Symdeko (Symkevi in the EU and U.K.) is a combination of tezacaftor and ivacaftor — all developed by Vertex Pharmaceuticals. It is an oral treatment that patients should take with fat-containing food.
The mutations for which the treatment can be used vary by country. In most cases, it is only approved for patients with two copies of the F508del mutation in the CFTR gene, or one copy of the F508del mutation and one of 14 other deletions. The U.S. expanded the treatment’s approval to 154 different mutations.
How does Symdeko work?
Cystic fibrosis (CF) is a genetic condition that leads to thick mucus building up in the lungs and other organs. It leads to symptoms such as severe breathing difficulties, a high risk of lung infections, and digestive problems.
The condition is caused by mutations in the CFTR gene, which provides the instructions necessary for cells to make the CFTR protein. This protein regulates the production of mucus necessary to lubricate the lungs and other organs. It does this by controlling the transport of charged ions such as chloride and sodium across cell membranes. The movement of ions also influences the movement of water in and out of cells.
Mutations in the CFTR gene lead to faulty ion and water transport that generates thick and sticky mucus. The most common CF-causing mutation is called F508del, which causes the CFTR protein to lose its normal three-dimensional shape.
Symdeko aims to restore the function of the CTFR protein. It contains tezacaftor, a corrector therapy that moves the defective CFTR protein to the cell membrane so it can transport chloride ions. The other component, ivacaftor — which the FDA approved as a stand-alone CF treatment under the brand name Kalydeco — improves the flow of chloride over the cell membrane by increasing the length of time that the channel facilitating this flow is open.
Symdeko in clinical trials
A number of Phase 3 clinical trials have shown the benefits of Symdeko in CF patients.
A 24-week Phase 3 trial (NCT02347657) called EVOLVE assessed Symdeko’s safety and effectiveness in CF patients with two copies of the F508del mutation. A total of 477 patients completed the randomized, double-blind, placebo-controlled trial. A key measure of effectiveness in the trial was forced expiratory volume in one second (FEV1). This is the amount of air a person can expel in one second after a deep breath.
The treated group achieved a mean improvement of 4.0 percentage points in FEV1 from baseline, compared with the placebo — a result that researchers considered significant. Symdeko was also found to reduce flare-ups compared with the placebo, and led to an increase in patients’ weight and quality of life, as measured by the cystic fibrosis questionnaire-revised scale.
Of the 477 patients, 461 decided to continue taking Symdeko in an open-label clinical trial called EXTEND (NCT02565914), which assessed the long-term safety and effectiveness of the treatment.
Another Phase 3 trial, EXPAND (NCT02392234), evaluated Symdeko’s safety and effectiveness for eight weeks in patients with two mutations that lead to less CFTR function — an F508del mutation and another that results in residual CFTR function. Trial participants were given Symdeko with ivacaftor, ivacaftor alone, or a placebo.
The 235 Symdeko-treated patients who completed the study showed a significant mean improvement of 6.8 percentage points in FEV1, compared with the placebo group. The combination was also more effective than ivacaftor alone, which generated a 4.7-percentage-point mean improvement in FEV1, compared with the placebo. Symdeko also improved patients’ quality of life, compared with the placebo.
Of the 235 patients in the trial, 227 also 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 combination therapy to the U.S. Food and Drug Administration and a marketing authorization application to the European Medicines Agency. The application to the FDA covered the combo as a treatment for CF patients, 12 and older, with one or two copies of the F508del mutation. The FDA approved the therapy on Feb. 12, 2018.
Vertex has also completed another Phase 3 trial (NCT02412111) of Symdeko in CF patients, 12 and older, with one F508del mutation and a second mutation that responds to ivacaftor treatment. The study recruited 156 children, 12 and older, to receive either Symdeko or Kalydeco for eight weeks after first receiving Kalydeco for four weeks. At the end of the treatment period, researchers compared changes in FEV1 between the two groups. The results showed that both treatments were generally safe, well-tolerated, and led to a clinical improvement of symptoms. The improvement with Symdeko was not significantly greater than Kalydeco alone, however.
An open-label Phase 3 study (NCT02953314) evaluated Symdeko in 70 children, 6 to 11 years old, with CF in the U.S and Canada. Results showed safety and tolerability data similar to previous trials in older patients. The expansion of the approval to children as young as 6 was largely based on the results of this trial.
The most common side effects of Symdeko include headache, nausea, sinus congestion, and dizziness.
Last updated: Jan. 19, 2021
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