Is There a Role for Lumacaftor/Ivacaftor in Young Children with Cystic Fibrosis?

To the Editor:

As experience with elexacaftor/tezacaftor/ivacaftor (ETI) in people with cystic fibrosis (pwCFs) accumulates, Stahl and colleagues (1), in their interesting paper, report on the effects of lumacaftor/ivacaftor (LUM/IVA) therapy in children aged 2–5 years with CF. Although less effective than ETI for pulmonary endpoints in older children (2), such studies exploring the impact of LUM/IVA on disease progression in younger children with CF are important because treatment options for this age group are currently limited. Stahl and coworkers’ observations reinforce the awareness that, in addition to improvement in respiratory outcomes, LUM/IVA therapy has the potential to provide additional clinical benefit in young children with CF by rescuing pancreatic function.

Exocrine pancreatic insufficiency (EPI) in CF manifests early and often precedes other CF-related complications. Approximately 85% of pwCFs have EPI, and approximately two thirds of these present with fecal elastase-1 (FE-1) levels below the diagnostic threshold of 200 μg/g stool in infancy (3). EPI has been associated with worse clinical outcomes, including lower nutritional status and pulmonary function, and is linked to impaired glucose tolerance and diabetes (4). Pancreatic damage in pwCFs was once considered progressive and irreversible; however, experience with CF transmembrane conductance regulator (CFTR) modulators demonstrates some plasticity in CF pancreatic disease.

Early findings from studies on the potentiator ivacaftor in pwCFs and CFTR gating mutations had shown that exocrine pancreatic function can be rescued, as one fourth to two thirds of children with CF with EPI became pancreatic-sufficient with ivacaftor treatment (5). We are now discovering that pancreatic function can also be improved with CFTR modulators in pwCFs homozygous for the Phe508del mutation, a group that usually requires lifelong pancreatic enzyme replacement therapy.

A previous study on LUM/IVA in Phe508del/Phe508del pwCFs in the 2–5-year age group saw 6 of 41 patients (15%) develop pancreatic sufficiency and mean improvements in FE-1 levels of 132.6 μg/g over 96 weeks of treatment (6). Notably, four of the six patients in whom exocrine pancreatic sufficiency had been achieved by the end of the study had baseline FE-1 levels ⩽15 μg/g before starting treatment, demonstrating that exocrine pancreatic sufficiency was achieved even in those with more impaired pancreatic function. In the study by Stahl and coworkers, 5 of 48 children (10%) with EPI at baseline became pancreatic-sufficient, with an average increase in FE-1 of 81.9 μg/g in the children who received LUM/IVA for the full 96 weeks and 47.5 μg/g in the group that initially received placebo. There are also reports showing that the development of EPI can be prevented or delayed in cases of intrauterine exposure to CFTR modulators (7), delivering a clear message that early intervention leads to more favorable pancreatic outcomes.

LUM/IVA is now predominantly used for Phe508del/Phe508del pwCFs if ETI is not (yet) available or not tolerated, but generally not with the intention to rescue or prevent EPI. Stahl and coworkers’ study, taken in the context of a growing body of evidence, provides support for early CFTR modulator therapy with the intention to preserve/rescue pancreatic function. As we continue to explore the impacts of early treatment with CFTR modulators, it is conceivable that avoiding early pancreatic damage will have positive ramifications on nutritional status and blood glucose control, ultimately improving clinical outcomes and quality of life for pwCFs. Different from ETI, LUM/IVA is approved for children with CF aged ≥1 year, although access and funding will vary depending on local reimbursement policies and access.

To summarize, because ETI is not yet available for the youngest children with CF, LUM/IVA should be considered as early therapy with the intention to preserve or rescue pancreatic function while awaiting approval of or access to ETI.