Vertex Pharmaceuticals Incorporated, a global biotechnology company, announced that it is initiating a phase 3 study of VX-659, tezacaftor and ivacaftor as an investigational triple combination regimen for people with cystic fibrosis (CF) who have two copies of the F508del mutation, the most common genetic form of the disease. The study will enroll approximately 100 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 an application for approval in patients with two copies of the F508del mutation in the US using data from the 4-week primary efficacy endpoint together with 24-week safety data generated from the recently initiated phase 3 study in patients with one F508del mutation and one minimal function mutation.

The initiation of the phase 3 study in people with CF who have two copies of the F508del mutation is based on data announced from a phase 2 study that showed a mean absolute improvement in ppFEV1 of 9.7 percentage points from baseline through week four of treatment when VX-659 (400 mg) was added in people with CF who have two F508del mutations and were already receiving tezacaftor in combination with ivacaftor. In the phase 2 study, the VX-659 triple combination regimen was generally well tolerated, the majority of adverse events were mild to moderate in severity and there were no discontinuations due to adverse events.

"We continue to make rapid and significant progress in our efforts to advance our two triple combination regimens into phase 3 development, with an ultimate goal of bringing the best triple combination to patients as quickly as possible," said Jeffrey Chodakewitz, M.D., executive vice president and chief medical officer at Vertex. "The first Phase 3 study we announced in February is designed to support approval of the VX-659 triple combination in patients with one F508del mutation and one minimal function mutation who currently have no treatment that addresses the underlying cause of disease. This second study is designed to enable us to broaden the potential label for this regimen to include those with the most common genetic form of cystic fibrosis."

The randomized, double-blind, controlled phase 3 study will evaluate four weeks of treatment with VX-659 or placebo in combination with tezacaftor and ivacaftor in approximately 100 patients ages 12 years or older who have two F508del mutations. Approximately 50 patients will receive VX-659, tezacaftor and ivacaftor and approximately 50 will receive placebo, tezacaftor and ivacaftor. All patients will receive tezacaftor in combination with ivacaftor during a 4-week run-in prior to the start of the triple combination treatment period. The primary endpoint of the study is the mean absolute change in lung function (ppFEV1) from baseline (end of the 4-week tezacaftor/ivacaftor run-in) at week four of treatment with VX-659 in combination with tezacaftor and ivacaftor compared to those who received placebo, tezacaftor and ivacaftor. Key secondary endpoints will also be measured at week four and include changes in patient-reported outcomes as measured by the respiratory domain of the Cystic Fibrosis Questionnaire-Revised (CFQ-R) and change in sweat chloride.

The study will evaluate a fixed-dose combination of VX-659 (240 mg) with tezacaftor (100 mg) and ivacaftor (150 mg) in the morning followed by ivacaftor (150 mg) in the evening, which is the same dosing regimen being evaluated in the ongoing phase 3 study in patients with one F508del mutation and one minimal function mutation. An open-label extension study will be conducted where all eligible patients, including those who received placebo, tezacaftor and ivacaftor, will receive the triple combination regimen for up to an additional 96 weeks.

The study is designed to support an application for US Food and Drug Administration (FDA) approval of the VX-659 triple combination regimen in patients with two copies of the F508del mutation based on data from the 4-week primary efficacy analysis and secondary safety analysis and on 24-week safety data from the phase 3 study in patients with one F508del mutation and one minimal function mutation. Vertex plans to use the study in patients with two F508del mutations to broaden the potential label for the VX-659 triple combination regimen and does not anticipate that the study will impact its initial planned submission of a New Drug Application to the US FDA for patients with one F508del mutation and one minimal function mutation. Data from the study in patients with two F508del mutations will also be used to support planned regulatory submissions in Europe and other regions.

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.