The combo therapy showed statistically significant improvements in lung function, as measured by percent predicted forced expiratory volume in one second (ppFEV1). The data was from a pre-specified interim analysis of the Phase III trial in individuals with one F508del mutation and one minimal function mutation. This showed a mean absolute improvement in ppFEV1 of 14.0 percentage points from baseline at week 4 compared to placebo.
In the Phase III trial in patients with F508del mutations, adding VX-659 to patients already receiving tezacaftor and ivacaftor showed a mean absolute improvement in ppFEV1 of 10.0 percentage points from baseline at week 4 compared to placebo.
Vertex stated that the safety and efficacy data support a possible New Drug Application (NDA) for the triple combination. It also indicated that enrollment is completed for both Phase III trials of the triple combination. It expects to report topline data from both trials in the first quarter of 2019.
The data reported data and in early 2019 will allow the company to pick the best regimen to submit to regulatory agencies worldwide, as well as the basis for an NDA to the U.S. Food and Drug Administration (FDA) by mid-2019.
Vertex has stated that its goal is to market therapies that could treat 90 percent of the genetic mutations that cause CF.
CF is a rare disease that affects about 75,000 people in North America, Europe and Australia. It is marked by a buildup of abnormally thick, sticky mucus that can lead to chronic lung infections, progressive lung damage and eventual death. The median age of death is in the mid-to-late 20s.
The disease is caused by a mutation in the CFTR gene or missing CFTR protein. Children must inherit two defective CFTR genes, one from each parent, in order to have the disease. There are about 2,000 known mutations in the gene, some of which can be identified by genetic testing.
The tezacaftor/ivacaftor and ivacaftor combination was approved by the FDA in February to treat CF in people ages 12 years or older who have two copies of the F508del mutation or one mutation that is responsive to the combination, which is marketed as Symdeko.
VX-659 is what is called a next-generation corrector. VX-659 and tezacaftor are both CFTR protein correctors, while ivacaftor, which is marketed as Kalydeco, is a potentiator of the protein. The F508del mutation causes the CFTR protein to misfold. Other mutations, like G551D, affect the opening of the protein. The correctors move the defective CFTR protein to the proper place on the cell’s surface, while ivacaftor helps in the opening of the protein.
“These data mark a major milestone in our efforts to develop new cystic fibrosis medicines as they underscore the important clinical benefit that a triple combination regimen may provide to the vast majority of cystic fibrosis patients who have at least one F508del mutation,” stated Vertex’s chief medical officer Reshma Kewalramani.
Paul Matteis, an analyst with Stifel, noted the data “live up to the hype” and wrote in a note to clients, “While details (as expected) are limited beyond the primary endpoint, from the press release there’s nothing to nitpick (in our view) for what has been reaffirmed as a transformational drug regimen in ‘het-min’ CF patients, a population that represents a multi-billion dollar opportunity with no targeted therapies approved today.”