Praxis Precision Medicines is set to present new preclinical and clinical data from its epilepsy programs at the American Epilepsy Society (AES) Annual Meeting in Los Angeles, December 6-10, 2024, highlighting advancements in therapies for central nervous system (CNS) disorders characterized by neuronal excitation-inhibition imbalance.
Relutrigine: Targeting DEEs with Precision
Relutrigine, a first-in-class small molecule, is being developed for the treatment of developmental and epileptic encephalopathies (DEEs). It functions as a preferential inhibitor of persistent sodium current, a key driver of seizure symptoms in severe DEEs. In vivo studies have demonstrated dose-dependent inhibition of seizures, even achieving complete control in SCN2A, SCN8A, and other DEE mouse models. Phase 1 studies have shown that relutrigine is generally well-tolerated and demonstrates biomarker changes indicative of NaV channel modulation. Data from the Phase 2 EMBOLD study demonstrated well-tolerated, robust, short- and long-term improvement in motor seizures alongside maintained seizure freedom in some patients with SCN2A- and SCN8A-DEE, in a heavily pre-treated population. Relutrigine has been granted Orphan Drug Designation (ODD) and Rare Pediatric Disease Designation by the FDA, and ODD by the European Medicines Agency for SCN2A-DEE and SCN8A-DEE.
Vormatrigine: A Next-Generation Solution for Focal Onset Seizures
Vormatrigine is a next-generation, functionally selective small molecule designed to target the hyperexcitable state of NaV channels in the brain. It is being developed as a once-daily, oral treatment for adult focal onset seizures and generalized epilepsy. Preclinical data suggests that vormatrigine is differentiated from the standard of care, potentially making it best-in-class for focal onset seizures. In vitro, vormatrigine has demonstrated superior selectivity for disease-state NaV channel hyperexcitability. In vivo studies have shown unprecedented potency in the maximal electroshock seizure (MES) model, a highly predictive translational model for efficacy in focal epilepsy. Data from the PRAX-628-101 study demonstrated that vormatrigine can be safely dosed in healthy subjects to greater than 15 times the predicted human equivalent of the rodent MES EC50, a translational indicator that suggests a therapeutic window with unprecedented magnitude relative to approved therapies.
Elsunersen: Addressing Early-Onset SCN2A-DEE
Elsunersen is a novel antisense oligonucleotide (ASO) designed to selectively decrease SCN2A gene expression, directly targeting the underlying cause of early-onset SCN2A-DEE to treat seizures and other symptoms in patients with gain-of-function SCN2A mutations. In vitro studies have demonstrated a reduction in both SCN2A gene expression and protein levels. In vivo, elsunersen has shown significant, dose-dependent reduction in seizures, improvement in behavioral and locomotor activity, and increased survival in SCN2A mouse models. Data from the EMBRAVE study demonstrated well-tolerated, significant, and sustained seizure reduction in patients with SCN2A-DEE. Elsunersen has received Orphan Drug Designation (ODD) and Rare Pediatric Disease Designation (RPD) from the US FDA, and ODD and PRIME designations from the European Medicines Agency (EMA) for the treatment of SCN2A-DEE. The Elsunersen program is ongoing under a collaboration with Ionis Pharmaceuticals and RogCon, Inc.
According to Steven Petrou, chief scientific officer and co-founder of Praxis, the company is on the brink of transformative change with a leading pipeline that includes relutrigine and vormatrigine, the most potent and most functionally selective anti-seizure medications developed to date.
