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Restore CFTR Protein Completed with Results

Phase 2 study of VX-659 combination drug in adults with cystic fibrosis (Vertex VX16-659-101)

This study evaluated the safety, tolerability and effectiveness of the drug VX-659 in combination with tezacaftor/ivacaftor (Symdeko®) in people who either have two copies of the F508del CFTR mutation or have one copy of F508del and one copy of a minimal function CFTR mutation.

 This study had three parts. In Part 1, participants who have one copy of F508del and one copy of a minimal function CFTR mutation were randomized to receive either 4 weeks of one of three doses of VX-659 (80mg, 240mg, or 400mg once per day) in triple combination with tezacaftor (100mg once per day) and ivacaftor (150 mg every 12 hours) or matching placebo. Following the 4-week treatment period, participants taking the VX-659 triple combination therapy received only tezacaftor/ivacaftor for 4 days in order to study the effect of eliminating VX-659. Part 2 enrolled participants who have two copies of the F508del CFTR mutation. Because dual combination CFTR modulators are available to people who have two copies of the F508del CFTR mutation, tezacaftor/ivacaftor was used as a part of the placebo control. All participants received 4 weeks of tezacaftor/ivacaftor before being randomized to either 4 weeks of VX-659 (400mg once per day) in triple combination with tezacaftor (100mg once per day) and ivacaftor (150 mg every 12 hours) or placebo plus tezacaftor/ivacaftor. Following the 4-week treatment period, all participants received only tezacaftor/ivacaftor for an additional 4 weeks in order to study the effect of eliminating VX-659. In Part 3, participants who have one copy of F508del and one copy of a minimal function CFTR mutation were randomized to either 4 weeks of VX-659 (400mg once per day) in combination with tezacaftor (100mg once per day) and VX-561 (deuterated ivacaftor, 150 mg once per day) or triple combination placebo.

Eligibility

See other primary eligibility criteria for more information.

  • Age:

    18 Years and Older

  • Mutation(s):

    Two Copies F508del or One Copy F508del

  • FEV1% Predicted:

    40% or greater

For more information about the results of this study and where it was conducted, visit ClinicalTrials.gov.

Other Primary Eligibility Criteria

There are over 195 minimal function mutations that are eligible for this study. Some of the most common eligible mutations include: G542X, N1303K, W1282X, R553X, 621+1G->T, 1717-1G->A, 3120+1G->A, I507del, R1162X, 3659delC, 1898+1G->A, G85E, R560T, R347P, 2184insA, 2184delA, Q493X This is not a complete list of eligible mutations. Please contact a research coordinator to find out if your particular mutation is eligible for this study.

Study Results

  • What We Learned:

    This study found that VX-659 in combination with tezacaftor/ivacaftor resulted in a significant improvement in lung function (ppFEV1), sweat chloride and quality of life (CFQ-R) when compared with placebo (in participants with one copy of F508del) or when compared with tezacaftor/ivacaftor alone (in participants with two copies of F508del).

     

    Additionally, VX-659 in combination with tezacaftor/ivacaftor was generally well-tolerated.  Elevated liver enzymes were seen in three participants taking VX-659 triple combination.

    Similar results were seen for the group of participants who received VX-659 in combination with tezacaftor and VX-561.

  • Primary Findings:

    Effectiveness:

    This study was conducted between July 2017 and March 2018. In Part 1 (participants who have one copy of F508del and one copy of a minimal function CFTR mutation), 63 participants were enrolled [N= 10 to placebo, N=11 to VX-659 (80mg), N=20 to VX-659 (240mg), N=22 to VX-659 (400mg)]. There was one discontinuation in Part 1 due to withdrawal of consent.

     

    In Part 2 (participants who have two copies of the F508del CFTR mutation), 29 participants were enrolled [=11 to placebo and N=18 to VX-659 (400mg)].  

     

    In Part 3 (participants who have two copies of the F508del CFTR mutation), 25 participants were enrolled [N=6 to placebo and N=19 to VX-659 (400mg)]. There was one discontinuation due to an adverse event.

     

    The primary efficacy objective was change in lung function from baseline as measured by absolute change in ppFEV1. This study met its primary endpoint as significant improvements in lung function from baseline were seen in participants who received the triple combination in all parts of the studies at all doses tested compared with placebo.

     

    Notably, at the dose of the triple combination selected to move forward into phase 3 (VX-659 240 mg + tezacaftor/ivacaftor), FEV1% predicted increased by 12% (p<0.001) for participants with one copy of the F508del mutation.  While the 240 mg dose of VX-659 was not tested in participants with two copies of F508del, at the 400mg dose there was a 9.7% (p<0.001) improvement in lung function (FEV1% predicted).

     

     

    Significant improvements were also seen in sweat chloride when compared with placebo. At the 240mg dose that moved into phase 3 trials, sweat chloride significantly dropped in participants with one copy of F508del (-44 mmol/L).

     

    Additionally, improvements were seen in the respiratory domain of a quality of life questionnaire (CFQ-R) in all genotypes.

     

    Safety:

    Overall, VX-659 in combination with tezacaftor/ivacaftor was well-tolerated. The most common adverse events in participants receiving the VX-659 triple combination (greater than 10%) were cough, infective pulmonary exacerbation, throat pain, and chest pain.

     

    Elevated liver enzymes (ALT or AST) greater than three times the upper limit of normal range occurred in two participants receiving VX-659 in triple combination. Elevated bilirubin greater than five times the upper limit of normal range occurred in one participant.

  • Citation:

    N Eng J Med 2018;DOI 10.1056/NEJMoa1807119. Epub 2018 Oct 18

For current information about the overall development status of this drug, please check the Drug Development Pipeline.

Study Design

  • Study Type: ?more info

    Interventional

  • Randomized Study: ?more info

    Yes

  • Placebo Controlled: ?more info

    Yes

  • Length of Participation:

    8 weeks

  • Number of Study Visits:

    6

Additional Information

Eligibility

See other primary eligibility criteria for more information.

  • Age:

    18 Years and Older

  • Mutation(s):

    Two Copies F508del or One Copy F508del

  • FEV1% Predicted:

    40% or greater

For more information about the results of this study and where it was conducted, visit ClinicalTrials.gov.

Other Primary Eligibility Criteria

There are over 195 minimal function mutations that are eligible for this study. Some of the most common eligible mutations include: G542X, N1303K, W1282X, R553X, 621+1G->T, 1717-1G->A, 3120+1G->A, I507del, R1162X, 3659delC, 1898+1G->A, G85E, R560T, R347P, 2184insA, 2184delA, Q493X This is not a complete list of eligible mutations. Please contact a research coordinator to find out if your particular mutation is eligible for this study.

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