Vanzacaftor, tezacaftor and deutivacaftor fixed-dose combination for cystic fibrosis

Background:
Cystic fibrosis is an autosomal recessive disorder. It is caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) protein, which regulates chloride transport across cell membranes. Defects in the CFTR protein result in the production of thick, sticky mucus, which affects many organs, particularly the lungs. Patients with cystic fibrosis typically have high concentrations of chloride in their sweat.

Treatment was mainly supportive until the development of drugs acting on the CFTR protein.¹ The first of these CFTR modulators was ivacaftor, but it was only effective for some mutations. Since its approval in 2013, therapy has evolved to cover more mutations, often with combinations of CFTR modulators to enhance CFTR production and function. A combination of ivacaftor, elexacaftor and tezacaftor has been available in Australia since 2021.

Mechanism of action:
Vanzacaftor and tezacaftor bind to the CFTR protein and act synergistically on intracellular processes to increase the amount of CFTR protein delivered to the cell surface.

Deutivacaftor is an analogue of ivacaftor with a longer half-life (19 hours versus 12 hours).² Like ivacaftor, deutivacaftor enhances chloride transport by potentiating the action of the CFTR protein.

Clinical trials:
The combination of vanzacaftor, tezacaftor and deutivacaftor was compared with placebo in adults for 4 weeks in a phase 2 trial.³ Depending on the dose, vanzacaftor, tezacaftor and deutivacaftor had a greater effect on sweat chloride and forced expiratory volume in 1 second (FEV₁) than placebo, or tezacaftor with ivacaftor.³

The efficacy of the combination was evaluated in the double-blind phase 3 SKYLINE trials.⁴ These trials involved 971 patients aged 12 years or older. One trial enrolled patients with the F508del-minimal function genotype, whereas the other enrolled patients with different genotypes. The 2 trials began with a 4-week run-in period, during which patients took elexacaftor 200 mg once daily, tezacaftor 100 mg once daily and ivacaftor 150 mg twice daily. They were then randomised to continue that treatment or switch to vanzacaftor 20 mg once daily, tezacaftor 100 mg once daily and deutivacaftor 250 mg once daily. For both trials, the primary outcome was the change in lung function after 24 weeks, measured as the change in FEV₁ (as a percentage of its predicted value) from baseline at the time of randomisation.

At baseline, approximately 20% of patients had a sweat chloride concentration in the normal range (below 30 mmol/L). At the end of the trials, this had increased to 31% of patients taking vanzacaftor, tezacaftor and deutivacaftor, compared with 23% of those who continued elexacaftor, tezacaftor and ivacaftor. The absolute change in percentage predicted FEV₁ from baseline to 24 weeks ranged from 0.0 to 0.5 across both trials. Small differences between the treatment groups mean that the combination of vanzacaftor, tezacaftor and deutivacaftor was not statistically inferior to elexacaftor, tezacaftor and ivacaftor (Table 1).⁴

Table 1 Phase 3 SKYLINE trials of vanzacaftor, tezacaftor and deutivacaftor in cystic fibrosis⁴

Genotype	F508del-minimal function		Various genotypes [NB1]
Treatment	Vanzacaftor, tezacaftor and deutivacaftor	Elexacaftor, tezacaftor and ivacaftor	Vanzacaftor, tezacaftor and deutivacaftor	Elexacaftor, tezacaftor and ivacaftor
Number of patients	196	202	284	289
Median age (years)	30	31	33	34
Percentage predicted FEV1, baseline mean	67	67.2	67.2	66.4
Percentage predicted FEV1, absolute change from baseline, 24-week mean	0.5	0.3	0.2	0.0
Sweat chloride concentration (mmol/L), baseline mean	53.6	54.3	43.4	42.1
Sweat chloride concentration (mmol/L), absolute change from baseline, 24-week mean	−7.5	0.9	−5.1	−2.3
FEV1 = forced expiratory volume in 1 second NB1: F508del–F508del, F508del-residual function, F508del-gating, and non-F508del genotypes responsive to the combination of elexacaftor, tezacaftor and ivacaftor

RIDGELINE was another phase 3 trial but involved a younger population (median age 9.3 years; 78 participants).⁵ After taking elexacaftor, tezacaftor and ivacaftor for at least 4 weeks, the children switched to vanzacaftor, tezacaftor and deutivacaftor for a median of 24 weeks. Although the primary endpoint was safety and tolerability, efficacy data showed sustained FEV₁ and reduced sweat chloride. By week 24, 52.6% of the children had normal chloride concentrations (below 30 mmol/L) compared with 39% at baseline.⁵

Adverse effects:
Adverse events were common in the phase 3 efficacy trials,⁴ although many were likely to be disease related. In both treatment groups, 4% of patients withdrew because of an adverse event, often due to elevated liver function tests. Serious adverse events occurred in 14% of the vanzacaftor, tezacaftor and deutivacaftor group and 16% of the elexacaftor, tezacaftor and ivacaftor group. Infective exacerbations of cystic fibrosis affected 28% and 32% of these groups, respectively. Most of the common adverse events, such as diarrhoea, occurred at similar rates in both groups. Events that were more frequent in patients taking vanzacaftor, tezacaftor and deutivacaftor included rashes, headache, fatigue and influenza.⁴

Similar adverse events were reported in children during the RIDGELINEtrial.⁵ The most common adverse events, such as cough, were probably related to cystic fibrosis itself. Only one child discontinued treatment.

Post-marketing reports have identified neuropsychiatric effects, including anxiety, depression, insomnia, and suicidal ideation or behaviour, in adults and children treated with vanzacaftor, tezacaftor and deutivacaftor within the first 3 months of starting treatment.²

Dosage and administration:
The recommended dose in patients weighing 40 kg or more is two tablets of vanzacaftor 10 mg, tezacaftor 50 mg and deutivacaftor 125 mg once a day. A lower dose is used in patients under 40 kg.² The combination should be taken with fatty food to improve absorption.

Precautions:
All 3 drugs are metabolised by cytochrome P450 (CYP) 3A4 and CYP3A5. Therefore, the dose should be reduced when co-administered with drugs that inhibit CYP3A (e.g. clarithromycin, ketoconazole), and grapefruit juice should be avoided. Drugs that strongly induce CYP3A4 (e.g. phenytoin) are not recommended. Because deutivacaftor may inhibit CYP2C9, caution is needed with drugs such as warfarin.

Vanzacaftor, tezacaftor and deutivacaftor are not recommended for patients with moderate or severe hepatic impairment.

Use in pregnancy:
Fertility is reduced in cystic fibrosis, but pregnancy is possible. Although the effects of vanzacaftor, tezacaftor and deutivacaftor are unknown in human pregnancy, animal studies of vanzacaftor, tezacaftor and ivacaftor have not reported teratogenicity.²

Place in therapy:
CFTR modulators have improved outcomes for patients living with cystic fibrosis. Evidence to date shows that the combination of vanzacaftor, tezacaftor and deutivacaftor has similar efficacy to the combination of elexacaftor, tezacaftor and ivacaftor.⁴ Both combinations are effective in patients with an F508del mutation, which is the most common cystic fibrosis mutation in Australia.

The RIDGELINEtrial⁵ suggests that vanzacaftor, tezacaftor and deutivacaftor are safe to use in children aged 6 to 11 years; however, efficacy will need to be confirmed in this age group.

Patients already responding to elexacaftor, tezacaftor and ivacaftor are unlikely to require a switch. Vanzacaftor, tezacaftor and deutivacaftor may have a role in patients with an inadequate response or intolerance to other CFTR modulators. However, there are no data in patients who have had adverse reactions to ivacaftor or tezacaftor. A potential advantage of the vanzacaftor, tezacaftor and deutivacaftor combination is that the tablets only need to be taken once a day, especially because each dose has to be taken with fatty food.

Practice points:
There are over 2000 possible mutations that can cause cystic fibrosis; therefore, it is important to identify the patient’s genotype and confirm it is responsive to vanzacaftor, tezacaftor and deutivacaftor before starting treatment.²

Hepatic enzymes may be affected by this combination, so regular monitoring with liver function tests is advised.

Patients and caregivers should be advised to monitor for changes in mood and behaviour and report these to a healthcare professional if they occur.

Some patients under 18 years of age have developed lens opacities while taking ivacaftor. Although the risk with deutivacaftor is unknown, ophthalmological examinations are recommended for children.²

The patient’s usual supportive care should continue during treatment.

This new drug comment was finalised on 28 August 2026. It was prepared by John Dowden, Medical Writer, and reviewed by Louis Nguyen, Paediatric Transplant and Cellular Pharmacist, Sydney Children’s Hospital.

At the time this new drug comment was prepared, the Australian Public Assessment Report was available from the Therapeutic Goods Administration. The sponsor did not provide the Clinical Evaluation Report.

This article is peer reviewed.

 

References

1. Bruorton M, Goddard T. Drug treatment of cystic fibrosis. Aust Prescr 2022;45:171–5.
2. Therapeutic Goods Administration. Australian Product Information - Alyftrek (vanzacaftor, tezacaftor and deutivacaftor). Department of Health, Disability and Ageing; 2025. Last updated 17 Aug 2026. [cited 2026 Aug 28]
3. Uluer AZ, MacGregor G, Azevedo P, Indihar V, Keating C, Mall MA, et al. Safety and efficacy of vanzacaftor-tezacaftor-deutivacaftor in adults with cystic fibrosis: randomised, double-blind, controlled, phase 2 trials. Lancet Respir Med 2023;11:550–62.
4. Keating C, Yonker LM, Vermeulen F, Prais D, Linnemann RW, Trimble A, et al. Vanzacaftor-tezacaftor-deutivacaftor versus elexacaftor-tezacaftor-ivacaftor in individuals with cystic fibrosis aged 12 years and older (SKYLINE Trials VX20-121-102 and VX20-121-103): results from two randomised, active-controlled, phase 3 trials. Lancet Respir Med 2025;13:256–71.
5. Hoppe JE, Kasi AS, Pittman JE, Jensen R, Thia LP, Robinson P, et al. Vanzacaftor-tezacaftor-deutivacaftor for children aged 6-11 years with cystic fibrosis (RIDGELINE Trial VX21-121-105): an analysis from a single-arm, phase 3 trial. Lancet Respir Med 2025;13:244–55.

The new drug comments in Australian Prescriber are prepared by the editors and reviewed by subject matter experts. Some of the views expressed on newly approved products should be regarded as preliminary, as there may be limited published data at the time of publication, and little experience in Australia of their safety or efficacy. Before new drugs are prescribed, it is important that more detailed information is obtained from the approved product information, a medicines information centre or some other appropriate source.

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