How tezacaftor/ivacaftor works
CF is an inherited condition that causes a damaging thick mucus to build up in the lungs and other organs. This results in symptoms such as severe breathing difficulties, increased risk of lung infections, and digestive problems.
The condition is caused by a mutation in the CFTR gene, which provides instructions for making the CFTR protein. This protein functions as a channel that regulates the production of a lubricating mucus required in organs like the lungs by controlling the transport of charged substances such as chloride and sodium over the cell membrane, which in turn influences the movement of water in and out of cells.
In cystic fibrosis, the faulty transport of those substances is caused by mutations in the CTFR gene, which results in thick and sticky mucus. The most common mutation that causes the disease is called F508del, which results in the CFTR protein breaking down quickly before it can reach the cell membrane and transport chloride. The tezacaftor/ivacaftor combination therapy is designed to restore functional activity to the CTFR protein.
The treatment consists of tezacaftor (VX-661) and Kalydeco (ivacaftor). Tezacaftor is a “corrector” therapy, meaning it acts to move the defective CFTR protein to the cell membrane so that it can transport chloride. Kalydeco is a therapy approved by the U.S. Food and Drug Administration (FDA) for the treatment of CF. It improves the flow of chloride over the cell membrane by increasing the length of time that the CFTR channel is open.
Tezacaftor/ivacaftor in clinical trials
The tezacaftor/ivacaftor combination therapy has been tested in multiple Phase 3 clinical trials and has demonstrated a clinical benefit. Additional trials are still ongoing. The treatment is delivered by mouth as 100 mg of tezacaftor once daily and 150 mg of ivacaftor every 12 hours.
A 24-week Phase 3 clinical trial called EVOLVE (NCT02347657) aimed to assess the effectiveness and safety of the tezacaftor/ivacaftor combo therapy in 509 CF patients who have two copies of the F508del mutation in the CFTR gene.
A total of 477 patients completed the randomized, double-blind, placebo-controlled trial, and the results were positive. Measures for efficacy included percent predicted forced expiratory volume in one second (ppFEV1), a measure of lung function that assesses the volume of air a person can expel in one second. A significant improvement in ppFEV1 of 4 percent was seen in the group given tezacaftor/ivacaftor treatment compared to placebo. Furthermore, a significant reduction in the number of pulmonary exacerbations was observed in the treatment group compared to the placebo group, as well as an increase in body mass index (BMI) and quality of life, measured by the Cystic Fibrosis Questionnaire-Revised, or CFQ-R.
Of the 477 patients who completed the EVOLVE trial, 461 elected to continue taking the combination therapy in an open-label clinical trial (NCT02565914) to evaluate the long-term safety and effectiveness of the combination therapy.
Another Phase 3 trial called EXPAND (NCT02392234) evaluated the efficacy and safety of the tezacaftor/ivacaftor combination for eight weeks in patients with one F508del mutation and a different mutation that results in reduced CTFR function, compared to ivacaftor alone and a placebo.
In the 235 patients who completed the study, a significant improvement was seen in ppFEV1. Patients given tezacaftor/ivacaftor showed a mean absolute improvement of 6.8 percent in ppFEV1 compared to the placebo. The combination was significantly more effective than ivacaftor alone, which resulted in a 4.7 percent improvement compared to the placebo. The combination therapy also significantly improved the quality of life of patients compared to the placebo, measured by the CFQ-R. Of the 235 patients from the EXPAND study, 227 agreed to enroll in a long-term, open-label trial (NCT02565914).
Following the results of these two key Phase 3 trials, Vertex has submitted a new drug application to the FDA for the tezacaftor/ivacaftor combination treatment and a marketing authorization application to the European Medicines Agency (EMA). The application is specifically for the tezacaftor/ivacaftor combo therapy for CF patients ages 12 and above with either one or two copies of the F508del mutation.
Vertex recently completed enrollment for another Phase 3 study (NCT02412111), the results of which are expected in late 2017. Another Phase 3 study(NCT02953314) evaluating the pharmacokinetics, safety, and tolerability of tezacaftor/ivacaftor in children ages 6 to 11 with CF is currently enrolling participants.
In June 2017, the tezacaftor/ivacaftor combination therapy was granted orphan drug status by the FDA for the treatment of CF.
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