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Abstract Details

PRAX-628: A Novel Sodium Channel Blocker with Greater Potency and Activity Dependence Compared to Standard of Care
Child Neurology and Developmental Neurology
P8 - Poster Session 8 (11:45 AM-12:45 PM)
4-012
This study investigates the in vitro effects of PRAX-628 on sodium current (INa) expressed by hNaV1.6. 
Voltage-gated sodium channels (NaV) are important therapeutic targets for anti-epileptic drugs (AEDs) due to their role in action potential initiation and propagation. Selective NaV blockade during periods of hyperexcitability (activity dependence) has been proposed as a pharmacological target for reducing pathologic neuronal hyperactivity, while sparing peak INa is critical for normal neuronal function.  

Persistent and peak INa inhibition was studied using automated patch clamp recordings of NaV expressed in HEK cells (hNaV1.6). Voltage protocols measured INa inhibition in multiple modes: persistent INa, tonic block (TB), voltage-dependent block (VDB), and activity/use-dependent block (UDB). PRAX-628 was compared to a panel of AEDs, non-AEDs, and investigational compounds. 

Binding kinetics were inferred from inhibition kinetics to calculate an apparent binding (KON) and unbinding (KOFF) rate.  

PRAX-628 exhibited potent activity dependence (UDB IC50 200nM, 44x preference to TB). PRAX-628 blocked hNaV1.6 persistent INa with an IC50 of 128nM (68x preference to TB); at least 550x more potent than other tested compounds. This profile differed from CBZ (persistent INa IC50 77,500nM, 30x preference to TB, no UDB observed) and cenobamate (persistent INa IC50 of 71,690nM, 24x preference to TB, UDB 2.3x preference to TB).  

The preference for persistent INa exhibited by PRAX-628 was not retained versus activity in the more depolarized VDB assay (0.56x preference to VDB); contrasting with the preferential persistent INa inhibitor PRAX-562 (2.2x preference to VDB). 

The enhanced activity dependence of PRAX-628 derives from a rapid KON and moderate KOFF.  
PRAX-628 is a next generation NaV blocker with increased potency and activity dependence for peak INa, and greater potency for persistent INa. This profile may translate to efficacy in epilepsy and other indications caused by hyperexcitability, without tolerability issues caused by excessive block of peak INa. 
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.
No disclosure on file
No disclosure on file