Vertex Pharmaceuticals Incorporated has announced that it is initiating the first phase 3 study of VX-659, tezacaftor and ivacaftor as an investigational triple combination regimen for people with cystic fibrosis (CF) who have one F508del mutation and one minimal function mutation. The study will enroll 360 patients, and the primary endpoint of the study is the mean absolute change from baseline in percent predicted forced expiratory volume in one second (ppFEV1) at week four of treatment. The study is designed to support the submission of a New Drug Application (NDA) in the US using data from the 4-week primary efficacy endpoint together with safety data through 12 weeks of treatment.

"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. "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."

"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 randomized, double-blind, placebo-controlled phase 3 study will evaluate VX-659 in combination with tezacaftor and ivacaftor, or triple placebo, in approximately 360 patients ages 12 and older who have one F508del mutation and one minimal function mutation. A list of the minimal function mutations currently included in this study can be found here. The primary endpoint of the study is the mean absolute change in lung function (ppFEV1) from baseline at week four of triple combination treatment compared to placebo.

The study is designed to support the submission of an NDA to the US Food and Drug Administration (FDA) based on data from the 4-week primary efficacy analysis and on safety data through 12 weeks of treatment. The study will evaluate VX-659 in combination with tezacaftor and ivacaftor for a total of 24 weeks of treatment to generate additional safety data and data for key secondary endpoints, including the number of pulmonary exacerbations, change in body mass index, 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. The 24-week data from this study are not required to complete the NDA submission. Data from this study will also be used to support planned regulatory submissions in Europe and other regions.

The study 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. An open-label extension study will be conducted where all eligible patients, including those who received placebo, will receive the triple combination regimen for up to an additional 96 weeks.

Vertex plans to initiate multiple additional phase 3 studies of VX-659 and VX-445 triple combination regimens in 2018. Regulatory discussions are ongoing regarding the design of these additional phase 3 studies.