Abstracts

Rationale: Approximately 3.5 million people in the United States have been diagnosed with epilepsy, with around 60% classified as focal onset seizures (FOS). Despite the availability of over 30 antiseizure medications (ASMs), 30-40% of patients remain refractory to current treatments, highlighting the urgent need for novel treatments. PRAX-628 is a next-generation functional state modulator that targets the hyperexcitable state of CNS sodium channels. It is currently in development for adult FOS, with emerging preclinical and clinical data pointing to an ideal precision ASM profile.

We recently implemented the Praxis Analysis of Concordance (PAC) framework to assess the translational concordance of common preclinical seizure models. Using this framework, we deployed a decision tree for accelerated FOS drug discovery that includes three acute seizure models with high predictive validity: audiogenic, maximal electroshock (MES) and 6-Hz (32 mA).

In this study we assess the antiseizure efficacy of PRAX-628 across these models, providing robust support for its accelerated development as a treatment for FOS.


Methods: Male and female juvenile DBA/2J mice were used to assess the antiseizure activity of PRAX-628 in the audiogenic seizure model. MES and 6-Hz experiments were conducted in adult male CD-1 mice. Mice were pre-treated with either vehicle or PRAX-628 by oral gavage 30 min prior to audio or electrical stimulus. For audiogenic seizure experiments, mice were exposed to 110 dB of white noise for 60 s and observed for the presence or absence of full tonic hindlimb extension. Electroshocks for MES experiments were 50 Hz, 0.8 s, 10 ms square pulse width, 50 mA, and for 6-Hz experiments were 6 Hz, 3 s, 0.2 ms rectangular pulse width, 32 mA. Mice were observed for the presence or absence of full tonic hindlimb extension (MES), or psychomotor seizures defined as stun/immobility, forelimb clonus, Straub tail and lateral head movement (6-Hz).


Results: Mice were completely protected from audiogenic-induced tonic hindlimb extension, with an ED₅₀ value of 0.55 mg/kg. In the MES acute seizure model, PRAX-628 (3 and 10 mg/kg) completely protected mice from tonic hindlimb extension, with an ED₅₀ value of 0.42 mg/kg. PRAX-628 also significantly reduced incidence of psychomotor seizures induced by 6-Hz (32 mA), with an ED₅₀ value of 1.9 mg/kg.


Conclusions: PRAX-628 exhibited potent antiseizure activity across three acute seizure models shown to have the highest predictive validity for FOS within our PAC framework. PRAX-628 surpasses thresholds needed to progress development, providing added support for plans to initiate FOS efficacy studies.


Funding: Praxis Precision Medicines.