Vanzacaftor Regimen Lets Some Children With Cystic Fibrosis Stop PERT

More than one-third of children with cystic fibrosis aged 2 years and older who enrolled in a pancreatic enzyme replacement therapy (PERT) substudy discontinued PERT after about 1 year of vanzacaftor–tezacaftor–deutivacaftor (Alyftrek), according to interim open-label extension data presented at the 2026 North American Cystic Fibrosis Conference (NACFC), held October 7 to 10 in Atlanta, Georgia.¹

The children previously completed the phase 3 TIMBERLINE trial, in which 24 weeks of vanzacaftor–tezacaftor–deutivacaftor further lowered sweat chloride from an elexacaftor–tezacaftor–ivacaftor baseline in 67 children aged 2 to 5 years and maintained mean fecal elastase-1 (FE-1) in the pancreatic sufficient range.² The extension analysis tested whether children meeting laboratory and symptom criteria could safely stop PERT.¹ The data are from a Vertex-sponsored poster and have not yet been published in a peer-reviewed journal.

"Children with undetectable baseline FE-1 had the least recovery of exocrine pancreatic function, emphasizing that even earlier intervention may be needed to maximize pancreatic organ preservation/recovery," wrote Ajay S. Kasi, MD, Emory University School of Medicine and Children's Healthcare of Atlanta, and colleagues.¹

PERT discontinuation criteria and FE-1 results in the vanzacaftor extension

Cohort 2 of the ongoing phase 3 open-label extension trial 121-106 enrolled children aged 2 years and older who completed TIMBERLINE.¹ Children were eligible for the PERT substudy if they completed extension week 24 while still receiving PERT, and 48 of 66 (73%) enrolled.¹ Discontinuation required 2 consecutive FE-1 values of at least 200 μg/g, the threshold for pancreatic sufficiency, with no clinical signs or symptoms of malabsorption and no intercurrent illness.¹

In the substudy, mean age was 3.9 years (standard deviation [SD], 1.0), 54.2% had the F508del–F508del genotype, and 89.6% had received elexacaftor–tezacaftor–ivacaftor before TIMBERLINE for a mean of 50.5 weeks.¹ Mean baseline FE-1 was 148.9 μg/g (SD, 184.9), with 70.5% (31/44) below 200 μg/g and 38.6% (17/44) below 15 μg/g.¹

After 52 weeks of vanzacaftor–tezacaftor–deutivacaftor, mean FE-1 was 239.7 μg/g (SD, 194.7), a mean increase of 110.2 μg/g (SD, 132.6) from TIMBERLINE baseline.¹ Of 35 children with available values at extension week 28, 48.6% (17/35) had FE-1 of at least 200 μg/g.¹

PERT independence by baseline pancreatic function

At the data cut, 37.5% (18/48) of substudy participants had discontinued PERT and not restarted it, after a mean of 54.5 weeks of vanzacaftor–tezacaftor–deutivacaftor (range, 51.1-60.0).¹ Mean age at discontinuation was 4.7 years, and mean time off PERT was 8.6 weeks (range, 1.9-17.6).¹ Including 15 children already off PERT before the substudy, 50% (33/66) of the cohort were off PERT.¹

Response depended on baseline pancreatic function. Children with pancreatic sufficient FE-1 maintained mean values of at least 200 μg/g, and those with baseline FE-1 of 15 to less than 200 μg/g rose to a mean of at least 200 μg/g.¹ Children with undetectable baseline FE-1, below 15 μg/g, remained below 200 μg/g on average, and only 1 of 18 children achieving PERT independence started in this category.¹

Mean baseline FE-1 among the 18 children achieving independence was 229.5 μg/g (SD, 196.5), and 72.2% had the F508del–F508del genotype.¹ One child restarted PERT 5 days after stopping because of upper abdominal pain, abdominal distension, and flatulence, which resolved, and no other adverse events related to PERT discontinuation were reported.¹

The analysis is an interim, single-arm, open-label extension with a short off-PERT follow-up, and durability of PERT independence beyond a few months is not yet known.¹ Most participants had substantial prior elexacaftor–tezacaftor–ivacaftor exposure, so the findings do not isolate the effect of vanzacaftor–tezacaftor–deutivacaftor alone.

References

1. Kasi AS, Hoppe JE, Mall MA, et al. Early intervention with highly effective CFTR modulator therapy can reverse exocrine pancreatic failure and achieve PERT independence: interim results from VNZ/TEZ/D-IVA open-label extension study in children with CF aged 2 years and older. Poster presented at: North American Cystic Fibrosis Conference; October 7-10, 2026; Atlanta, GA. Poster 774.

2. Rayment JH, Davies G, Gaffin JM, et al. 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. Lancet Respir Med. Published online September 8, 2026. doi:10.1016/S2213-2600(26)00257-2