Indianapolis, Indiana – The next-generation triple-combination CFTR modulator Alyftrek has demonstrated a favorable safety profile and improved CFTR function in children with cystic fibrosis (CF) as young as 2, according to findings from a Phase 3 clinical trial.
The study, known as TIMBERLINE (NCT05422222), also found that children who switched from Trikafta to Alyftrek experienced further improvements in CFTR activity, as measured by reductions in sweat chloride levels.
The trial was funded by Vertex Pharmaceuticals, which markets both treatments. The company initially presented the findings earlier this year, and the final results have now undergone peer review and been published in The Lancet Respiratory Medicine under the title, “Safety and efficacy of vanzacaftor–tezacaftor–deutivacaftor in children with cystic fibrosis aged 2–5 years (TIMBERLINE Trial VX21-121-105): a phase 3, open-label study.”
Understanding CFTR modulators and Alyftrek
Cystic fibrosis is a genetic disorder caused by mutations in the CFTR gene, which provides instructions for producing a protein that regulates the movement of salt and water across cell membranes. When the CFTR protein is defective or absent, the body produces abnormally thick, sticky mucus that can accumulate in the lungs and other organs, leading to breathing difficulties, infections, digestive problems, and other CF-related complications.
Defective CFTR function also disrupts chloride transport, resulting in elevated chloride concentrations in sweat. For this reason, sweat chloride testing is commonly used to help diagnose CF and assess CFTR function.
CFTR modulators are a class of medications designed to improve the function of defective CFTR proteins in people with specific CF-causing mutations. By restoring some of the protein’s activity, these therapies can help regulate mucus production, improve organ function, and reduce disease symptoms.
Trikafta (elexacaftor/tezacaftor/ivacaftor) was the first widely available triple-combination CFTR modulator. In the U.S., it is approved for eligible patients with CF as young as 2, including those carrying the most common CF-causing mutation, F508del.
Alyftrek (vanzacaftor/tezacaftor/deutivacaftor) is a newer triple-combination therapy containing two novel modulators and one component also found in Trikafta. It is designed to provide comparable or greater CFTR activity with the added convenience of once-daily dosing, compared with Trikafta’s twice-daily regimen.
Alyftrek is currently approved in the U.S. for eligible people with CF ages 6 and older. It has also received approval in several other countries, including Canada, the U.K., and the European Union.
TIMBERLINE trial evaluated Alyftrek in children ages 2–5
To investigate the safety and effectiveness of Alyftrek in younger children, Vertex sponsored the Phase 3 TIMBERLINE trial, which was conducted in two parts.
The first part enrolled 20 children with CF between the ages of 2 and 5. Participants received Alyftrek for approximately three weeks, allowing researchers to assess its initial safety and determine the appropriate dose for further evaluation.
The second and main part of the study involved 67 children ages 2–5 who were already receiving Trikafta. All participants switched to Alyftrek and continued treatment for at least six months, with doses adjusted according to body weight.
The primary objective was to evaluate Alyftrek’s safety and tolerability in this younger age group.
Alyftrek demonstrated a favorable safety profile
The trial results showed that Alyftrek was generally well tolerated among children ages 2–5. No serious adverse events considered related to treatment were reported, and the overall safety findings were consistent with the medication’s previously established safety profile in older children and adults.
Commonly reported side effects of Alyftrek include respiratory infections, cough, headache, rash, nasal congestion, and fever.
Researchers also found no new safety concerns, or safety signals, during the study. These findings support the treatment’s continued evaluation in younger children with CF.
Sweat chloride levels improved after switching from Trikafta
In addition to assessing safety, researchers evaluated CFTR function by measuring sweat chloride concentrations before and after participants switched from Trikafta to Alyftrek.
After six months of treatment with Alyftrek, mean sweat chloride levels decreased by 9.6 millimoles per liter (mmol/L), indicating improved CFTR activity.
Sweat chloride concentrations of 60 mmol/L or higher are considered consistent with a CF diagnosis, while levels between 30 and 60 mmol/L may indicate possible CF. Levels below 30 mmol/L are generally considered within the normal range.
Changes in sweat chloride levels
Percentage of children meeting each sweat chloride threshold before and after switching to Alyftrek
Below 60 mmol/L
On Trikafta
86%
92%
Below 30 mmol/L
On Trikafta
38%
65%
Percentages reported in the trial. The Alyftrek results refer to evaluable children after six months of treatment.
Before switching treatments, 86% of participants receiving Trikafta had sweat chloride levels below 60 mmol/L, while 38% had levels below 30 mmol/L. After six months on Alyftrek, these proportions increased to 92% and 65%, respectively.
The researchers noted that the findings suggest Alyftrek may help more children achieve sweat chloride concentrations typically observed in people without CF. However, further long-term studies are needed to determine whether these improvements in CFTR function translate into meaningful clinical benefits over time.
Lung function, pancreatic health, and growth remained stable
Researchers also assessed lung function, pancreatic health, and growth throughout the trial.
On average, participants’ lung function and pancreatic health measurements were generally within normal ranges while they were receiving Trikafta. These measures remained within normal ranges after switching to Alyftrek.
Similarly, children’s growth patterns were generally consistent with expected ranges during the study, with no major changes reported following the treatment switch.
These findings indicate that the improvements in sweat chloride levels observed with Alyftrek occurred alongside the maintenance of generally normal measures of lung function, pancreatic health, and growth in the children studied.
Further research will assess long-term benefits
Overall, the TIMBERLINE trial demonstrated that Alyftrek was generally well tolerated in children with CF ages 2–5 and was associated with improved CFTR function after switching from Trikafta.
The researchers concluded that the treatment provides a once-daily option with greater correction of the underlying CFTR defect in some children, while maintaining a safety profile consistent with that observed in older patients.
However, the study’s open-label design, relatively small number of participants, and six-month treatment period mean that further research is needed to establish the long-term safety and clinical benefits of Alyftrek in this age group.
Longer-term studies will be particularly important to determine whether the observed improvements in CFTR activity lead to sustained benefits in respiratory health, nutritional status, disease progression, and overall quality of life.
Contact
Prof James F Chmiel MD
Indiana University School of Medicine
Email: [email protected]