How Symdeko (tezacaftor/ivacaftor) works
CF is an inherited condition that leads to thick mucus building up in the lungs and other organs. It generates symptoms such as severe breathing difficulties, increased risk of lung infections, and digestive problems.
The condition is caused by mutations of the CFTR gene, which provides instructions for making the CFTR protein. The protein regulates the production of mucus needed to lubricate lungs and other organs. It does this by controlling the transport of charged substances such as chloride and sodium across cells’ membranes. Controlling the ions also influences the movement of water in and out of cells.
Mutations of the CFTR gene lead to the faulty ion and water transport in cystic fibrosis that generates thick and sticky mucus. The most common mutation that causes the disease is called F508del. It causes the CFTR protein to break down before it can reach the cell membrane and transport chloride. The tezacaftor/ivacaftor combo is designed to restore the CTFR protein’s function.
The treatment consists of tezacaftor and Kalydeco, or ivacaftor. Tezacaftor is a corrector therapy, meaning that it moves the defective CFTR protein to the cell membrane so it can transport chloride. The FDA has approved Kalydeco as a stand-alone CF treatment. It improves the flow of chloride over the cell membrane by increasing the length of time the channel that facilitates the flow is open.
Symdeko (tezacaftor/ivacaftor) in clinical trials
A number of Phase 3 clinical trials have shown that the tezacaftor/ivacaftor combo benefits CF patients. The treatment is delivered by mouth as 100 mg of tezacaftor once a day and 150 mg of ivacaftor every 12 hours.
The 24-week Phase 3 EVOLVE trial (NCT02347657) assessed the combo’s effectiveness and safety in 509 CF patients with two copies of the CFTR gene’s F508del mutation.
Four hundred seventy-seven patients completed the randomized, double-blind, placebo-controlled trial, which yielded positive results.
A key measure of effectiveness in the trial was a lung function yardstick known as forced expiratory volume in one second, or FEV1. This is the amount of air a person can expel in one second after a deep breath.
The combo-treated group achieved a 4 percent improvement in FEV1, compared with a placebo — a result considered significant. In addition, the combo reduced patients’ disease flare-ups, compared with the placebo group. And it led to an increase in patients’ weight and quality of life, as measured by the Cystic Fibrosis Questionnaire-Revised scale.
Four hundred sixty-one of the 477 patients who completed the EVOLVE trial decided to continue taking the combo in an open-label clinical trial (NCT02565914) assessing its long-term safety and effectiveness.
Another Phase 3 trial, EXPAND (NCT02392234), evaluated the combo’s safety and effectiveness for eight weeks in patients with two mutations that lead to less CTFR function — one an F508del mutation and one another kind. The trial compared the combo with ivacaftor alone and a placebo.
The 235 combo-treated patients who completed the study showed a significant improvement of 6.8 percent in FEV1, compared with the placebo group. The combination was also much more effective than ivacaftor alone, which generated a 4.7 percent improvement in FEV1, compared with the placebo. And the combination therapy significantly improved patients’ quality of life, compared with the placebo. Two hundred twenty-seven of the 235 patients in the EXPAND study enrolled in the long-term, open-label extension trial.
Vertex used the results of the two key Phase 3 trials to submit a New Drug Application for the combo to the FDA and a marketing authorization application to the European Medicines Agency. The application to the FDA covered the combo as a treatment for CF patients ages 12 and older with either one or two copies of the F508del mutation. The FDA approved it on February 12, 2018.
Vertex has also completed another Phase 3 trial (NCT02412111) of the combo in CF patients ages 12 and above with one F508del mutation and a second mutation that has been shown to be responsive to ivacaftor. Results have yet to be published.
A Phase 3 study (NCT02953314) evaluating the combo in children ages 6 to 11 with CF is enrolling participants in the U.S and Canada.
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