Abstract Details

Title PRAX-628 is a Novel, Well-Tolerated, Activity Dependent Sodium Channel Blocker with Potent Anticonvulsant Activity

Topic Child Neurology and Developmental Neurology

Presentation(s) P4 - Poster Session 4 (8:00 AM-9:00 AM)

Poster/Presentation
Number 4-012

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.

Authors/Disclosures
Kris Kahlig, PhD (Praxis Precision Medicines) PRESENTER	Dr. Kahlig has received personal compensation for serving as an employee of Praxis Precisoin Medicines. Dr. Kahlig has stock in Praxis Precision Medicines.
William A. Eckert III, PhD (Praxis Precision Medicines)	Dr. Eckert has received personal compensation for serving as an employee of Praxis Precision Medicines. Dr. Eckert has received personal compensation for serving as an employee of Janssen Research & Development, LLC. Dr. Eckert has received personal compensation for serving as an employee of Inspire Pharmaceuticals, Inc.. Dr. Eckert has stock in Praxis Precision Medicines. Dr. Eckert has stock in Janssen Research and Development. Dr. Eckert has received intellectual property interests from a discovery or technology relating to health care.
Lyndsey A. Anderson, PhD (Praxis Precision Medicines)	Dr. Anderson has received personal compensation for serving as an employee of Praxis Precision Medicines.
	No disclosure on file

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