Objective:

We sought to define the in vivo efficacy and tolerability profile of PRAX-628, a novel activity dependent sodium channel blocker.  

Background:

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 further define its in vivo efficacy and tolerability profile in mice.  

Design/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.