Key result
Linzagolix shows no adverse cardiovascular, respiratory, or CNS effects across preclinical safety models.
Why the study?
Because sex hormone suppression can affect the central nervous, cardiovascular, and respiratory systems, the non-clinical safety pharmacology of the GnRH antagonist linzagolix on these systems needed to be verified.
Does linzagolix affect central nervous, cardiovascular, or respiratory system function or exhibit off-target pharmacological activity in non-clinical safety pharmacology models?
Does linzagolix affect central nervous, cardiovascular, or respiratory system function or exhibit off-target pharmacological activity in non-clinical safety pharmacology models?
Preclinical safety pharmacology studies demonstrate that linzagolix has no detectable adverse effects on CNS, respiratory, or cardiovascular systems (including hERG and cardiac repolarization) at exposures substantially exceeding human therapeutic levels.
Supports linzagolix advancement to human trials without CNS or CV signals; leaves open translation of these animal findings to clinical use.
Background Linzagolix is a potent gonadotropin-releasing hormone (GnRH) antagonist used for the treatment of uterine fibroids and endometriosis. Because of the potential effects of sex hormone suppression on the central nervous, cardiovascular, and respiratory systems, we evaluated the effects of linzagolix on these systems in non-clinical settings to verify its safety. Methods An ICH S7-compliant safety pharmacology program was conducted, including the modified Irwin test in rats, telemetry assessment in conscious cynomolgus monkeys, electrophysiological evaluation of human ether-à-go-go-related gene (hERG) and other cardiac ion channels, action potential recordings in isolated guinea pig papillary muscles, and radioligand binding assays against 75 targets. Results Single oral administration of linzagolix at doses up to 2000 mg/kg showed no detectable effects on the central nervous system (CNS) in female rats. In conscious female monkeys, single oral administration of linzagolix at doses up to 1000 mg/kg showed no detectable effects on the body temperature and did not affect the respiratory system or the blood pressure, heart rate, and electrocardiographic parameters (RR, QRS, PR, QT, and QTcF intervals). In in vitro cardiovascular studies, linzagolix had no effects on the hERG tail current and cardiac ion channel or on action potential parameters in guinea pig papillary muscles. Moreover, linzagolix showed no off-target activity up to a concentration of 10 µmol/L in radioligand binding assays. Conclusions Linzagolix showed no detectable effects on the safety pharmacology endpoints evaluated in this study at concentrations and doses that provided exposures exceeding those achieved at approved therapeutic doses in humans. These findings indicate a low potential for CNS, cardiovascular, respiratory, cardiac electrophysiological, and off-target pharmacological effects under the conditions tested.
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Tamai et al. (2026) studied Preclinical safety pharmacology for uterine fibroids and endometriosis treatment (n=44). Linzagolix vs. Vehicle control (0.5% methylcellulose aqueous solution in vivo; 0.2% DMSO in vitro) and positive controls (E-4031 0.1 µmol/L, sotalol 30 µmol/L) was evaluated on Safety pharmacology endpoints across CNS (modified Irwin test), cardiovascular/respiratory telemetry (BP, HR, ECG intervals RR, QRS, PR, QT, QTcF, body temperature, respiratory rate), in vitro cardiac ion channels (hERG, hNaV1.5, hCaV1.2, hKv4.3, hKir2.1, hKCNQ1/E1, hKv1.5), guinea pig papillary muscle action potentials, and 75 off-target radioligand binding assays. Linzagolix showed no detectable effects on CNS, respiratory, or cardiovascular parameters (up to 1000 mg/kg in monkeys and 100 µmol/L in vitro) and ≤29.69% off-target inhibition at 10 µmol/L.
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