FDA Approves Alyftrek (vanzacaftor/tezacaftor/deutivacaftor) for the Treatment of Cystic Fibrosis

By: Zainab Masood, PharmD Candidate c/o 2026, Ansha Hamid, PharmD Candidate c/o 2027, Gabriella Lamantea, PharmD Candidate c/o 2027 & Ishrat Iqbal, PharmD Candidate c/o 2027

Cystic fibrosis is a chronic genetic disorder that follows an autosomal recessive inheritance pattern which affects children and adults.¹ There is a genetic mutation on chromosome 7 that codes for the CFTR protein, a chloride channel that regulates salt and water balance in the body.¹  Defects in this protein disrupts chloride ion transport, leading to thick mucus accumulation, organ dysfunction, and electrolyte imbalances.¹ Symptoms can appear in infancy through childhood and be diagnosed through newborn screening and genetic testing.¹ Adults exhibit cystic fibrosis with symptoms affecting multiple organs such as the lungs, pancreas, and liver. Patients with cystic fibrosis are estimated to live until their forties before requiring lung transplantation.¹

There is currently no cure for cystic fibrosis; however, there are treatments to manage the respiratory symptoms, such as CFTR modulators and antibiotics. These treatments have several functions, which include, minimizing respiratory infections, clearing out mucus in airways, optimizing nutritional status with pancreatic enzyme supplements, and treating any other health complications that may arise. CFTR modulators are a class of drugs that focus on enhancing the CFTR protein by folding this protein correctly and allowing it to reach the cell surface. These therapies are intended to improve the production, intracellular processing, or function of the CFTR protein caused by the mutated gene, with each targeting a distinct dysfunction caused by a gene mutation. An example of a CFTR modulator is Ivacaftor. For patients with the G551D mutation, the CFTR protein is not able to open correctly. The drug Ivacaftor opens a chloride channel and restores the flow of chloride ions through the cell membrane by the CFTR protein. For patients with the F508del mutation in which the CFTR protein misfolds, drugs like Lumacaftor help the CFTR protein fold correctly. Individuals with cystic fibrosis tend to have severe lung infections, in which antibiotics are used to treat them. Moreover, for end stage lung disease, a lung transplant is used to replace the diseased lung. Some symptoms that affect people with cystic fibrosis are coughs with thick mucus, constipation, abdominal pain, and salty-tasting sweat. Mucus thinners like Pulmozyme break down mucus by cleaving extracellular DNA. ² Stool softeners help with constipation. In addition, those with cystic fibrosis may have a dysfunctional pancreas which does not create enzymes necessary for digestion. Pancreatic enzyme supplements help with this issue as it contains all three main groups of digestive enzymes (lipase, amylase, and protease). ³ Ongoing advancement in treatments continue to create more options. Alyftrek, a newly approved CFTR modulator, joins the list of cystic fibrosis treatments.

On December 20, 2024, the Food and Drug Administration (FDA) approved Vertex’s ALYFTREK (vanzacaftor, tezacaftor, and deutivacaftor) for patients 6 years and older with at least one F508del mutation or another responsive mutation in the CFTR gene.⁴ Alyftrek is a fixed-dose combination of vanzacaftor 4 mg, tezacaftor 20 mg, and decutivacaftor 50mg for ages 6 to 12 years. For ages above 12, the fixed-dose combination is vanzacaftor 10 mg, tezacaftor 50 mg, and decutivacaftor 125mg. It is recommended that Alyftrek be taken orally with fat-containing food, once daily, at the same time each day. ⁴

Common adverse reactions to ALYFTREK include cough, nasopharyngitis, upper respiratory tract infection, headache, and increase in liver enzymes. It can also cause cataracts, a condition where the lens of the eye becomes cloudy, resulting in blurred vision. Therefore, eye examinations before and during the treatment of the medication is necessary. Liver enzymes must be checked before administering the drug and throughout the course of the treatment. If a patient experiences pain, swelling, or discomfort in the upper right stomach, nausea and vomiting, darkened urine, yellowing of the white part of the eye, fluid in your stomach area, the medication must be stopped immediately.

The clinical effect of Alyftrek was studied by the VX18-561-101 trial and the VX18-121-101 trial, which were two phased, randomized, double-blind, controlled, studies. The VX18-561-101 trial was conducted at 40 sites in North America, Europe, and Australia which assessed deutivacaftor monotherapy in people with cystic fibrosis aged 18 years or older with a CFTR gating mutation and who were previously stable on ivacaftor monotherapy. ⁵ VX18-121-101 was conducted at 26 sites in USA, UK, Germany, Netherlands, and Portugal to evaluate the safety and efficacy of vanzacaftor–tezacaftor– deutivacaftor in adults with cystic fibrosis aged 18 years or older who were homozygous for the F50del mutation (F/F genotype) or heterozygous for F508del and a minimal function mutation (F/MF genotype). ⁵ People with a history of cirrhosis with or without portal hypertension, risk factors for Torsade de Pointes and other ventricular arrhythmias, upper or lower respiratory infection, pulmonary exacerbation, lung infections, history of organ transplantation, pregnant or nursing were excluded from the study. ⁵  

In the VX18-156-101 trial, deutivacaftor monotherapy was compared with ivacaftor monotherapy. Participants received a 4-week ivacaftor monotherapy after which they received varying doses of deutivacaftor (25mg, 50mg, 150mg, or 250mg) once daily or ivacaftor 150 mg every 12 hours for 12 weeks. ⁵

The primary endpointfor the VX18-156-101 trial was absolute change in ppFEV1 from baseline at week 12. ⁵ ppFEV1 is used to indicate lung function and is measured by the percent predicted forced expiratory volume in one second. ⁶  A low value of ppFEV1 indicates reduced lung function. The mean absolute change in ppFEV1 from baseline at week 12 was 3.1 percentage points for deutivacaftor 150 mg once daily and 2.7 percentage points for deutivacaftor 250 mg once daily. However, Ivacaftor 150 mg every 12 hours showed a -0.8 percentage point absolute change from baseline at week 12. These findings suggest that deutivacaftor outperformed ivacaftor in improving lung function over 12 weeks.

The secondary endpoints were safety and tolerability and absolute change in sweat chloride concentration from baseline at week 12.⁵  Sweat chloride concentration is a measurement in mmol/L of chloride in a person’s sweat. ⁷ It is a diagnostic method for cystic fibrosis. A sweat chloride level of 60 mmol/L or above is indicative of cystic fibrosis. ⁷  The mean change in sweat chloride concentration from baseline at week 12 was 3.3 mmol/L (95% CI –4.6 to 11.2) for deutivacaftor 150 mg and –6.5 mmol/L (–14.1 to 1.2) for deutivacaftor 250 mg, compared with 0·9 mmol/L (–9.5 to 11.3) for ivacaftor 150 mg. ⁵ These values do not show statistical significance, but deutivacaftor 250 mg shows the greatest improvement in sweat chloride concentration suggesting that it can provide greater restoration of CFTR function. ⁵

The VX18-121-101 trial was conducted in two parts. In part 1, participants with F/MF genotypes received varying doses of vanzacaftor ( 5 mg, 10 mg, or 20 mg) in triple combination with tezacaftor–deutivacaftor or triple placebo for 4 weeks with an 18 day wash-out period.⁵ In the washout period, the vanzacaftor groups received tezacaftor-deutivacaftor and the triple placebo group received dual placebo. In part 2, participants received a 4-week texacaftor-ivacaftor run-in period after which the participants with F/F genotype received either 20 mg vanzacaftor in triple combination with tezacaftor-deutivacaftor or tezacaftor-ivacaftor alone for 4 weeks. ⁵

The primary endpoints for parts 1 and 2 of the VX18-121-101 trial were safety and absolute change in ppFEV1 from baseline to day 29. ⁵ The mean absolute changes from baseline in ppFEV1 for the treatments that included vanzacaftor 5 mg, 10 mg, and 20 mg combination in participants with F/MF genotypes were 4.6 percentage points (95% CI –1.3 to 10.6), 14.2 percentage points (10.0 to 18.4), and 9.8 percentage points (5.7 to 13.8), respectively, to day 29 compared with an absolute mean change of 1.9 percentage points (–4.1 to 8.0) for participants receiving placebo. ⁵ These values suggest that Vanzacaftor at 10 mg and 20 mg showed statistically significant improvement in lung function. There was also an increase in the ppFEV1 through day 29  in participants with F/F genotypes given the vanzacaftor 20 mg combination (15.9 percentage points [95% CI 11·3 to 20·6]) compared with participants receiving tezacaftor–ivacaftor alone (–0.1 percentage points (–6.4 to 6.0). These values offer evidence that vanzacaftor 20 mg triple combination offers improvement in lung function as compared to the standard treatment.

Secondary efficacy endpoints were absolute change from baseline at day 29 in sweat chloride concentration and cystic fibrosis questionnaire-review (CFQ-R) respiratory domain score. ⁵  Improvements in both, the sweat chloride concentration and CFQ-R respiratory domain score in participants with F/MF and F/F genotypes were seen. ⁵ Mean changes in sweat chloride concentration from baseline to day 29 in participants with F/MF genotypes given vanzacaftor 5 mg, 10 mg, and 20 mg combination were −42.8 mmol/L (95% CI –51.7 to –34.0), −45.8 mmol/L (–51.9 to –39.7), and −49.5 mmol/L (–55.9 to –43.1), respectively, and 2.3 mmol/L (–7.0 to 11.6) for participants receiving placebo. ⁵ Compared to the placebo, the three doses of vanzacaftor combination led to greater reductions in sweat chloride. Additionally, these participants with F/MF genotypes that were given vanzacaftor 5 mg, 10 mg, and 20 mg combination had mean changes in CFQ-R domain score at day 29 of 17.6 points (95% CI 3.5 to 31.6), 21.2 points (11.9 to 30.6), and 29.8 points (21.0 to 38.7), respectively, while the participants receiving placebo had a mean change of 3.3 points (–10.1 to 16.6). ⁵  These values emphasizes that patients with F/MF genotype felt significantly better on the vanzacaftor combination with improved symptoms.

In participants with the F/F genotype who were given the vanzacaftor 20 mg combination had a mean change in sweat chloride of −45.5 mmol/L (–49.7 to –41.3) compared with –2.6 mmol/L (–8.2 to 3.1) for participants receiving tezacaftor–ivacaftor alone. ⁵ Moreover, these participants had a mean change of 19.4 points (10.5 to 28.3) while those who received tezacaftor–ivacaftor had a change of –5.0 points (–16.9 to 7.0). ⁵ These values suggest the strong improvement in CFTR function caused by the vanzacaftor combination. 

In conclusion, the study shows that vanzacaftor in triple combination with tezacaftor and deutivacaftor is efficacious in adults with cystic fibrosis who have F/MF or F/F genotypes. The triple combination marks a promising addition to the list of treatments for cystic fibrosis. Clinical trials demonstrate that this therapy is well tolerated and offers improvements in lung function, respiratory symptoms, and CFTR function. ⁵

References:

1. Yu E, Sharma S. Cystic Fibrosis. National Library of Medicine. Published December 11, 2024. https://www.ncbi.nlm.nih.gov/books/NBK493206/
2. Pulmozyme® (dornase alfa) Mechanism of Action (MoA). pulmozyme. https://www.pulmozyme.com/hcp/about/moa.html
3. ‌Somaraju URR, Solis-Moya A. Pancreatic enzyme replacement therapy for people with cystic fibrosis. Cochrane Database Syst Rev. 2020;8(8):CD008227. Published 2020 Aug 5. doi:10.1002/14651858.CD008227.pub4
4. ALYFTREK (Vanzacaftor, tezacaftor, and Deutivacaftor tablets) [package insert] (2024)
5. Uluer AZ, MacGregor G, Azevedo P, 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(6):550-562. doi:10.1016/S2213-2600(22)00504-5
6. David S, Edwards CW. Forced Expiratory Volume. PubMed. Published October 14, 2024. https://www.ncbi.nlm.nih.gov/books/NBK540970/
7. Schmidt H, Sharma G. Sweat Testing. PubMed. Published 2020. https://www.ncbi.nlm.nih.gov/books/NBK547728/