A combination of tezacaftor and ivacaftor significantly improved lung function in cystic fibrosis (CF) patients 12 years and older who had a F508del mutation, according to two Phase 3 clinical trials conducted by Vertex Pharmaceuticals.
Tezacaftor (VX-661) works by correcting the CFTR channel’s position on cell surfaces, according to Vertex, which developed it. Mutations of the CFTR protein are the cause of CF.
Kalydeco, the brand name of ivacaftor, is an approved CF treatment. It is a potentiator of CFTR protein functioning, which means it helps facilitate that functioning.
One of the Phase 3 trials, EVOLVE (NCT02347657), assessed the effectiveness and safety of tezacaftor and Kalydeco in 477 patients 12 years and older who had two copies of the F508del CFTR mutation. Patients on the treatment received 100 mg of tezacaftor once a day and 150 mg of Kalydeco every 12 hours.
Researchers assessed patients’ change in ppFEV1, a measure of respiratory capacity, from the start of the study to the 24th week. Patients receiving the combo treatment had a 4 percent improvement in their mean absolute ppFEV1 score, compared with those taking a placebo.
The EXPAND trial (NCT02392234) investigated the effectiveness and safety of the combination treatment in patients 12 and older carrying one CFTR F508del mutation and one mutation that triggered residual CFTR activity.
Patients were divided into three groups. One received the tezacaftor/Kalydeco combination, another Kalydeco alone, and the third a placebo.
After eight weeks of treatment, patients were followed an additional eight weeks, but received no treatment. They were then added to one of the other two treatment groups for eight weeks. Doses of the two drugs were the same as in the EVOLVE study.
Researchers assessed the absolute change in patients’ ppFEV1 scores between the start of the treatment and either the fourth or eighth week, compared with the placebo. The tezacaftor/Kalydeco combination improved patients’ mean absolute score by 6.8 percentage points, compared with the placebo. Kalydeco alone improved the mean absolute score by 4.7 percentage points.
The combination therapy was well tolerated, both trials showed. The most frequent complaints of patients on either regimen was infection-related pulmonary exacerbations and cough. Few patients had to discontinue treatment due to adverse events — and the rates were similar between groups.
Rates of respiratory anomalies were similar between the treatment and placebo groups. The figure was 11.4 percent of the tezacaftor/Kalydeco group, and 15 percent of the placebo group.
“The tezacaftor/ivacaftor combination treatment demonstrated clinically meaningful benefits, with a favorable safety profile, across multiple patient groups,” Jeffrey Chodakewitz, MD, Vertex’s executive vice president and CMO, said in a press release. “This combination treatment may provide a promising new option for treating the underlying cause of CF in the future and brings us increasingly closer to our goal of developing new medicines for all people with the disease.”
Vertex plans to submit a New Drug Application (NDA) for the combo therapy to the U.S. Food and Drug Administration (FDA) and a Marketing Authorization Application (MAA) to the European Medicines Agency (EMA) this year. The applications will seek approval for the combination to be used to treat patients 12 and older who carry either two copies of the F508del mutation or one copy of the F508del mutation and one mutation that triggers residual CFTR function.