PRAX-562 is a Well-Tolerated Novel Persistent Sodium Current Blocker with Potent Anticonvulsant Activity in Models of SCN2A and SCN8A Gain of Function Epilepsy
Abstract number :
Submission category :
7. Anti-seizure Medications / 7A. Animal Studies
Submission ID :
Presentation date :
12/4/2021 12:00:00 PM
Published date :
Nov 22, 2021, 12:54 PM
Liam Scott, BSs, MSc - Praxis Medicines, Inc.; Zoe A. Hughes, PhD – Praxis Precision Medicines, Inc.; Erin Baker – Northwestern University; Jennifer Kearney – Northwestern University; Pravin Wagley – University of Virginia; Manoj Patel – University of Virginia; Marion Wittmann – Praxis Precision Medicines, Inc.; Kristopher Kahlig – Praxis Precision Medicines, Inc.
Rationale: Persistent sodium current (INa) is a subthreshold depolarizing current that contributes to the amplification of synaptic activity and enhancement of repetitive firing. Gain of function (GoF) pathogenic variants in voltage-gated sodium channel (Nav) genes can increase persistent INa leading to neuronal hyperexcitability and severe developmental epileptic encephalopathies (DEE). We show in Kahlig et al., (this meeting) that PRAX-562 inhibits persistent INa with improved selectivity over peak INa compared to standard of care carbamazepine (CBZ) and lamotrigine (LTG). Here we seek to define its in vivo efficacy and tolerability profile in outbred CD-1 mice and genetic mouse models for SCN8A (NaV1.6) and SCN2A (NaV1.2) DEE.
Methods: Anticonvulsant activity of PRAX-562 (0.3-10 mg/kg) was assessed using the maximal electroshock seizure (MES) assay in outbred CD-1 mice. Effects of PRAX-562 (10-40 mg/kg) on spontaneous locomotor activity (sLMA) were measured to assess tolerability. The protective index (PI) of PRAX-562 was determined as the ratio of brain 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.
Prevention of audiogenic seizures was assessed by exposing Scn8a-N1768D/+ mice to a 14 kHz tone 60 min after PRAX-562 (1-10 mg/kg) or vehicle. The proportion of mice seizing was compared across treatments.
Prevention of spontaneous seizures in Scn2aQ54 mice was determined by comparing number of seizures in 30 min periods before and 60-90 min after dosing with PRAX-562 (0.3-10 mg/kg) or vehicle.
The concentration of PRAX-562 in terminal plasma and brain samples were measured using mass spectrometry.
Results: In CD-1 mice, PRAX-562 (10 mg/kg) completely blocked evoked seizures (MES ED50 2 mg/kg, brain EC50 116 ng/g) without affecting sLMA (TD50 44 mg/kg, brain TC50 1899 ng/g; PI 16x). In contrast, CBZ and LTG had PIs of 5-6x; full anticonvulsant efficacy was not achieved without reducing sLMA.
PRAX-562 prevented audiogenic seizures in Scn8a-N1768D/+ mice in a dose-dependent manner with an ED50 of 3.7 mg/kg and full protection at 10 mg/kg.
PRAX-562 also produced dose-dependent prevention of spontaneous seizures in Scn2aQ54 mice with an ED50 of 0.73 mg/kg and complete protection at 3 mg/kg.
Conclusions: PRAX-562 exhibited robust anticonvulsant activity in mouse models of DEE caused by SCN8A or SCN2A GoF variants. Moreover, PRAX-562 exhibited markedly improved preclinical tolerability compared to standard of care NaV blockers, potentially due to its selectivity for persistent INa. The profile of PRAX-562 may translate into well-tolerated efficacy in epilepsy as well as other indications caused by neuronal hyperexcitability.
Funding: Please list any funding that was received in support of this abstract.: All work was funded by Praxis Precision Medicines.