Vertex Pharmaceuticals selected its VX-445 (elexacaftor) triple regimen to apply for regulatory approvals in the U.S. and Europe over the third and fourth quarters of 2019. The therapeutic regimen is intended for the treatment of cystic fibrosis (CF) in patients 12 and older.
The triple combo consists of VX-445, a CFTR corrector, added to tezacaftor (VX-661) and Kalydeco (ivacaftor), and is intended for CF patients with two copies of the F508del mutation (F/F) or one F508del mutation plus one minimal function mutation (F/MF).
Now, the company has selected the VX-445 combo regimen to advance for global approvals, based on final positive data of two Phase 3 trials — a 24-week and a 4-week study.
According to Vertex, both trials met their primary efficacy goal as the VX-445 combo significantly improved lung function, as measured by forced expiratory volume in one second (FEV1).
Vertex’s Phase 3 program for the VX-445 regimen consists of two randomized, double-blind Phase 3 trials in patients with CF caused by one F508del plus one minimal function mutation (NCT03525444) or by two F508 del mutations (NCT03525548).
The trial in F/MF population enrolled 403 CF patients, age 12 and older, who received a fixed-dose combination of either VX-445 triple combination or triple placebo during a period of up to 24 weeks. A list of the minimal function mutations included in this study can be found here.
Final data from this trial showed that patients receiving the combo therapy had a mean improvement in percent predicted FEV1 (ppFEV1) of 14.3 percentage points, from study start through week 24, compared with those given placebo.
Moreover, patients treated with the VX-445 regimen also gained significant improvements in all secondary endpoints of the trial, including a 63% reduction in the annual rate of pulmonary exacerbations compared to placebo.
In addition, their sweat chloride levels were significantly reduced, body mass index was raised, and patients reported better overall health (measured by CFQ-R) through week 24.
The other Phase 3 study was a 4-week trial conducted in F/F CF patients. A total of 107 patients, age 12 and older, were randomized to receive treatment with VX-445 or a placebo in combination with tezacaftor and Kalydeco.
At four weeks, results showed that those on VX-445 also had a significant mean increase of 10 percentage points in ppFEV1.
In both studies, the VX-445 triple combination regimen was generally well-tolerated. The majority of adverse events were mild or moderate, and more than 98% of the patients completed the trials. In the 24-week trial, two people in the VX-445 group discontinued treatment because of adverse events.
Patients who completed the trial studies will now have the opportunity to continue on treatment by entering an open-label extension study (NCT03525574).
“People with CF who have one F508del mutation and one minimal function mutation are the largest remaining group of CF patients without a treatment option for the underlying cause of their disease. The final Phase 3 data announced today represent a significant step toward bringing a disease-modifying medicine to these patients, as well as toward providing significantly enhanced benefits to patients with two F508del mutations,” Reshma Kewalramani, MD, executive vice president and chief medical officer at Vertex, said in a press release.
Steven M. Rowe, MD, director of the Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama at Birmingham and chair of Vertex’s triple combination steering committee, said: “The substantial improvements in lung function and other measures of CF seen in these Phase 3 studies are unprecedented and represent a defining moment in the journey to provide medicines that treat the underlying cause of CF to the vast majority of people with CF.”
Based on the data obtained — including favorable safety, the ability for co-administration with hormonal contraceptives, and the lack of photosensitivity — Vertex considered that the VX-445 triple combo could benefit the greatest number of CF patients, and is now seeking its global approval.
The company plans to file a New Drug Application to the U.S. Food and Drug Administration (FDA) in the third quarter of 2019, followed by a Marketing Authorization Application to the European Medicines Agency in the fourth quarter of 2019.
“We could not have achieved this important milestone without the support of the entire CF community, and we are particularly grateful to those who participated in the triple combination clinical trials. We now look forward to completing our regulatory submissions with the aim of bringing the VX-445 triple combination regimen to as many patients as possible,” Kewalramani said.