Treatment with a triple combination — the new CFTR corrector VX-659, together with tezacaftor and Kalydeco (ivacaftor) — significantly improved lung function and was well-tolerated by cystic fibrosis (CF) patients, ages 12 and older, with at least one F508del mutation in two Phase 3 studies, according to Vertex Pharmaceuticals.
This data support a potential request for approval of this triple combination for its respective patient groups, likely in the coming year, the company said.
Specifically, results from an early analysis of a Phase 3 trial (NCT03447249) in people with one F508del mutation (the most common CF mutation) and one other eligible mutation, conferring minimal function to CFTR (the defective gene in CF), showed a 14.0% mean absolute improvement in lung function in treated patients from baseline (study start) to four weeks of treatment compared to those given placebo. Lung function was measured by percentage change in the amount of air exhaled in one second (ppFEV1).
The trial included 385 CF patients, and four-week data was available for 380 of them.
The VX-659 triple combination regimen was generally well-tolerated, as assessed on 302 patients who had reached week 12 of treatment (151 patients on each group), and 58 participants who completed the final 24-week visit (28 patients on VX-659, and 30 on placebo). The study is ongoing, but the four-week lung function measure was its primary goal.
A separate trial in people with two F508del mutations (NCT03460990), adding VX-659 to a regimen of tezacaftor and Kalydeco led to a mean absolute improvement in ppFEV1 of 10.0% from baseline to week four, compared to patients given a triple combo of placebo plus tezacaftor and Kalydeco. Again, measures of lung function at four weeks was the study’s primary goal, or endpoint.
All 111 patients were treated with tezacaftor and Kalydeco for an initial four weeks, before being randomized to one dose of a treatment (including VX-659) or a placebo triple combination. The VX-659 triple combination was generally well-tolerated.
“These data mark a major milestone in our efforts to develop new CF medicines as they underscore the important clinical benefit that a triple combination regimen may provide to the vast majority of CF patients who have at least one F508del mutation,” Reshma Kewalramani, MD, Vertex’s executive vice president, global medicines development and medical affairs and chief medical officer, said in a press release.
Patients enrolled in these two Phase 3 trials are eligible to continue or start triple combination treatment with VX-659 in open-label extension studies.
Vertex also announced that patient enrollment is complete for its two Phase 3 studies of another triple combination — the next-generation corrector VX-445, together with tezacaftor and Kalydeco in CF patients with one F508del mutation and one minimal function mutation (NCT03525444), and in patients with two F508del mutations (NCT03525548).
Topline data of the four-week efficacy goals for these studies — with similar designs and lung function evaluations as those with VX-659 — are expected in the first quarter of 2019.
According to Vertex, results from VX-445 and the VX-659 trials will be used to choose the best regimen to submit for potential regulatory approvals, including a new drug application (NDA) for a triple combination treatment to the U.S. Food Drug Administration (FDA) possibly no later than mid-2019.
Regulatory submissions outside of the U.S. are planned for late 2019.
Vertex said additional safety and efficacy data from the two trials of VX-659 will not be released until the second half of 2019, when the VX-659 and VX-445 Phase 3 studies are completed.