Elexacaftor/Tezacaftor/Ivacaftor and Neuropsychiatric Symptoms: Nonclinical and Clinical Studies
Discuss this preprint
Start a discussion What are Sciety discussions?Listed in
This article is not in any list yet, why not save it to one of your lists.Abstract
Rationale
Cystic fibrosis (CF) is a chronic, life-limiting genetic disease. CFTR modulators such as elexacaftor (ELX)/tezacaftor (TEZ)/ivacaftor (IVA) have significantly improved clinical outcomes and quality of life for many people with CF. While most individuals report no change or improvement in neuropsychiatric symptoms with ELX/TEZ/IVA, a minority experience new or worsening symptoms.
Objectives
Assess whether neuropsychiatric symptoms are an off-target or on-target pharmacological effect of ELX/TEZ/IVA.
Methods
To evaluate potential off-target or on-target effects of ELX/TEZ/IVA on neuropsychiatric symptoms we conducted: (a) in vitro off-target screening at clinically relevant concentrations; (b) non-clinical, in vivo behavioral pharmacology studies; (c) analysis of clinical trial and real-world data for evidence of neuropsychiatric adverse events; and (d) human genetic analysis of ∼1M individuals with neuropsychiatric disorders to assess for potential associations with CFTR functional variants.
Measurements and Main Results
No off-target effects of ELX, TEZ, or IVA were observed in vitro or in vivo animal studies at clinically relevant free concentrations. Clinical trial and real-world data covering >52,000 patient-years of experience with ELX/TEZ/IVA showed no increase in risk of neuropsychiatric adverse events. Human genetic analyses of functional CFTR variants did not show association with any of 23 neuropsychiatric conditions.
Conclusions
Multiple independent lines of investigation failed to show any evidence for off-target or on-target effects of CFTR modulators, CFTR human genetic variants and neuropsychiatric symptoms.
