Evaluation of potential relationship between CFTR modulators, CFTR and neuropsychiatric symptoms in CF

Cystic fibrosis (CF) is a chronic, life-limiting genetic disease. Treatment with CFTR modulators (CFTRm), such as the triple combination therapies elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) and vanzacaftor/tezacaftor/deutivacaftor (VNZ/TEZ/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.

To 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.

No 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. Up to date analysis of 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.

Multiple 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.