Symdeko (tezacaftor/ivacaftor) for cystic fibrosis
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What is Symdeko for CF?
Symdeko (Symkevi in the EU and U.K.) is an approved oral combination of tezacaftor and ivacaftor for treating cystic fibrosis (CF). It’s marketed by Vertex Pharmaceuticals.
Therapy Snapshot
| Brand Name: | Symdeko |
| Chemical Name: | tezacaftor/ivacaftor |
| Usage: | CFTR modulator |
| Administration: | Oral tablets |
How does Symdeko work?
CF leads to thick mucus building up in the lungs and other organs. Symptoms include breathing difficulties, lung infections, and digestive problems.
The condition is caused by mutations in the CFTR gene, which provides the instructions to make the CFTR protein. CFTR regulates the transport of chloride and water across cell membranes, which is key for producing the needed mucus to lubricate the lungs and other organs. Mutations in the CFTR gene lead to a thick and sticky mucus.
Symdeko aims to restore the function of the CFTR protein. It contains tezacaftor, a corrector therapy that helps CFTR fold correctly into its three-dimensional shape so it can reach the cell surface. The other component, ivacaftor — marketed as a stand-alone CF treatment called Kalydeco — is a CFTR potentiator that works to keep open the protein gate so water and salts flow more smoothly.
Who can take Symdeko?
First approved by the U.S. Food and Drug Administration in February 2018, Symdeko initially was indicated in the U.S. for patients ages 12 and older. The FDA expanded the treatment’s approval in 2020 to patients 6 and older with one of 154 different mutations.
In Europe and Australia, the therapy also is approved for patients ages 6 and older, while in Canada it’s indicated for those 12 and older.
The therapy also is approved in Brazil, Israel, Switzerland, and other places.
Who should not use Symdeko?
There are no contraindications for Symdeko. However, the therapy’s FDA label warns that it is not recommended for patients being treated with antibiotics such as rifampin and rifabutin, seizure treatments, antifungal medications, and the herbal therapy St. John’s wort.
How is Symdeko administered?
Symdeko is available as an oral tablet in weekly wallets. Each wallet contains 14 tablets that come in the following strengths:
- white capsule-shaped tablets debossed with “V50” on one side and plain on the other, containing tezacaftor 50 mg combined with ivacaftor 75 mg
- light blue capsule-shaped tablets printed with “V75” in black ink on one side and plain on the other, containing ivacaftor 75 mg
- yellow capsule-shaped tablets debossed with “V100” on one side and plain on the other, containing tezacaftor 100 mg/ivacaftor 150 mg
- light blue capsule-shaped tablets printed with “V150” in black ink on one side and plain on the other, containing ivacaftor 150 mg.
It should be taken twice a day, with doses about 12 hours apart. Patients should swallow the tablets whole along with fat-containing food. Food and drinks containing grapefruit should be avoided.
Recommended doses depend on patients’ ages and weight. In children ages 6 to 11 and weighing less than 30 kg (66 lbs), the recommended dose is:
- one tablet containing tezacaftor 50 mg/ivacaftor 75 mg in the morning
- one tablet containing ivacaftor 75 mg in the evening.
Adults and children ages 12 and older, as well as younger children weighing 30 kg or more are recommended to take:
- one tablet containing tezacaftor 100 mg/ivacaftor 150 mg in the morning
- one tablet containing ivacaftor 150 mg in the evening.
Symdeko in clinical trials
A number of Phase 3 clinical trials have shown the benefits of Symdeko in CF patients and led to its approval.
EVOLVE and EXTEND trials
A 24-week trial called EVOLVE (NCT02347657) assessed Symdeko’s safety and effectiveness in CF patients with two copies of the F508del mutation, which is the most common CF-causing mutation. A total of 475 patients completed the treatment period. The primary measure of effectiveness was forced expiratory volume in one second (FEV1), the amount of air a person can exhaled in one second after a deep breath.
The treated group achieved a mean improvement of 4 percentage points in FEV1 from baseline, compared with a placebo. Symdeko also was found to reduce pulmonary exacerbations — acute episodes in symptom worsening — by 35% compared with the placebo and led to an improvement in the respiratory domain of quality of life.
A total of 461 participants opted to continue taking Symdeko in an open-label clinical trial called EXTEND (NCT02565914), which assessed the long-term safety and effectiveness of the treatment. Results showed Symdeko’s efficacy, safety, and tolerability were sustained for up to 120 weeks, or more than two years.
EXPAND trial
A trial called EXPAND (NCT02392234) evaluated Symdeko’s safety and efficacy for eight weeks in patients with a F508del mutation and another mutation that results in residual CFTR function. Trial participants were given Symdeko with ivacaftor, ivacaftor alone, or a placebo.
A total 234 participants completed treatment. 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 improvement in FEV1. Symdeko also improved patients’ quality of life.
Other Phase 3 trials
Vertex 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. The study recruited 156 participants to receive either Symdeko or Kalydeco for eight weeks after first receiving Kalydeco for four weeks. At the end of the treatment period, the researchers compared changes in FEV1 between the two groups.
Symdeko was found to be generally safe and well tolerated, and led to clinical improvements. However, the improvement with Symdeko was not significantly greater than with Kalydeco alone.
An open-label Phase 3 study (NCT02953314) evaluated Symdeko in children 6 to 11 with CF in the U.S. and Canada. Results showed safety and tolerability data similar to previous trials in older patients. The results supported the FDA expansion of the approval to children as young as 6.
Ongoing trials
A Phase 1 trial (NCT03587961) is testing the use of off-label CFTR modulators in patients with mutations other than those now approved for these therapies. The study aims to enroll 20 patients ages 6 and older.
Depending on the mutation response in lab tests, patients will be given Symdeko, Orkambi (lumacaftor/ivacaftor), or Kalydeco (ivacaftor). The trial’s main goal is change in lung function.
Common side effects of Symdeko
The most common side effects of Symdeko include:
- headache
- nausea
- sinus congestion
- dizziness.
Liver damage and elevated levels of liver enzymes
High levels of liver enzymes in the blood may occur with Symdeko, which may indicate liver damage. Levels of liver enzymes should be assessed before starting the treatment, every three months during the first year, and annually thereafter. Patients who have had elevated liver enzyme levels should be more frequently monitored. The treatment should be interrupted in those with significant elevations of transaminases. A reduced dose in patients with moderate and severe liver injury is recommended.
Eye problems
Some children treated with Symdeko experienced cataracts, a clouding in the eye lens. Eye assessments at the beginning of treatment and during follow-up are recommended.
Use with other medications
Use of strong CYP3A inducers — such as rifampin and St. John’s wort — while on Symdeko is not recommended. Those medications may decrease the exposure to Symdeko, reducing its therapeutic efficacy.
An adjusted dose of Symdeko is recommended for patients treated with strong or moderate CYP3A inhibitors, such as certain antifungal medications, as they may increase Symdeko’s exposure.
Use in pregnancy and breastfeeding
Because data regarding Symdeko use in pregnant women are limited, it’s not known if it will harm the developing fetus. It’s also unknown if Symdeko may pass to breast milk. Patients should talk to their healthcare team if they are pregnant or plan to become pregnant, are breastfeeding or plan to do so.
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FAQs about Symdeko
There are no known interactions between Symdeko and alcohol. Patients are advised to speak with their healthcare team about whether it is safe to drink alcohol while on this medication.
Animal studies generally indicated no treatment-related adverse effects on the fetus when using either of Symdeko’s active components, except decreased fetal body weight and early developmental delays with tezacaftor. However, data on pregnant women are limited. It is not known whether this treatment passes to human breast milk. Before taking Symdeko, patients should inform their healthcare team if they are pregnant or plan to become pregnant, are breastfeeding, or plan to do so.
Neither hair loss nor abnormal weight gain have been reported as a side effect of Symdeko. Patients who experience unanticipated effects after starting a new cystic fibrosis therapy are advised to talk to their healthcare provider.
In a Phase 3 trial that supported Symdeko’s initial approval, lung function improvements were seen within 15 days after treatment start. These gains were sustained through treatment conclusion at 24 weeks or about six months. However, each person may respond differently to treatment, so patients are advised to discuss with their healthcare team how Symdeko may help in their particular case.
Symdeko was approved by the U.S. Food and Drug Administration in February 2018 for cystic fibrosis (CF) patients, ages 12 and older, carrying two copies of the F508del mutation in the CFTR gene or with one mutation that responds to Symdeko. This approval was later expanded, now covering individuals 6 years and older with CF caused by one of 154 genetic mutations.
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