Vertex Pharmaceuticals is planning to request regulatory approval from the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) during the third and fourth quarters of 2019, respectively, for VX-659 or VX-445 triple combination regimens.
If approved, these new combo therapies will represent an alternative and effective strategy to treat cystic fibrosis (CF) patients with two copies of F508del mutation (F) or one F508del mutation plus one minimal function mutation (MF).
The company’s decision to advance these combo regimens for global approval is supported by positive clinical data from several Phase 3 trials.
“Both the VX-659 and VX-445 triple combination regimens showed highly consistent and significant improvements in lung function across our Phase 3 programs,” Reshma Kewalramani, MD, executive vice president, global medicines development and medical affairs and chief medical officer at Vertex, said in a press release.
The AURORA program consists of two randomized, double-blind Phase 3 trials — AURORA F/MF (NCT03525444) and F/F (NCT03525548) trials — in patients with CF caused by F/F or F/MF mutations. All participants who complete these studies have the opportunity to continue treatment with the triple combo therapy in an additional 96-week, open-label extension trial (NCT03525574).
The AURORA F/MF study enrolled 403 CF patients, age 12 and older, who received at least one dose of either the VX-445 triple combination regimen or triple placebo. A list of the minimal function mutations included in this study can be found here.
The second Phase 3 study, AURORA F/F trial, randomized 108 CF patients, age 12 and older, to receive VX-445 or a placebo in combination with tezacaftor and Kalydeco.
In both studies, VX-445 triple combo regimen promoted improvement in CF patients’ respiratory function. Interim analysis showed that four weeks of therapy in F/MF patients resulted in an absolute mean improvement in ppFEV1 (percent predicted forced expiratory volume in one second; a measure of lung function) of 13.8 percentage points compared to before triple treatment initiation, while in the F/F population it led to a mean improvement of 10 percentage points.
In general, the combination of VX-445 with tezacaftor and Kalydeco was well-tolerated, showing an acceptable safety profile similar to that previously reported.
These studies are ongoing, and Vertex anticipates announcing more topline data on safety and efficacy of the VX-445 triple combination regimen data upon completion of 24 weeks of treatment in both trials.
During this period, researchers will assess the ability of the combo therapy to reduce sweat chloride levels, which are elevated in CF patients, and the number of pulmonary exacerbations. Changes in patient-reported outcomes, as measured by the Cystic Fibrosis Questionnaire-Revised (CFQ-R) respiratory domain score, will also be determined.
All patients who have participated in the AURORA program and have already completed the 24-week treatment regimen decided to enter the open-label extension study, Vertex announced.
These positive preliminary clinical data on VX-445 triple combination therapy follow similar results reported in November 2018 for the Phase 3 ECLIPSE program of VX-659, tezacaftor, and Kalydeco combo.
Interim data of VX-659 triple combination demonstrated that it can improve lung function of both F/F (NCT03460990) and F/MF (NCT03447249) CF patients, with absolute mean improvement in ppFEV1 of 10 percentage points and 14 percentage points, compared to before the start of treatment.
Vertex plans to use the final 24-week data from these clinical studies to choose the best regimen to submit for regulatory approvals worldwide.