Elexacaftor/Tezacaftor/Ivacaftor and Neuropsychiatric Symptoms: Nonclinical and Clinical Studies

RationaleCystic fibrosis (CF) is a chronic, life-limiting genetic disease. Treatment with CFTR modulators (CFTRm), such as the triple combination therapies of elexacaftor (ELX)/tezacaftor (TEZ)/ivacaftor (IVA) and vanzacaftor (VNZ), TEZ, and deutivacaftor (D-IVA), have significantly improved clinical outcomes and quality of life for many people with CF. While most individuals treated with CFTRm report no change or improvement in neuropsychiatric symptoms, a minority have reported new or worsening symptoms. This has led to hypotheses that CFTRm or CFTR function could have relationships to neuropsychiatric symptoms. ObjectivesTest specific hypotheses about potential relationships between CFTRm, CFTR function, and neuropsychiatric symptoms. MethodsTo evaluate potential off-target or on-target effects of CFTRm and/or CFTR function on neuropsychiatric symptoms, we conducted four independent analyses: (a) in vitro off-target screening at clinically-relevant free concentrations; (b) nonclinical, in vivo behavioral pharmacology studies; (c) analysis of clinical trial and real-world evidence of CFTRm neuropsychiatric adverse events; and (d) human genetic analysis of CFTR functional variants in [~]1 million individuals diagnosed with neuropsychiatric disorders. Measurements and Main ResultsNo off-target effects of ELX, VNZ, TEZ, or IVA were observed in vitro at clinically-relevant free concentrations, nor were any behavioral findings observed in vivo animal studies. Clinical trial and real-world data covering >250,000 patient-years of experience with CFTRm did not show any increase in risk of neuropsychiatric adverse events. Human genetic analyses of functional CFTR variants did not identify association with any of 23 neuropsychiatric conditions. ConclusionsMultiple independent lines of investigation failed to show any evidence for off-target or on-target effects of CFTRm and/or CFTR function on neuropsychiatric symptoms.