Vertex Pharmaceuticals is launching Phase 3 clinical trials to evaluate the safety and effectiveness of its investigational therapy, VX-445, in combination with VX-661 (tezacaftor) and Kalydeco (ivacaftor) for cystic fibrosis (CF).
The AURORA program will consist of two randomized, double-blind Phase 3 trials — AURORA F/MF and F/F trials — to test the triple combo therapy in patients with one or two copies of the F508del mutation in the CFTR gene — the gene that is defective in CF.
The AURORA F/MF study is expected to enroll 360 participants, ages 12 and older, with one F508del mutation and one minimal function mutation in CFTR, who have not responded to VX-661, Kalydeco, or their combo regimen. A list of the minimal function mutations currently included in this study can be found here.
Half of the participants will receive the triple combination treatment, and the remaining patients will receive a placebo for 24 weeks.
The second Phase 3 study, AURORA F/F trial, will enroll about 100 patients, ages 12 and older, with two copies of the F508del mutation — the most common genetic form of the disease. Participants will be treated with VX-661 plus Kalydeco for four weeks, after which they will be randomized to receive VX-661 and Kalydeco plus VX-445 or placebo for an additional four weeks.
In both trials, researchers will evaluate the potential of the combo therapy to enhance predicted forced expiratory volume, a measure of lung function, as well as to reduce sweat chloride, levels of which are elevated in cystic fibrosis patients, and the number of pulmonary exacerbations. Change in patient-reported outcomes as measured by the Cystic Fibrosis Questionnaire-Revised (CFQ-R) respiratory domain score will also be determined.
All participants who complete the studies will have the opportunity to continue treatment with the triple combo therapy in an additional 96-week, open-label extension trial.
Vertex is anticipating that the safety and efficacy data collected in these trials will help broaden the approval of VX-445 and support the submission of a new drug application for the triple combo therapy in the U.S. and Europe.
“The initiation of pivotal development for VX-445 marks important progress toward our goal of advancing two different next-generation triple combination regimens into pivotal development to allow us to bring the best regimen to people with CF,” Jeffrey Leiden, MD, PhD, chairman, president, and CEO of Vertex, said in a press release.
Launch of the AURORA F/F trial was supported by recent data from a randomized, double-blind Phase 2 trial on VX-445 (NCT03227471). Efficacy data showed a mean improvement of 11 percentage points from baseline (the start of the study) in the predicted forced expiratory volume in one second (ppFEV1) by the fourth week in CF patients with two F508del mutations receiving VX-445 plus VX-661 and Kalydeco. The triple combo was shown to significantly reduce sweat chloride as well, and to improve the mean absolute scores of patient-reported outcomes by about four times, compared with VX-661 and Kalydeco combo therapy.
During the Phase 2 study, the triple combination treatment was generally well-tolerated, and most of the adverse events were mild to moderate in severity.
The company is also recruiting participants for its Phase 3 ECLIPSE program testing the triple combination of VX-659 plus VX-661 and Kalydeco in CF patients (NCT03447249 and NCT03460990). This program will also have an extension study (NCT03447262).
“We recognize that many people with CF are awaiting the first treatment for the underlying cause of their disease, and I am pleased that we have been able to advance both VX-659 and VX-445 into pivotal studies,” Leiden said. “We look forward to the rapid progression of these and other studies over the coming year, including studies in people currently eligible for our approved medicines where a triple combination regimen may provide significant benefit.”
Vertex’s investigational CFTR potentiator VX-561
The company also tested both VX-659 and VX-445 in combination with VX-661 plus once-daily VX-561 in two Phase 2 trials (NCT03224351 and NCT03227471, respectively) to treat CF patients with one F508del mutation and one minimal function mutation.
In the first trial, a total of 19 patients were treated with a once-daily dose of 400 mg of VX-659, 100 mg of VX-661, and 200 mg of VX-561, and six patients received a daily placebo for four weeks.
Patients on the triple combo therapy experienced significant improvements in lung function — improving ppFEV1 by 12.2 percentage points, compared with baseline. A significant reduction of mean levels of sweat chloride was also reported by the end of the four-week treatment.
Patient-reported outcomes also demonstrated the beneficial effect of the triple combo therapy compared with placebo. The triple combination led to a mean absolute improvement of 14.7 points in the CFQ-R respiratory domain score, compared with a decrease of 4.1 points in the placebo group.
The second Phase 2 trial, which tested a once-daily dose of 150 mg of VX-561 plus 200 mg of VX-445 and 100 mg of VX-661, also revealed positive results.
After four weeks of treatment, the 21 patients treated with the triple combo therapy experienced an improvement of a mean 11.7 percentage points in ppFEV1 compared with 1.2 percentage points in the eight patients in the placebo group. This combination also resulted in a significant improvement in sweat chloride levels.
Both triple combinations were generally well-tolerated, and the safety profile was similar to that observed in previously reported parts of the Phase 2 trials.
Most adverse events were mild to moderate. Some of the most common adverse effects reported were cough, infective pulmonary exacerbation, nausea, throat pain, fever, and rash.
Vertex will discuss these results with the U.S. Food and Drug Administration, and plans to conduct additional dose-ranging studies with VX-561. This clinical data could provide additional evidence to support future Phase 3 trials to evaluate these once-daily triple combination regimens.