Abstract Details

Title PRAX-562 is a Well-Tolerated, Novel Persistent Sodium Channel Blocker with Broad Anticonvulsant Activity in Multiple DEE Mouse Models

Topic Child Neurology and Developmental Neurology

Presentation(s) S34 - Child Neurology and Developmental Neurology 2 (2:12 PM-2:24 PM)

Poster/Presentation
Number 007

Objective We previously showed PRAX-562 inhibits persistent sodium current (I_Na) with preference over peak I_Na compared to standard-of-care. This profile was efficacious in two DEE mouse models with gain-of-function (GoF) mutations in voltage-gated sodium channels (Na_V). Here we investigated the anticonvulsant activity of PRAX-562 in two non-Na_V DEE mouse models: Kcnq2^K556E/+and Kcnc1^R320H/+.

Background Persistent I_Na, a subthreshold depolarizing current, contributes to the amplification of synaptic activity and enhancement of repetitive firing. Some Na_V GoF variants cause pathologic increases in persistent I_Na that contribute to the neuronal hyperexcitability observed in severe DEEs.

Design/Methods Maximal electroshock seizure (MES) and spontaneous locomotor activity (sLMA) assays were used to assess anticonvulsant activity and tolerability of PRAX-562, respectively. For comparison, carbamazepine and lamotrigine were also assessed in MES and sLMA. Protective indices (PI) were calculated by dividing the sLMA plasma TC₅₀ by the MES EC₅₀. PRAX-562 was evaluated on audiogenic-induced (14-kHz tone) seizures in Scn8a^N1768D/+ mice. Spontaneous seizure frequency was measured in Scn2a^Q54 mice pre- and post-treatment with PRAX-562. The effect of PRAX-562 on latency to PTZ-induced seizures in Kcnq2^K556E/+and Kcnc1^R320H/+ mice was examined. Terminal plasma and brain PRAX-562 concentrations were measured in all experimental mice.

Results The PI for PRAX-562 calculated as ~14x (Plasma: sLMA TC₅₀ 1385 ng/mL; MES EC₅₀ 102 ng/mL) was greater than those calculated for carbamazepine (~3x) and lamotrigine (~6x). Scn2a^Q54 and Scn8a^N1768D/+mice were completely protected from spontaneous or audiogenic-induced seizures, respectively, following treatment with 10 mg/kg PRAX-562. PRAX-562 (10 mg/kg) was also anticonvulsant in Kcnq2^K556E/+and Kcnc1^R320H/+mice, significantly prolonging the latency to PTZ-induced seizures.

Conclusions PRAX-562 exhibited robust anticonvulsant activity in multiple DEE (Na_V and non-Na_V) mouse models indicating broad efficacy regardless of the underlying genetic basis. Moreover, PRAX-562 markedly improved preclinical tolerability compared to standard-of-care. The profile of PRAX-562 may translate into well-tolerated efficacy in epilepsy and other indications caused by neuronal hyperexcitability.

Authors/Disclosures
Lyndsey A. Anderson, PhD (Praxis Precision Medicines) PRESENTER	Dr. Anderson has received personal compensation for serving as an employee of Praxis Precision Medicines.
	No disclosure on file
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.
	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
Kris Kahlig, PhD (Praxis Precision Medicines)	Dr. Kahlig has received personal compensation for serving as an employee of Praxis Precisoin Medicines. Dr. Kahlig has stock in Praxis Precision Medicines.
	No disclosure on file

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