Preschoolers With Cystic Fibrosis Get Close to Normal on Alyftrek

In cystic fibrosis, vanzacaftor-tezacaftor-deutivacaftor (VTD; Alyftrek) showed great potential for modifying the progression of disease in young children, according to the TIMBERLINE study.

Assessing safety and tolerability of VTD in 67 children age 2-5 years old already on an existing triple combination cystic fibrosis transmembrane conductance regulator (CFTR) modulator, investigators found 96% of the children had adverse events, mostly mild (52%) or moderate (39%) in severity. Another 3% had serious adverse events, none considered related to VTD.

In the transition from baseline elexacaftor-tezacaftor-ivacaftor (ETI; Trikafta) therapy to VTD, mean sweat chloride concentration, a proxy for CFTR function, fell from 38.4 mmol/L at baseline to 28.9 mmol/L at week 24, reported Marcus Mall, MD, of Charité-Universitätsmedizin Berlin and the German Center for Lung Research, at the European Respiratory Society (ERS) Congress in Barcelona, Spain.

The proportions of children who reached sweat chloride concentrations <60 mmol/L (the diagnostic threshold for cystic fibrosis) and <30 mmol/L were 92% and 65%, respectively — demonstrating “the greatest sweat chloride reduction seen to date in this age group, but also in any age group with any CFTR modulator,” Mall stressed to the audience.

TIMBERLINE was simultaneously published in Lancet Respiratory Medicine.

In their report, Mall and colleagues also reported low rates of pulmonary exacerbations, maintenance of pancreatic exocrine function in the sufficient range, and sustained normal growth and lung function in the study cohort.

“In children with prior exposure to ETI that already improved their health status, there is still evidence of CF [cystic fibrosis]-related end organ involvement, as shown by the elevated LCI [lung clearance index]. The ongoing improvements in this clinical outcome are observed after transitioning to VTD, and initiation of VTD very early in life may therefore ultimately result in better long-term health outcomes compared to ETI,” Mall concluded.

VTD was initially FDA approved in 2024 for adults and older children with cystic fibrosis and was recently expanded for a wider pool of gene compatibility.

Only ETI is indicated for triple combination CFTR modulation in the 2-5 age range, however.

ERS session discussant Refika Ersu, MD, of Children’s Hospital of Eastern Ontario and University of Ottawa, noted the interest in even earlier CFTR triple therapy, perhaps starting as early as the fetus stage.

Mall agreed that there is a general need to push treatment earlier in life. “From earlier observational studies that studied children after establishment of the diagnosis by newborn screening, and this was an average of about 3 months of life, we already know there are already early structural changes. There is already early neutrophilic inflammation … I want to remind you that some of the extrapulmonary manifestations, the pancreas, are also already damaged in utero,” he said.

“We have now women with CF that are getting pregnant, and they decide not to stop the treatment during pregnancy. So we are seeing the first babies with in utero exposure, and see that that also, for example, preserves pancreatic function. We just had one boy that also had preserved vas deferens. So this is sort of the future,” he told the audience. “The problem is there is no regulatory path for this at the moment, so that’s also something we have to work on.”

Pierre-Régis Burgel, MD, PhD, of Université Paris-Cité and Cochin Hospital, also suggested that there is still much work left to be done after TIMBERLINE.

“Overall, [VTD] was more effective than [ETI] at restoring chloride transport in children aged 2-5 years, and there were no specific safety concerns. Whether these effects translate into better pulmonary and extrapulmonary outcomes remains to be established in longer studies,” he commented in an accompanying editorial.

“Current data suggest that CFTR modulators should be started as early as possible, as there might be a window of opportunity to reverse early pulmonary disease and prevent the development of further pulmonary disease. Furthermore, several extrapulmonary manifestations are likely to persist if treatment is started later in life,” Burgel wrote. “However, the safety of starting treatment in the first months of life, or even before birth, must be carefully monitored.”

Of note, the CFTR modulator carries a boxed warning over the risk of drug-induced liver injury and liver failure in its FDA label. Other side effects of concern are rashes, hypersensitivity reactions, and potential behavioral and mental health effects.

Close monitoring of side effects remains a priority, Ersu said, adding that future research should also look into VTD’s effects on inflammation and lung structure.

“We really are super excited” about this therapy, she said. “CFTR modulators, which have made wonders in the life of our children with CF and adults alike … We also need to think about providing global access to these transformative therapies to all people with cystic fibrosis, because this remains as a main concern.”

TIMBERLINE was a phase III open-label study split into two parts: a dose-finding part A (conducted at 11 sites in the U.S.; n=20) and a larger part B evaluating VTD’s safety, tolerability, pharmacokinetics, pharmacodynamics, and efficacy over a 24-week period (conducted at 30 sites in nine countries; n=67).

Investigators enrolled children with cystic fibrosis ages 2-5 years with an ETI-responsive genotype. Before the 24-week VTD treatment period in part B, all children were either on a stable regimen of ETI for at least 28 days before screening or underwent a 4-week ETI run-in.

In part B, mean age was 3.9 years. Nearly half had the F508del–F508del genotype and one in three had an F508del-minimal function genotype.

During the VTD treatment period, children weighing less than 12 kg received vanzacaftor 8 mg once daily, tezacaftor 32 mg once daily, and deutivacaftor 100 mg once daily; children weighing 12 kg or more received vanzacaftor 12 mg once daily, tezacaftor 48 mg once daily, and deutivacaftor 150 mg once daily, orally.

Lung clearance index averaged 6.63 at baseline with ETI, rising by 0.02 at week 24 on VTD. Mean fecal elastase-1 went from 224.2 µg/g to improve, with VTD, by an average 29.1 µg/g or a median 0.01 µg/g.

Mall’s group reported that no child discontinued VTD due to adverse events.

As for pulmonary exacerbations, 16% of the children had one event through the 24 weeks of VTD treatment for an observed pulmonary exacerbation event rate of 0.36 per person per year. There were no pulmonary exacerbation events requiring hospitalization or IV antibiotics.

Among the limitations of the study was the lack of a control group.