2023 American Academy of Neurology Abstract Website

Objective:

This study investigates the in vitro effects of PRAX-628 on sodium current (I_Na) expressed by hNa_V1.6.

Background:

Voltage-gated sodium channels (Na_V) are important therapeutic targets for anti-epileptic drugs (AEDs) due to their role in action potential initiation and propagation. Selective Na_V blockade during periods of hyperexcitability (activity dependence) has been proposed as a pharmacological target for reducing pathologic neuronal hyperactivity, while sparing peak I_Na is critical for normal neuronal function.

Design/Methods:

Persistent and peak I_Na inhibition was studied using automated patch clamp recordings of Na_V expressed in HEK cells (hNa_V1.6). Voltage protocols measured I_Na inhibition in multiple modes: persistent I_Na, 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 (K_ON) and unbinding (K_OFF) rate.

Results:

PRAX-628 exhibited potent activity dependence (UDB IC₅₀ 200nM, 44x preference to TB). PRAX-628 blocked hNa_V1.6 persistent I_Na with an IC₅₀ of 128nM (68x preference to TB); at least 550x more potent than other tested compounds. This profile differed from CBZ (persistent I_Na IC₅₀ 77,500nM, 30x preference to TB, no UDB observed) and cenobamate (persistent I_Na IC₅₀ of 71,690nM, 24x preference to TB, UDB 2.3x preference to TB).

The preference for persistent I_Na 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 I_Na inhibitor PRAX-562 (2.2x preference to VDB).

The enhanced activity dependence of PRAX-628 derives from a rapid K_ON and moderate K_OFF.

Conclusions:

PRAX-628 is a next generation Na_V blocker with increased potency and activity dependence for peak I_Na, and greater potency for persistent I_Na. This profile may translate to efficacy in epilepsy and other indications caused by hyperexcitability, without tolerability issues caused by excessive block of peak I_Na.