Authors :
Presenting Author: Samata Kamireddy, MD – Praxis Precision Medicines
Silvana Frizzo, MD – Praxis Precision Medicines
Brian Spar, BS – Praxis Precision Medicines
Poppy Guest, BS – Praxis Precision Medicines
Kelley Del Real, MEd – Praxis Precision Medicines
Henry Jacotin, MD – Praxis Precision Medicines
Steven Petrou, PhD – Praxis Precision Medicines
Marcio Souza, PharmD, MBA – Praxis Precision Medicines
Linda Laux, M.D. – Ann & Robert H. Lurie Children's Hospital of Chicago
Antonio Gil-Nagel, MD, PhD – Hospital Ruber Internacional de Madrid
Rationale:
Developmental and epileptic encephalopathies (DEEs) are devastating neurological disorders presenting in infancy and early childhood, characterized by severe, frequent seizures and increased early mortality. Relutrigine is a differentiated functional state sodium channel modulator with demonstrated superior selectivity for disease-state sodium channel hyperexcitability, a known cause of seizure manifestation in all DEEs. Preclinical and emerging clinical data suggest a wide therapeutic window and potential for superior safety and efficacy over current standard-of-care for broad DEEs. The EMBOLD study (NCT05818553) is a Phase 2 randomized clinical trial exploring the safety, tolerability, efficacy, and pharmacokinetics of relutrigine in pediatric participants with seizures associated with early onset SCN2A-DEE and SCN8A-DEE.
Methods:
This multicenter, double-blind, placebo-controlled, randomized study, followed by open-label extension (OLE), enrolled 16 eligible male and female participants aged 2-18 years, inclusive, with a diagnosis of early onset SCN2A-DEE or SCN8A-DEE. Participants were randomized (1:1) to receive relutrigine QD for 16 weeks, or relutrigine QD for 12 weeks and matching placebo QD for 4 weeks, with timing of placebo administration blinded for both participants and investigator. Dose was administered orally or via gastrostomy/jejunostomy tube, with dose adjustment permitted from initial 0.5 mg/kg/day to a maximum of 1.0 mg/kg/day. The OLE is ongoing. Participants had the option to undergo study assessments in a hybrid fashion (in-clinic and at-home visits) or with at-home visits only (fully decentralized). Key endpoints included incidence and severity of TEAEs, and efficacy assessments based on changes from baseline in monthly (28-day) motor seizure frequency, seizure freedom and clinical (CGI) and caregiver (CgGI) global impression of improvement and severity.
Results:
Relutrigine continues to be well tolerated, with AEs mostly mild to moderate, no study drug-related SAEs and no dose reduction required. Relutrigine demonstrated a 46% placebo-adjusted reduction in motor seizures during the double-blind portion of the study, with significant reductions observed per 28-day period (27%, n=8 vs 1.6% placebo, n=7). At 16 weeks, 33% of patients were seizure-free. Meaningful gains in patient wellbeing were further observed at 16 weeks, with ~30-70% improvements across multiple clinician- and caregiver-reported domains.
OLE data through 11 months support sustained seizure reduction (90%, n=13) and sustained seizure-free periods (mean longest period without seizures, 67 days vs. 3 at baseline) with continued relutrigine exposure on top of standard-of-care.
Conclusions:
Relutrigine is poised to be a first-line, best-in-class treatment for broad DEEs, demonstrating well-tolerated, robust, short- and sustained long-term improvement in motor seizures alongside marked seizure freedom. A registration-enabling EMBOLD cohort extension is ongoing with topline results anticipated no later than 1H 2026. The EMERALD study is set to initiate globally by mid-2025 in a broader, pan-DEE patient population.
Funding:
Praxis Precision Medicines.