Safety and efficacy of ivacaftor in infants aged 1 to less than 4 months with cystic fibrosis

Paul McNally; Alvin Singh; Susanna A McColley; Jane C Davies; Mark Higgins; Meng Liu; Jennifer Lu; Violeta Rodriguez-Romero; Judy L Shih; Margaret Rosenfeld; VX15-770-124 Study Group

doi:10.1016/j.jcf.2024.03.012

Safety and efficacy of ivacaftor in infants aged 1 to less than 4 months with cystic fibrosis

J Cyst Fibros. 2024 Apr 4:S1569-1993(24)00042-0. doi: 10.1016/j.jcf.2024.03.012. Online ahead of print.

Authors

Affiliations

¹ RCSI University of Medicine and Health Sciences and Children's Health Ireland, Dublin, Ireland.
² Children's Mercy Kansas City, Kansas City, MO, USA.
³ Ann & Robert H. Lurie Children's Hospital of Chicago and Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
⁴ NHLI, Imperial College London & Royal Brompton Hospital, Part of Guy's & St Thomas' Trust, London, UK.
⁵ Vertex Pharmaceuticals Incorporated, Boston, MA, USA.
⁶ Center for Clinical and Translational Research, Seattle Children's Research Institute, and Department of Pediatrics, University of Washington School of Medicine, Seattle, WA, USA. Electronic address: margaret.rosenfeld@seattlechildrens.org.

PMID: 38580563
DOI: 10.1016/j.jcf.2024.03.012

Abstract

Background: Ivacaftor (IVA) has been shown to be safe and efficacious in children aged ≥4 months with cystic fibrosis (CF) and CFTR gating variants. We evaluated safety, pharmacokinetics (PK), and efficacy of IVA in a small cohort of infants aged 1 to <4 months with CF.

Methods: In this phase 3, open-label study, infants 1 to <4 months with CF and an IVA-responsive CFTR variant received an initial low dose of IVA based on age and weight. Because IVA is a sensitive CYP3A substrate and CYP3A maturation is uncertain in infants, doses were adjusted at day 15 to better match median adult exposures based on individual PK measurements taken on day 4. Primary endpoints were safety and PK measurements.

Results: Seven infants (residual function CFTR variants [n=5]; minimal function CFTR variants [n=2]) received ≥1 dose of IVA. Six infants had doses adjusted at day 15 and one infant did not require dose adjustment; subsequent PK analyses showed mean trough concentrations for IVA and metabolites were within range of prior clinical experience. Four infants (57.1%) had adverse events (AEs); no serious AEs were noted. One infant discontinued study drug due to a non-serious AE of elevated alanine aminotransferase >8x the upper limit of normal. Mean sweat chloride concentration decreased (-40.3 mmol/L [SD: 29.2]) through week 24. Improvements in biomarkers of pancreatic function and intestinal inflammation, as well as growth parameters, were observed.

Conclusions: In this small, open-label study, IVA dosing in infants achieved exposures previously shown to be safe and efficacious. Because PK was predictable, a dosing regimen based on age and weight is proposed. IVA was generally safe and well tolerated, and led to improvements in CFTR function, markers of pancreatic function and intestinal inflammation, and growth parameters, supporting use in infants as young as 1 month of age.

Keywords: CFTR potentiator; Cystic fibrosis transmembrane conductance regulator; Infants; Ivacaftor; Pharmacokinetics.