Quantitative Systems Toxicology Modeling with DILIsym to Support Phase 3 Dose Selection for Fezolinetant.

Area of Science:

• Pharmacology
• Toxicology
• Hepatology

Background:

• Fezolinetant is a novel neurokinin 3 receptor antagonist for menopausal vasomotor symptoms.
• Phase 2b trials indicated potential for drug-induced liver injury (DILI) with elevated transaminases.
• Quantitative systems toxicology modeling was employed to predict hepatotoxicity risk.

Purpose of the Study:

• To assess the potential hepatotoxicity of fezolinetant using the DILIsym model before Phase 3 trials.
• To simulate fezolinetant's liver injury risk across different doses and virtual populations.
• To inform dose selection and clinical trial design based on predicted safety profiles.

Main Methods:

• Utilized the DILIsym quantitative systems toxicology platform.
• Integrated in vitro toxicity data and physiologically-based pharmacokinetic (PBPK) estimates.
• Simulated virtual patient populations, including those with metabolic syndrome-associated fatty liver disease (MAFLD).

Main Results:

• DILIsym predicted a dose-dependent relationship between fezolinetant exposure and hepatotoxicity, linked to electron transport chain inhibition.
• No significant ALT elevations were predicted in healthy volunteers at therapeutic doses.
• A single Hy's Law case was predicted in the MAFLD population, mitigated by simulating mitochondrial biogenesis.

Conclusions:

• Quantitative systems toxicology modeling supported the acceptable liver safety profile of fezolinetant at therapeutic doses.
• Simulations informed Phase 3 dose selection (30 and 45 mg QD) and trial initiation.
• Phase 3 studies confirmed efficacy and acceptable liver safety, leading to regulatory approval.