Authors :
First Author: Lyndsey Anderson, PhD – Praxis Precision Medicines
Presenting Author: Kris Kahlig, PhD – Praxis Precision Medicines
kris kahlig, PhD – Praxis Precision Medicines; Steven Petrou, PhD – Praxis Precision Medicines
Rationale:
Standard anti-seizure medications (ASMs) that block sodium (NaV) channels can cause severe side effects at therapeutic doses, presumably due to excessive inhibition of the peak sodium current necessary for normal neuronal function. A more selective inhibition of NaV channels during periods of pathologically heightened excitability, without affecting physiological activity, could improve efficacy and tolerability. PRAX-628 is a novel compound with superior potency and selectivity for functional state NaV channel hyperexcitability currently in development for treatment of adult focal epilepsy. This study explores the in vivo anti-seizure efficacy of PRAX-628 in mice, comparing it to standard-of-care NaV channel blockers, carbamazepine, lamotrigine and cenobamate that exhibit less activity-dependence, as well as the Kv7 opener, XEN1101.Methods:
The anticonvulsant activity of PRAX-628 was assessed across multiple acute seizure models in outbred male CD-1 mice: maximal electroshock (MES), 6 Hz and pentylenetetrazole (PTZ). Mice were pre-treated with either vehicle or PRAX-628 by oral gavage 30 min prior to the electrical stimulus or chemoconvulsant. Electroshocks (50 Hz, 0.8 s, 10 ms square pulse width, 50 mA or 6 Hz, 3 s, 0.2 ms rectangular pulse width, 32 mA) were delivered for MES and 6 Hz experiments, respectively. 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). PTZ (85 mg/kg) was administered as a subcutaneous injection and mice were observed for the presence or absence of generalized clonic seizure. The effects of standard-of-care comparators, carbamazepine, cenobamate, lamotrigine and XEN1101, were also assessed in MES. Results:
PRAX-628 (3 and 10 mg/kg) completely protected mice from tonic hindlimb extension induced by MES, with an ED50 value of 0.42 mg/kg. ED50 values of comparators in MES ranged from 3.8 to 5.4 mg/kg. PRAX-628 also significantly reduced incidence of psychomotor seizures induced by 6 Hz (ED50 1.9 mg/kg) and clonic seizures induced by PTZ (ED50 2.6 mg/kg). Conclusions:
PRAX-628 exhibited potent anticonvulsant activity in various acute seizure models. Importantly it displayed anticonvulsant activity at doses lower than standard-of-care ASMs in the MES acute seizure model. PRAX-628 is currently being developed as a once daily, oral treatment for adult focal onset epilepsy. Recent results demonstrate favorable tolerability in healthy adult participants, implying a wider potential therapeutic range compared to conventional ASMs.
Funding: Praxis Precision Medicines