PRAX-562 is a Well-Tolerated, Novel Persistent Sodium Channel Blocker with Broad Anticonvulsant Activity in Multiple DEE Mouse Models
Lyndsey Anderson1, Nikola Jancovski2, William Eckert1, Erin Baker3, Pravin Wagley4, Snezana Maljevic2, Christopher Reid2, Manoj Patel4, Jennifer Kearney3, Kristopher Kahlig1, Steven Petrou1
1Praxis Precision Medicines, 2Florey Institute of Neuroscience and Mental Health, 3Northwestern University Feinberg School of Medicine, 4University of Virginia Health System
Objective:
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/+.
Background:
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.
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 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.
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). 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.
Conclusions:
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.