ivacaftor showed that the triple drug combination was well tolerated and that the addition of elexacaftor resulted in improvements in lung function, CFTR function, and a patient-reported outcome measure that reports respiratory symptoms. A PubMed search of clinical trials, with no restrictions on publication date or language, with the search terms “elexacaftor” or “VX-445”, or both, done on July 30, 2019, revealed only one publication, describing the above-mentioned phase 2 study of elexacaftor plus tezacaftor plus ivacaftor.

Added value of this study

The present study is the first phase 3 trial of elexacaftor plus tezacaftor plus ivacaftor in people with cystic fibrosis homozygous for the F508del mutation. The results demonstrate, in a larger cohort, profound improvements in lung function, CFTR function, and respiratory-related quality of life with the triple combination regimen compared with tezacaftor plus ivacaftor, along with a favourable safety profile. Evidence of a systemic effect was also seen, with rapid improvements in bodyweight—an important predictor of survival in cystic fibrosis.

Implications of all the available evidence

The introduction of the triple combination of elexacaftor plus tezacaftor plus ivacaftor could extend highly effective CFTR modulator therapy to those homozygous for the F508del mutation—a large proportion of people with cystic fibrosis. This advance in therapy is likely to modify the natural course of the disease, leading to meaningful improvements in the lives of people with cystic fibrosis, and profoundly affecting the face of cystic fibrosis care.

At present, most treatments for people with cystic fibrosis address the downstream complications of CFTR dysfunction, independently of the CFTR genetic defect. Small molecules have been developed to address the basic defect through modulation of CFTR protein function. The first CFTR modulator therapy to be developed and approved was ivacaftor, a highly effective CFTR modulator in people with cystic fibrosis who have the G551D mutation.

Ivacaftor successfully potentiates this CFTR protein by increasing the open probability of the channel, and led to unprecedented improvements in sweat chloride (an in-vivo marker of CFTR function), lung function, respiratory-related quality of life, bodyweight, and pulmonary exacerbations, which were all sustained over 48 weeks in a placebo-controlled trial.7

Ivacaftor alone does not restore F508del-CFTR function;8 CFTR dysfunction caused by F508del is multifactorial, with defective protein processing and trafficking to the cell surface, reduced channel gating, and high turnover once at the cell surface.2, 9, 10 However, these defects can be partially overcome with a combination of CFTR modu-lators. Correctors such as lumacaftor and tezacaftor aid in processing and trafficking of the protein to the cell surface, and the potentiator ivacaftor addresses the gating defect.

Studies of lumacaftor plus ivacaftor and tezacaftor plus ivacaftor showed improvements in lung function (2·6–4·0 percentage points of the percentage predicted forced expiratory volume in 1 s [ppFEV1]) and decreases in the rate of pulmonary exacerbations (a reduction of 35–39%) in people with cystic fibrosis homozygous for the F508del mutation.11, 12

Given the multiple defects in F508del-CFTR affecting processing and trafficking, the magnitude of clinical improvements was consistent with the degree of correction of F508del-CFTR by a single CFTR corrector.13, 14 To further enhance the modulation of F508del-CFTR, it was hypothesised that the addition of a second corrector to a corrector–potentiator combination, acting with a complementary mechanism of action, would be necessary to more fully restore CFTR processing and trafficking.

Elexacaftor (VX-445) is a next-generation CFTR corrector that was shown, in vitro, to substantially increase the amount of mature CFTR protein and CFTR activity when added to the combination of tezacaftor plus ivacaftor.15 The triple combination of elexacaftor plus tezacaftor plus ivacaftor showed encouraging results in a phase 2 study of a small sample of people with cystic fibrosis homozygous for the F508del mutation.15 The present study was done as part of an ongoing development programme to evaluate the efficacy of elexacaftor plus tezacaftor plus ivacaftor compared with tezacaftor plus ivacaftor alone and to evaluate its safety, in people with cystic fibrosis homozygous for the F508del mutation.16

Section snippets

Study design and participants

This phase 3, multicentre, randomised, double-blind, active-controlled trial of elexacaftor in combination with tezacaftor plus ivacaftor was done at 44 sites in four countries (Belgium, the Netherlands, the UK, and the USA). An independent review board or ethics committee for each site approved the trial protocol and informed consent forms. All enrolled participants, or their legal guardians, provided written informed consent (and assent, when appropriate).

Male and female participants aged 12

Results

Between Aug 3 and Dec 28, 2018, 113 participants were enrolled. Following the 4-week tezacaftor plus ivacaftor run-in period, 107 participants were randomly assigned and received at least one dose of the trial drug; 55 in the elexacaftor plus tezacaftor plus ivacaftor group and 52 in the tezacaftor plus ivacaftor group. All 107 participants completed the 4-week treatment period and entered the open-label triple combination regimen extension trial (figure 1; appendix p 5). Demographics and

Discussion

In this phase 3 trial in people with cystic fibrosis homozygous for the F508del mutation, in which all participants had a 4-week pre-treatment period with tezacaftor plus ivacaftor, treatment with the triple combination regimen of elexacaftor plus tezacaftor plus ivacaftor resulted in substantial improvements in lung function, sweat chloride concentration, respiratory-related quality of life, and nutritional parameters compared with tezacaftor plus ivacaftor alone. Similar results were observed

Data sharing

Vertex Pharmaceuticals is committed to advancing medical science and improving patient health. This commitment includes the responsible sharing of clinical trial data with qualified researchers. Proposals for the use of these data will be reviewed by a scientific board. Approvals are at the discretion of Vertex Pharmaceuticals and will be dependent on the nature of the request, the merit of the research proposed, and the intended use of the data. Please contact [email protected] if you would like

References (28)

  • S Charman et al.

    UK Cystic Fibrosis Registry. Annual data report 2017

    (2018)
  • A Zolin et al.

    ECFSPR annual report 2017

    (2019)
  • B Marshall et al.

    Cystic Fibrosis Patient Registry. 2017 Annual data report

    (2018)
  • CFMDB statistics

  • Cited by (0)

    *

    Contributed equally

    Members of the VX17-445-103 Trial Group are listed in the appendix

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