The first Phase 3 study will evaluate approximately 360 people with CF who have one copy of the F508del mutation and one minimal function mutation and is designed to support the submission of a New Drug Application (NDA) in the U.S. using data from the study’s 4-week primary efficacy endpoint together with safety data through 12 weeks of treatment.
The second Phase 3 study will evaluate approximately 100 people with CF who have two copies of the F508del mutation, the most common genetic form of the disease, and is designed to support the submission of an application for approval in patients with two copies of the F508delmutation in the U.S. using data from the study’s 4-week primary efficacy endpoint together with 24-week safety data generated from the Phase 3 study in patients with one F508del mutation and one minimal function mutation.
The initiation of the study in people with two copies of the F508del mutation is supported by data announced today from a Phase 2 study that showed an incremental mean absolute improvement in percent predicted forced expiratory volume in one second (ppFEV1) of 11.0 percentage points from baseline through week four of treatment when VX-445 (200 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-445 triple combination regimen was generally well tolerated, and the majority of adverse events were mild to moderate in severity.
Vertex chairman, president and CEO Jeffrey Leiden said: "The initiation of pivotal development for VX-445 marks important progress toward our goal of advancing two different next-generation triple combination regimens into pivotal development to allow us to bring the best regimen to people with CF.
“We recognize that many people with CF are awaiting the first treatment for the underlying cause of their disease, and I am pleased that we have been able to advance both VX-659 and VX-445 into pivotal studies. We look forward to the rapid progression of these and other studies over the coming year, including studies in people currently eligible for our approved medicines where a triple combination regimen may provide significant benefit.”
Vertex also today announced safety and efficacy results for the once-daily potentiator, VX-561, when dosed as part of a triple combination regimen with a next-generation corrector (VX-659 or VX-445) and tezacaftor in Phase 2 studies of people with one F508del mutation and one minimal function mutation.
In these studies, mean absolute improvements in ppFEV1 of 12.2 and 11.7 and percentage points from baseline through week four of treatment were observed for the VX-659 and VX-445 triple combination regimens, respectively.
The once-daily triple combination regimens were generally well tolerated, and the majority of adverse events were mild to moderate in severity. Following discussions with the U.S. Food and Drug Administration (FDA), Vertex plans to conduct additional dose-ranging for VX-561 to support potential late-stage development of future once-daily triple combination regimens.
About the VX-445 Phase 3 Study in People with One F508del Mutation and One Minimal Function Mutation
The randomized, double-blind, placebo-controlled Phase 3 study will evaluate VX-445 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 triple placebo.
The study is designed to support the submission of an NDA to the U.S. 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-445 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 change in patient-reported outcomes as measured by the respiratory domain score of the Cystic Fibrosis Questionnaire-Revised (CFQ-R), among others. 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-445 (200 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 triple placebo, will receive the VX-445 triple combination regimen for up to an additional 96 weeks.
About the VX-445 Phase 3 Study in People with Two F508del Mutations
The randomized, double-blind, controlled Phase 3 study will evaluate four weeks of treatment with VX-445 or placebo in combination with tezacaftor and ivacaftor in approximately 100 patients ages 12 years or older who have two F508del mutations. 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-445 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 change in sweat chloride and change in patient-reported outcomes as measured by the CFQ-R respiratory domain score.
The study is designed to support an application for U.S. FDA approval of the VX-445 triple combination regimen in patients with two copies of the F508delmutation 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-445 triple combination regimen and does not anticipate that the study will impact its initial planned submission of an NDA to the U.S. 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.
The study will evaluate a fixed-dose combination of VX-445 (200 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 Phase 3 study of 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 VX-445 triple combination regimen for up to an additional 96 weeks.
Phase 2 Data for VX-445 Triple Combination in People with Two F508del Mutations
The initiation of the Phase 3 study in people with two F508del mutations is supported by data announced today from a randomized, double-blind, controlled Phase 2 study where the primary objectives were safety, tolerability and efficacy as assessed by mean absolute change in ppFEV1 from baseline (end of the 4-week tezacaftor/ivacaftor run-in period) through week four of treatment. Secondary endpoints included absolute change in sweat chloride and change in the CFQ-R respiratory domain score.
All patients received a 4-week run-in of tezacaftor in combination with ivacaftor. Patients were then randomized to add either once-daily VX-445 (200 mg) or placebo to tezacaftor and ivacaftor for four weeks. After the 4-week triple combination dosing period, all patients received four weeks of tezacaftor and ivacaftor, followed by a 4-week safety follow-up period.