Vertex Discontinues One Study of VX-661/Ivacaftor Combo in Cystic Fibrosis

Development program continues in CF subgroups

Vertex Pharmaceuticals has provided an update on the ongoing phase 3 development program for its investigational compound VX-661 in combination with ivacaftor, which includes four studies that are expected to enroll more than 1,000 subjects with cystic fibrosis (CF). Based on a futility analysis conducted by the study’s independent data safety monitoring board (DSMB), Vertex plans to stop the study of VX-661 and ivacaftor in subjects with one copy of the F508del mutation and one copy of a mutation that results in minimal CF transmembrane conductance regulator (CFTR) protein function (F508del het/min).

In April, Vertex completed the enrollment of approximately 150 subjects in part A of a two-part trial evaluating subjects with mutations that result in minimal CFTR function. A planned interim futility analysis was conducted by the study’s independent DSMB after at least eight weeks of dosing to determine whether to stop the study or to continue the study and initiate enrollment in part B.

The analysis showed that the combination of VX-661 and ivacaftor did not result in a prespecified improvement in lung function. The DSMB recommended that Vertex stop the study and not initiate enrollment in part B. No safety concerns were noted in the DSMB’s review of the data. Vertex plans to close this study, based on the recommendation of the DSMB, and patients from part A of the study who were enrolled into the long-term extension study will be transitioned off the combination of VX-661 and ivacaftor.

The study findings suggest that a triple combination regimen may provide this group of CF patients with the best chance at obtaining a meaningful clinical benefit, a company spokesman said.

In addition to the terminated trial, the VX-661 phase 3 program includes three studies in different groups of subjects with CF who have at least one copy of the F508del mutation. The studies are evaluating VX-661 dosed at 100 mg once daily in combination with ivacaftor dosed at 150 mg every 12 hours. These studies include subjects with CF with the following mutations:

  • Two copies of the F508del mutation. In August, Vertex completed enrollment in a study evaluating 24 weeks of treatment with VX-661 in combination with ivacaftor in approximately 500 subjects with CF who have two copies of the F508del mutation. Results from this study are expected in the first half of 2017.
  • One copy of the F508del mutation and a second mutation that results in residual CFTR function. In September, Vertex expects to complete enrollment in a study evaluating VX-661 in combination with ivacaftor in approximately 200 subjects with residual function mutations. The crossover study includes two eight-week dosing periods, separated by an eight-week washout period. The study includes an arm of ivacaftor monotherapy, in addition to an arm evaluating VX-661 in combination with ivacaftor and a placebo arm. Results from this study are expected in the first half of 2017.
  • One copy of the F508del mutation and a second mutation that results in a gating defect in the CFTR protein. Enrollment is ongoing in a study designed to evaluate VX-661 in combination with ivacaftor in subjects with gating mutations that have been shown to be responsive to ivacaftor alone. The study is expected to enroll approximately 200 subjects and is evaluating eight weeks of treatment with VX-661 in combination with ivacaftor. Enrollment is expected to be completed in late 2016 or early 2017.

Vertex plans to submit a new drug application (NDA) to the FDA for VX-661 in combination with ivacaftor in the second half of 2017, pending data from the phase 3 program. The NDA is expected to include results from the study in subjects with minimal function mutations.

CF is a rare, life-shortening genetic disease affecting approximately 75,000 people in North America, Europe, and Australia. The median predicted age of survival for a person with CF is between 34 and 47 years, but the median age of death remains in the mid-20s.

CF is caused by a defective or missing CFTR protein resulting from mutations in the CFTR gene. Children must inherit two defective CFTR genes—one from each parent—to develop CF. There are more than 1,900 known mutations in the CFTR gene. Some of these mutations, which can be determined by a genotyping test, lead to CF by creating nonworking or too few CFTR proteins at the cell surface. The defective function or absence of CFTR proteins in people with CF results in a poor flow of salt and water into and out of cells in a number of organs, including the lungs. This leads to the buildup of abnormally thick, sticky mucus that can cause chronic lung infections and progressive lung damage.

Source: Vertex Pharmaceuticals; August 15, 2016.