Small Study Shows Cystic Fibrosis Drug Alyftrek Cuts Sweat Chloride Levels in Preschoolers, But It's Not Approved for This Age Group Yet

A study of 67 preschoolers with cystic fibrosis found that switching them to a newer drug, Alyftrek, pushed a key biological marker of the disease down further than any CFTR modulator has managed before in that age group, according to findings presented by Marcus Mall, MD, of Charité-Universitätsmedizin Berlin, at the European Respiratory Society Congress in Barcelona.

The study, called TIMBERLINE, was published simultaneously in Lancet Respiratory Medicine.

What The Study Actually Did

All 67 children in the trial, ages 2 to 5, were already on an existing triple-combination CFTR modulator called Trikafta (elexacaftor-tezacaftor-ivacaftor, or ETI). Researchers switched them to Alyftrek (vanzacaftor-tezacaftor-deutivacaftor, or VTD) and tracked what happened over 24 weeks.

Mean sweat chloride concentration, the standard proxy doctors use to measure how well a patient's CFTR protein is functioning, fell from 38.4 mmol/L at baseline to 28.9 mmol/L at week 24. Lower is better. Anything under 60 mmol/L is the diagnostic threshold for cystic fibrosis; under 30 mmol/L is considered close to normal function.

92% of the kids in the study got below 60 mmol/L. 65% got below 30 mmol/L.

Mall told the ERS audience this was "the greatest sweat chloride reduction seen to date in this age group, but also in any age group with any CFTR modulator." That's a strong claim, and it's coming from the study's own lead investigator, not an independent third party.

The Safety Numbers

96% of the children had some kind of adverse event during the trial. Of those, 52% were mild and 39% were moderate. Only 3% were serious, and researchers said none of the serious events were considered related to VTD itself.

Investigators also reported low rates of pulmonary exacerbations, pancreatic exocrine function staying in the sufficient range, and normal growth and lung function holding up over the study period.

Not Approved For This Age Group

Alyftrek got FDA approval in 2024 for adults and older children with cystic fibrosis, and that approval was recently expanded to cover a wider range of patients based on genetic compatibility. But right now, Trikafta (ETI) is the only triple-combination CFTR modulator actually indicated for children ages 2 to 5. Alyftrek isn't approved for that age bracket yet.

That means any use of VTD in preschoolers right now would be off-label, and doctors would need to weigh the TIMBERLINE data against the fact that regulators haven't signed off on it for this population.

The Fair Counterargument

A reasonable skeptic would point out several things this study doesn't answer. It had no placebo arm and no comparison group still on Trikafta. It followed just 67 children for 24 weeks and measured a biomarker (sweat chloride) rather than hard outcomes like hospitalizations or lung function decades down the road. Sweat chloride is a well-established proxy in cystic fibrosis research, but a proxy is still a proxy, not a guarantee of long-term clinical benefit.

Nearly all children in the trial had an adverse event of some kind, even if most were mild. A single-arm, open-label design like this one makes it harder to tell how much of that is the drug versus how much is normal childhood illness in a study population being monitored closely.

What Researchers Are Already Asking Next

ERS session discussant Refika Ersu, MD, of Children's Hospital of Eastern Ontario and the University of Ottawa, raised the question of pushing CFTR modulator treatment even earlier, potentially to the fetal stage.

Mall agreed there's a case for starting sooner. He pointed to earlier observational research showing that by around 3 months of age, after diagnosis through newborn screening, children with cystic fibrosis already show structural lung changes and early neutrophilic inflammation. He also noted the pancreas can already be damaged before birth.

Mall's team also flagged something else in the data worth watching. Even in children who'd already improved on Trikafta before switching, lung clearance index, a marker of small-airway function, remained elevated. That suggests some degree of lung damage persists even with early triple-modulator therapy, according to Mall. He said the ongoing improvements seen after switching to VTD raise the question of whether starting VTD earlier in life could beat ETI on long-term outcomes.

That's a hypothesis, not a finding. No trial has yet tested VTD as a first-line therapy in newly diagnosed infants, and no regulator has approved it for children under 6. The next step is whichever pediatric approval application Vertex Pharmaceuticals, the company behind both Trikafta and Alyftrek, decides to pursue with the FDA and other regulators for this younger age group.