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

Fezolinetant is a first-in-class, selective, non-hormonal, neurokinin 3 receptor antagonist that is approved for the treatment of moderate to severe vasomotor symptoms due to menopause. In a phase 2b clinical study (n = 352), nine study participants experienced elevations in serum transaminases exceeding three times the upper limit of normal. DILIsym, a quantitative systems toxicology model of drug-induced liver injury, was used to assess the potential hepatotoxicity of fezolinetant prior to initiating phase 3 trials. In vitro toxicity assays and physiologically-based pharmacokinetic estimates of fezolinetant and primary metabolite exposure were leveraged to simulate the incidence of hepatotoxicity for various fezolinetant treatment regimens and virtual simulated populations. DILIsym simulations indicated a dose-dependent relationship between fezolinetant exposure and hepatotoxicity primarily caused by electron transport chain inhibition. At therapeutic doses, no ALT elevations exceeding three times the upper limit of normal were predicted for healthy volunteers. In a metabolic syndrome-associated fatty liver disease (MAFLD) population with compromised mitochondrial function, mild increases in ALT elevation frequency above placebo were observed in all fezolinetant treatment groups and included a single Hy's Law case at 45 and 60 mg once daily. The predicted Hy's Law case in the MAFLD population was mitigated by the incorporation of mitochondrial biogenesis. These predictions aided discussions with internal and external stakeholders regarding dose selection and initiation of the phase 3 clinical studies. Phase 3 studies were subsequently completed and confirmed the efficacy and acceptable liver safety of fezolinetant at 30 and 45 mg QD, leading to drug approval at 45 mg QD.