Abstracts

Rationale: Gain-of-function (GoF) pathogenic variants in voltage-gated sodium channel (Na_v) genes can increase persistent sodium current (I_Na) leading to neuronal hyperexcitability and severe developmental and epileptic encephalopathies (DEE). We show in Kahlig et al., (this meeting) that PRAX-628 inhibits I_Na with greater activity dependence compared to standard of care carbamazepine (CBZ) and lamotrigine (LTG). Here we seek to define its in vivo efficacy and tolerability profile in mice.

Methods: The anticonvulsant activity of PRAX-628 (0.3-10 mg/kg) was assessed using the maximal electroshock seizure (MES) assay in outbred CD-1 mice. Effects of PRAX-628 (3-20 mg/kg) on spontaneous locomotor activity (sLMA) were measured to assess tolerability. The protective index (PI) of PRAX-628 was determined as the ratio of plasma concentrations in sLMA (TC₅₀) to MES (EC₅₀). The effects of CBZ and LTG were also assessed using MES (3-30 mg/kg and 1-10 mg/kg, respectively) and sLMA (30-96 mg/kg and 20-63.4 mg/kg, respectively), and their corresponding PIs computed. The concentration of PRAX-628 in terminal plasma and brain samples was measured using mass spectrometry.

Results: PRAX-628 (10 mg/kg) completely blocked evoked seizures (MES ED₅₀ 0.67 mg/kg, brain EC₅₀ 67.2 ng/g) without affecting sLMA (TD₅₀ 10.27 mg/kg, plasma TC₅₀ 1123 ng/g; PI 16.7). In contrast, CBZ and LTG had PIs of 5-6x; full anticonvulsant efficacy with CBZ or LTG was not achieved without reducing sLMA.

Conclusions: PRAX-628 exhibited markedly improved preclinical tolerability compared to standard of care Na_V blockers, potentially due to its improved activity dependent inhibition of peak I_Na. The profile of PRAX-628 may translate into well-tolerated efficacy in epilepsy as well as other indications caused by neuronal hyperexcitability.

Funding: Praxis Precision Medicines