Rare Disease Report

Vertex Initiates Phase 3 of Triple Combination for Cystic Fibrosis

FEBRUARY 22, 2018
Mathew Shanley
Vertex Pharmaceuticals, Inc. has initiated the first Phase 3 study of VX-659, Tezacaftor and Ivacaftor for the treatment of people with cystic fibrosis (CF) who have one F508del mutation and one minimal function mutation.

Earlier this month, Vertex announced that VX-659, a next-generation corrector, was being advanced into Phase 3 development as part of the triple combination regimen.

The decision to advance VX-659 was based on initial Phase 2 data that displayed mean absolute improvements in percent predicted forced expiratory volume in one second (ppFEV1) of up to 13.3 percentage points from baseline through 4 weeks of treatment for the triple combination regimen with VX-659 (400mg QD), in people who have a F508del mutation and a minimal function mutation (F508del/Min.).

The 508del mutation commonly leads to decreased activity of conductance regulator (CFTR) protein and chloride secretion loss. The combination can cause impaction of mucus in the airways, gastrointestinal tract, and exocrine organs, and can ultimately result in severe clinical consequences including steady loss of lung function, nutritional insufficiencies, pulmonary exacerbations, and respiratory failure.

It is the most rampant CFTR mutation worldwide, and an estimated 46% of American CF patients are affected by it.

“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,” said Jeffrey Chodakewitz, M.D., Executive Vice President and Chief Medical Officer at Vertex in a press release. “We’re pleased to initiate this study and look forward to working closely with the CF community to advance our two different triple combination regimens through Phase 3 development.”

The Phase 3 study intends to enroll 360 patients ages 12 years and older and the primary endpoint is the mean absolute change from baseline in ppFEV1 at week 4 of treatment.

“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,” said Steven M. Rowe, M.D., M.S.P.H., Director of the Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama at Birmingham, and co-chair of Vertex's Triple Combination Steering Committee. “The Phase 2 data for the triple combination of VX-659, tezacaftor and ivacaftor 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.”

The study is designed to accumulate additional safety data, as well as data for key secondary endpoints, including the number of pulmonary exacerbations, change in body mass index (BMI), change in sweat chloride, and changes in patient-reported outcomes as measured by the respiratory domain of the Cystic Fibrosis Questionnaire-Revised (CFQ-R) among others. It will evaluate a fixed-dose combination of VX-659 (240 mg), tezacaftor (100 mg) and ivacaftor (150 mg) in the morning, followed by ivacaftor (150 mg) in the evening.

Vertex plans to conduct an open-label extension study where all eligible patients – including those who received placebo – will receive the triple combination regimen for up to an additional 96 weeks. Additional Phase 3 studies of VX-659 will be initiated in 2018, as well.

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