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Abstract Details

PRAX-562 is a Well-Tolerated, Novel Persistent Sodium Channel Blocker with Broad Anticonvulsant Activity in Multiple DEE Mouse Models
Child Neurology and Developmental Neurology
S34 - Child Neurology and Developmental Neurology 2 (2:12 PM-2:24 PM)
007
Persistent INa, a subthreshold depolarizing current, contributes to the amplification of synaptic activity and enhancement of repetitive firing. Some NaV GoF variants cause pathologic increases in persistent INa that contribute to the neuronal hyperexcitability observed in severe DEEs. 
We previously showed PRAX-562 inhibits persistent sodium current (INa) with preference over peak INa 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 (NaV). Here we investigated the anticonvulsant activity of PRAX-562 in two non-NaV DEE mouse models: Kcnq2K556E/+and Kcnc1R320H/+
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 Scn8aN1768D/+ mice. Spontaneous seizure frequency was measured in Scn2aQ54 mice pre- and post-treatment with PRAX-562. The effect of PRAX-562 on latency to PTZ-induced seizures in Kcnq2K556E/+ and Kcnc1R320H/+ mice was examined. Terminal plasma and brain PRAX-562 concentrations were measured in all experimental mice.  
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). Scn2aQ54 and Scn8aN1768D/+ 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 Kcnq2K556E/+and Kcnc1R320H/+mice, significantly prolonging the latency to PTZ-induced seizures.
PRAX-562 exhibited robust anticonvulsant activity in multiple DEE (NaV and non-NaV) 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 Anderson Anderson, PhD (Praxis Precision Medicines)
PRESENTER
Dr. Anderson has received personal compensation for serving as an employee of Praxis Precision Medicines.
Nikola Jancovski Nikola Jancovski has nothing to disclose.
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.
Erin Marie Baker, PhD (Northwestern University) The institution of Dr. Baker has received research support from Praxis Precision Medicines, Inc.
Pravin Wagley (Nemours Children's Health) Mr. Wagley has nothing to disclose.
Snezana Maljevic Snezana Maljevic has nothing to disclose.
Christopher Reid Christopher Reid has nothing to disclose.
Manoj Patel, PhD (University of Virginia) Dr. Patel has received personal compensation for serving as an employee of GenEP. Dr. Patel has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Gep Ep. Dr. Patel has stock in GenEP.
Jennifer Kearney, PhD (Northwestern University) Prof. Kearney has received personal compensation in the range of $500-$4,999 for serving as a Consultant for PTC Therapeutics. Prof. Kearney has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Neurocrine Biosciences. The institution of Prof. Kearney has received research support from NIH. The institution of Prof. Kearney has received research support from Dravet Syndrome Foundation. The institution of Prof. Kearney has received research support from Lennox Gastaut Foundation. The institution of Prof. Kearney has received research support from Pfizer. The institution of Prof. Kearney has received research support from Neurocrine Biosciences. The institution of Prof. Kearney has received research support from Praxis Precision Medicines. Prof. Kearney has received intellectual property interests from a discovery or technology relating to health care. Prof. Kearney has received intellectual property interests from a discovery or technology relating to health care. Prof. Kearney has received intellectual property interests from a discovery or technology relating to health care. Prof. Kearney has received intellectual property interests from a discovery or technology relating to health care. Prof. Kearney has received intellectual property interests from a discovery or technology relating to health care. Prof. Kearney has received intellectual property interests from a discovery or technology relating to health care. Prof. Kearney has received intellectual property interests from a discovery or technology relating to health care. Prof. Kearney has received intellectual property interests from a discovery or technology relating to health care. Prof. Kearney has received intellectual property interests from a discovery or technology relating to health care. Prof. Kearney has received intellectual property interests from a discovery or technology relating to health care. Prof. Kearney has received intellectual property interests from a discovery or technology relating to health care. Prof. Kearney has received intellectual property interests from a discovery or technology relating to health care. Prof. Kearney has received intellectual property interests from a discovery or technology relating to health care. Prof. Kearney has received intellectual property interests from a discovery or technology relating to health care. Prof. Kearney has received intellectual property interests from a discovery or technology relating to health care. Prof. Kearney has received intellectual property interests from a discovery or technology relating to health care. Prof. Kearney has received intellectual property interests from a discovery or technology relating to health care.
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.
Steven Petrou Steven Petrou has received personal compensation in the range of $100,000-$499,999 for serving as a Consultant for Praxis Precision Medicines. Steven Petrou has stock in Praxis Precision Medicines. The institution of Steven Petrou has received research support from Praxis Precision Medicines. The institution of Steven Petrou has received research support from Medical Research Future Fund. Steven Petrou has received intellectual property interests from a discovery or technology relating to health care. Steven Petrou has received intellectual property interests from a discovery or technology relating to health care.