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Action Points
- Two parallel phase II trials of next-generation CFTR correctors showed that both VX-445 and VX-659 improved predicted FEV1 when combined with tezacaftor and ivacaftor in cystic fibrosis patients with either homozygous or heterozygous Phe508del alleles.
- The regimens were well-tolerated and according to an accompanying editorial, represent an exciting breakthrough in cystic fibrosis with durability of effect to be tested in ongoing phase III trials.
Adding a next-generation, small-molecule CFTR protein corrector to dual therapy with ivacaftor and tezacaftor significantly improved lung function in cystic fibrosis (CF) patients with one or two Phe508del alleles.
Patients treated with one of two new-generation CFTR correctors — VX-445 or VX-659 — who were already receiving first-generation corrector dual therapy, also showed greater improvements in sweat chloride concentrations and better results on Cystic Fibrosis Questionnaire-Revised respiratory domain scores.
Phase II results from two parallel studies of VX-445 and VX-659 were published online in the New England Journal of Medicine, in conjunction with presentation at the North American Cystic Fibrosis Conference in Denver.
The CFTR potentiator therapy ivacaftor and the CFTR correctors lumacaftor and tezacaftor have not shown efficacy when given individually in the treatment of CF with Phe508del CFTR mutations, which occur in approximately two-thirds of CF patients.
Dual CFTR modulator therapy with a potentiator and a corrector has been shown to have modest efficacy in patients homozygous for the CFTR mutation (Phe508del-Phe508del), but the combination has not been shown to be effective in patients with Phe508del-minimal function (MF) mutations.
The phase II data from the two new studies suggest that the triple-therapy approach, which includes one of the new-generation CFTR correctors, could potentially treat the underlying cause of CF in approximately 90% of patients, researchers in both studies concluded.
In an editorial published with the two papers, Fernando Holguin, MD, of the University of Colorado at Aurora, characterized the triple-therapy studies as “a major breakthrough in cystic fibrosis therapeutics, with the potential for improving health and possibly survival in all patients who carry the most common CFTR mutation.”
Patients who received the triple combination treatment in both trials received the therapy for 4 weeks. Holguin wrote that it remains to be seen whether the observed lung function effects can be sustained for longer treatment periods “or whether these compounds will effectively reduce exacerbating rates and address other meaningful outcomes, such as weight gain.”
He noted that ongoing phase III trials of triple therapy with VX-445 and VX-659, funded by developer Vertex Pharmaceuticals, should answer these questions.
Phase III Data for Both Expected in the Coming Months
A spokesperson for Vertex told MedPage Today that the company expects to release phase III data from the VX-659 trial later this year, with the phase III findings from VX-445 scheduled for release early next year.
The spokesperson said that based on the phase III findings, the company plans to choose one of the two therapies to submit to the FDA for regulatory approval by no later than the middle of next year.
VX-659 and VX-445 bind to different sites on the CFTR protein than the first-generation correctors do, and have been shown to have synergistic effects with dual therapy in vitro using human bronchial epithelial cells from CF patients.
Both the VX-659 and the VX-445 trials included patients who were heterozygous for the Phe508del mutation and a minimal-function CFTR mutation (Phe508del-MF genotype) or homozygous for the Phe508del CFTR mutation (Phe508del-Phe508del genotype) who were already receiving dual therapy with tezacaftor and ivacaftor.
In the VX-659 trial, patients with Phe508del-MF genotype were randomized to receive 80, 240, or 400 mg of VX-659 in triple combination with tezacaftor and ivacaftor versus triple placebo for 4 weeks. Patients with the Phe508del-Phe508del genotype underwent a 4-week run-in phase with tezacaftor and ivacaftor before being randomly badigned to additional treatment with 400 mg of VX-659.
The VX-445 trial had the same intervention according to genotype, except patients received lower doses of the drug (50, 100, or 200 mg in the Phe508del-MF patients and 200 mg in the Phe508del-Phe508del patients).
The results shows that compared with placebo:
- 4 weeks of triple therapy including VX-659 significantly increased the primary end point of predicted percentage of forced expiratory volume in 1 second (FEV1) in both genotype groups by an average of 13.3% in the Phe508del-MF group and 9.7% in the Phe508del-Phe508del group
- Triple therapy with VX-445 significantly increased FEV1 in patients with Phe508del-MF by 13.8% and Phe508del-Phe508del by 11.0%
- Both of the new-generation CFTR modulator therapies improved sweat chloride concentrations and results on Cystic Fibrosis Questionnaire-Revised respiratory domain scores in both genotypes
Adverse events were common, but most were categorized as mild or moderate, the researchers reported.
Three of the 122 patients in the VX-445 trial discontinued treatment due to severe adverse events. Overall, five serious events occurred in the three patients receiving the combination treatment, with two events of distal intestinal obstruction syndrome and two events of infective pulmonary exacerbation of CF; one patient had both adverse events and jugular venous thrombosis, but no deaths occurred during the trial.
The VX-659-Tezacaftor-Ivacaftor and VX-445-Tezacaftor-Ivacaftor trials were funded by Vertex Pharmaceuticals, which also received funding from the Cystic Fibrosis Foundation.
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Reviewed by
Dori F. Zaleznik, MD Associate Clinical Professor of Medicine (Retired), Harvard Medical School, Boston and Dorothy Caputo, MA, BSN, RN, Nurse Planner
2018-10-18T15:30:00-0400
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