Alyftrek (vanzacaftor/tezacaftor/deutivacaftor) for cystic fibrosis

Last updated Jan. 9, 2025, by Marisa Wexler, MS
Fact-checked by Jose Lopes, PhD

What is Alyftrek for cystic fibrosis?

Alyftrek (vanzacaftor/tezacaftor/deutivacaftor) is a next-generation, triple-combination CFTR modulator therapy approved for certain cystic fibrosis (CF) patients ages 6 and older. Developed by Vertex Pharmaceuticals, the oral treatment is intended to have similar or better efficacy, and more convenient dosing, than the also-approved therapy Trikafta (elexacaftor/tezacaftor/ivacaftor).

During development, the treatment was referred to as the “vanza triple.”

Therapy snapshot

How does Alyftrek work?

CF is caused by mutations in the gene that provides instructions to make the CFTR protein. This protein helps to control the movement of water and salt molecules in and out of cells, which is vital for the production of mucus in the body. In CF, the protein cannot function properly, and as a result, the body makes unusually thick and sticky mucus that builds up in the lungs, digestive system, and other organs. This buildup of thick mucus ultimately drives most of the symptoms of CF.

CFTR modulators are a class of medications that can boost the functionality of the mutated CFTR protein in patients carrying specific disease-causing mutations. By improving the protein’s functionality, modulators can help to normalize the movement of salts and water, ultimately allowing the body to make thinner, more watery mucus, and therefore easing the buildup of thick mucus that drives CF symptoms.

Alyftrek comprises a combination of three CFTR modulators that act in concert to improve the protein’s functionality in people with amenable mutations. It’s meant as a next-generation successor to Trikafta, an older triple-combination therapy also developed by Vertex. The newer therapy contains one of the modulators used in Trikafta, tezacaftor, alongside two novel molecules called vanzacaftor, or VX-121, and deutivacaftor, known as VX-561. Alyftrek is designed to be better at boosting CFTR protein functionality, as well as allowing more convenient dosing – the next-generation therapy is taken once daily whereas Trikafta needs to be taken twice per day.

Who can use Alyftrek?

Alyftrek was approved by the U.S. Food and Drug Administration (FDA) in December 2024. It is indicated for people with CF, ages 6 and older, who carry at least one copy of the F508del mutation — the most common CF-causing mutation — or another mutation that is responsive to the modulator therapy.

The FDA’s approval of Alyftrek meant that people with 31 additional mutations not responsive to other CFTR modulator therapies could be eligible for this type of treatment for the first time.

Who should not use Alyftrek?

The prescribing information for Alyftrek does not list any contraindications, or reasons for the medication to not be used in certain patients. However, the label does carry a boxed warning noting a risk of drug-induced liver injury and liver failure, and that serious and potentially fatal cases have been reported in people taking Trikafta — the earlier CF medication that has the same or similar components as Alyftrek.

Alyftrek should not be used in individuals who have severe liver impairment. In patients with moderate liver impairment, the therapy is not recommended and should be used only if there’s a clear medical need and the benefits outweigh the risks.

How is Alyftrek administered?

Alyftrek is available in film-coated, purple tablets at two dosage strengths:

• round tablets embossed with “V4” on one side, which contain 4 mg vanzacaftor, 20 mg tezacaftor, and 50 mg deutivacaftor
• oblong tablets embossed with “V10” on one side, which contain 10 mg vanzacaftor, 50 mg tezacaftor, and 125 mg deutivacaftor.

Alyftrek tablets should be taken once per day, at about the same time each day. The tablets should be swallowed whole alongside a fat-containing food such as butter, oil, eggs, peanut butter, cheese, nuts, whole milk, or meat.

For children ages 6 to 11 who weigh less than 40 kg (88 lbs), the recommended dose is three V4 tablets, which works out to a total dose of 12 mg vanzacaftor, 60 mg tezacaftor, and 150 mg deutivacaftor.

For children who weigh at least 40 kg and patients ages 12 and older, the recommended dose is two V10 tablets, which works out to a total dose of 20 mg vanzacaftor, 100 mg tezacaftor, and 250 mg deutivacaftor.

If Alyftrek is used in patients with mild or moderate liver impairment, the recommended dosage is the same as for individuals with normal liver function.

If a dose of Alyftrek is missed, it may be taken within six hours of when it’s normally scheduled. If it’s been more than six hours since the missed dose, the dose should be skipped and dosing should resume at the normal time the following day.

Alyftrek in clinical trials

FDA approval of Alyftrek was based mainly on data from the SKYLINE 103 (NCT05076149) and SKYLINE 102 (NCT05033080) studies. These two Phase 3 clinical trials collectively enrolled about 1,000 people with CF, ages 12 and older, who carried at least one copy of F508del or another responsive mutation.

All participants were initially given Trikafta. They then were randomly assigned to stay on Trikafta or switch to Alyftrek for about six months.

The studies’ main goal was to see if Alyftrek was at least as good as Trikafta at maintaining ppFEV1, or percent predicted forced expiratory volume in one second, which is a common measure of lung function based on how much air a person can blow out in a sharp breath. Both trials met their goal, with the results showing comparable ppFEV1 effects in people given either Trikafta or Alyftrek. Indeed, in both studies, the difference between average ppFEV1 in patients given either of the medications was less than one percentage point from the trial’s start, or baseline, to week 24.

A key secondary goal of the two SKYLINE studies was to compare the effects of Alyftrek and Trikafta on sweat chloride levels. Chloride is a salt molecule — half of table salt or sodium chloride. Dysfunction of the CFTR protein leads to abnormally high levels of chloride in patients’ sweat.

Data from the SKYLINE studies indicated that Alyftrek was better than Trikafta at reducing sweat chloride levels, which implies that the next-generation therapy has a more potent effect on CFTR functionality. The average difference in sweat chloride levels was 8.4 millimole per liter (mmol/L) in one trial and 2.8 mmol/L in the other.

Ongoing study in children

An ongoing Phase 3 clinical trial (NCT05422222) is evaluating Alyftrek in children with CF, ages 1 through 11, who carry at least one responsive mutation.

All participants in the study are being treated with Alyftrek, with the main goals of evaluating the therapy’s safety profile and pharmacological properties in these young patients. The study also will examine the therapy’s effect on sweat chloride levels and ppFEV1, among other efficacy assessments such as the number of CF-related hospitalizations, and the number of pulmonary exacerbations, or periods of sudden symptom worsening.

Common side effects of Alyftrek

Common side effects of Alyftrek include:

• cough
• nasopharyngitis, or the common cold
• upper respiratory tract infection
• headache
• oropharyngeal, or throat, pain
• influenza
• fatigue
• sinus congestion
• rash
• increased levels of liver enzymes.

Drug-induced liver damage

Alyftrek contains a boxed warning noting the risk of drug-induced liver injury and liver failure. Serious and potentially fatal cases have been reported in patients on Trikafta, which has the same or similar active ingredients to Alyftrek.

Tests of liver function should be performed for CF patients before starting on Alyftrek, and then monthly for the first six months of treatment. After that, such tests should be done every three months for the next year, and at least annually after that. More frequent monitoring may be needed in individuals who show signs of liver abnormalities or who have a history of liver disease.

Alyftrek should be interrupted if patients show signs of liver damage on lab tests, or symptoms indicative of liver damage. Such symptoms may include jaundice, a yellowing of the skin and eyes, pain in the upper right part of the abdomen, nausea, vomiting, or altered mental status. Patients should be monitored closely until signs of liver damage resolve; if symptoms do resolve, patients may restart on Alyftrek with careful monitoring of liver function.

The medication should not be used in patients with severe liver impairment. In individuals with moderate liver impairment, it may be used if the benefits clearly outweigh the risks, but close monitoring is needed.

Allergic reactions

Allergic reactions to Alyftrek may occur, including serious reactions called anaphylaxis. If a serious allergic (hypersensitivity) reaction develops, Alyftrek should be stopped and appropriate treatment to manage the reaction should be given. After the reaction resolves, patients and clinicians should weigh the risks and benefits of restarting Alyftrek on a case-by-case basis.

Patients who stopped other modulators due to side effects

No reliable data are available on whether Alyftrek can safely be used in individuals who stopped Trikafta or other modulator therapies due to adverse reactions. For such patients, the benefits and risks of initiating treatment should be carefully weighed, and if the decision is made to start Alyftrek, patients should be monitored closely.

Use with other medications

Alyftrek may affect the way other drugs work, and vice versa. Specifically, substances that are inducers or inhibitors of CYP3A, a family of enzymes that helps to break down certain medications in the body, may lower the efficacy of Alyftrek or increase the risk of side effects.

It’s not recommended to use Alyftrek alongside substances that are strong or moderate inducers of CYP3A; these include certain antibiotics and seizure medications, as well as St. John’s wort.

In patients taking strong or moderate inhibitors of CYP3A — which include some drugs used to treat fungal or viral infections — a reduced dosing schedule of Alyftrek is recommended.

Eye problems

Cataracts, or clouding of the lenses of the eyes, have been reported in children taking other CFTR modulators similar to Alyftrek. Monitoring of eye health is recommended for pediatric patients given Alyftrek.

Use in pregnancy and breastfeeding

No solid data are available on the use of Alyftrek in people who are pregnant or breastfeeding. Animal studies that separately tested components in Alyftrek did not reveal any major developmental issues associated with the use of the compounds during pregnancy. Data from such studies did suggest that the components of Alyftrek are likely secreted in breast milk, though the impacts on a breastfeeding infant are not known. Use of Alyftrek in these situations should be decided on an individual basis, taking into account the possible benefits and risks of treatment.

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