Authors :
Presenting Author: Lyndsey Anderson, PhD – Praxis Precision Medicines
Kristopher Kahlig, PhD – Praxis Precision Medicines
Marcio Souza, PharmD, MBA – Praxis Precision Medicines
Steven Petrou, PhD – Praxis Precision Medicines
Rationale:
Dravet syndrome is a severe, intractable developmental epileptic encephalopathy (DEE) largely resulting from SCN1A haploinsufficiency and is characterized by frequent seizures, behavioral and developmental delays and increased mortality. While the use of sodium channel blockers in Dravet syndrome remains controversial, emerging preclinical and clinical data suggest that sodium channel modulation may be an appropriate therapeutic strategy in Dravet syndrome.
Relutrigine represents a differentiated functional state sodium channel modulator class which exhibits selectivity for disease-state sodium channel hyperexcitability and is currently in development as a first- and best-in-class sodium channel modulator for broad DEEs. Relutrigine has recently received Rare Pediatric Disease designation for Dravet syndrome, building on encouraging clinical findings from the EMBOLD study demonstrating well-tolerated seizure reduction and freedom in SCN2A and SCN8A-DEE. Here, we evaluate its effect in a zebrafish model of Dravet syndrome.
Methods:
The anticonvulsant potential of relutrigine was assessed in an established zebrafish model of Dravet syndrome and compared to that of fenfluramine. Locomotor activity of individual treated and untreated scn1Labs552/s552 larvae was tracked with the DanioVision/EthoVision automated tracking system.
Results:
Relutrigine significantly reversed seizure-like behavior in the scn1Labs552/s552 zebrafish model of Dravet syndrome and was more potent than fenfluramine.
Conclusions:
Preliminary findings in a zebrafish model support relutrigine’s anticonvulsant action in Dravet syndrome and the potential for superior efficacy over current standard-of-care. In combination with recent results from the EMBOLD study in SCN2A and SCN8A, these findings emphasize its promising potential to address significant unmet needs across broad DEEs.
Funding:
Praxis Precision Medicines.