Vertex Begins First Phase 3 Trial Testing CF Triple Combo Therapy VX-659, Tezacaftor and Kalydeco

Vertex Begins First Phase 3 Trial Testing CF Triple Combo Therapy VX-659, Tezacaftor and Kalydeco

Vertex Pharmaceuticals launched the first Phase 3 clinical trial investigating the triple combination therapy of VX-659tezacaftor (VX-661), and Kalydeco (ivacaftor) in cystic fibrosis (CF) patients with one F508del mutation and one minimal function mutation in the CFTR gene, which is defective in CF patients.

Vertex hopes the results from the triple combo treatment will support a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA), and later to regulatory agencies in Europe and elsewhere.

The Phase 3 trial (NCT03447249) is supported by early positive data from an ongoing Phase 2 study (NCT03224351) testing this triple combination.

Minimal function mutations in the CFTR gene lead to a poorly or non-functioning CFTR protein, so patients who carry it are unable to respond to Kalydeco or tezacaftor treatment alone — or both those therapies combined.

Design of the Phase 3 Study

The clinical trial is enrolling 360 CF patients ages 12 or older with one F508del mutation and one minimal function mutation at sites in the U.S., U.K., Canada, Australia, Denmark, Germany, Ireland, Israel, Norway, Poland, Spain, and Switzerland. Vertex has provided a detailed list of the minimal function mutations eligible for the study; enrollment information is available here.

Participants will be randomized to the triple combo or to placebo (the control group). Patients in the combo group will receive a fixed-dose of each drug — VX-659 (240 mg), tezacaftor (100 mg) and Kalydeco (150 mg) — administered in the morning followed by Kalydeco (150 mg) alone in the evening.

The trial also includes an open-label extension phase (NCT03447262) where all eligible patients, including those on placebo, will receive the triple combo therapy for up to 96 weeks (1.8 years).

Its primary objective (endpoint) is measures of the mean absolute change in lung function in CF patients after four weeks of treatment compare to those in the placebo group.

Vertex hopes the resulting four-week efficacy data and the safety profile of the combo therapy, measured after 12 weeks, will support its NDA submission.

The trial will continue for a total of 24 weeks of treatment to gather additional data on the triple combo therapy’s safety and other (secondary) endpoints, including the number of pulmonary exacerbations, and changes in several parameters — body mass index, sweat chloride, patient-reported outcomes (via the Cystic Fibrosis Questionnaire-Revised).

Results from the 24-week study will not be included in the NDA.

“Our goal is to bring the best triple combination to patients as rapidly as possible, and this first Phase 3 study of VX-659 in combination with tezacaftor and ivacaftor is a significant step toward that goal,” Jeffrey Chodakewitz, MD, executive vice president and chief medical officer at Vertex, said in a press release.

Steven M. Rowe, MD, MSPH, co-chair of Vertex’s Triple Combination Steering Committee, said there is a “significant unmet medical need to treat the underlying cause of CF for those with one F508del mutation and a minimal function mutation, and these patients are eagerly awaiting new treatment options.

“The Phase 2 data for the triple combination of VX-659, tezacaftor and ivacaftor [Kalydeco] showed impressive improvements in multiple measures of CF for patients with minimal function mutations, and I am pleased that this Phase 3 study is designed to enable rapid advancement of the VX-659 regimen toward patients,” he added.

Rowe is also director of the Gregory Fleming James Cystic Fibrosis Research Center at the University of Alabama at Birmingham.

Additional trials testing Vertex next-generation correctors VX-659 and VX-445 in triple combinations are planned for 2018.


  1. Solomon Adelaida says:

    My son is 15,has one mutation F508del, the other one was not identified. Is there any chance to take part in these trials if we live in Romania?

  2. Mousa Amayreh says:

    I am eager to see this treatment soon. I have my son (32yrs.) and my daughter (24yrs.) both are cf. I am from Jordan. I’d like to include them in future studies.

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