Authors :
Presenting Author: Silvana Frizzo, MD – Praxis Precision Medicines, Boston, MA, USA
Brian Spar, BS – Praxis Precision Medicines, Boston, MA, USA
Kelley Dalby, MEd, BA – Praxis Precision Medicines, Boston, MA, USA
Poppy Guest, BS – Praxis Precision Medicines, Boston, MA, USA
Dharit Patel, MBBS, MPH – Praxis Precision Medicines, Boston, MA, USA
Henry Jacotin, MD – Praxis Precision Medicines, Boston, MA, USA
Steven Petrou, PhD – Praxis Precision Medicines, Boston, MA, USA
Marcio Souza, PharmD, MBA – Praxis Precision Medicines, Boston, MA, USA
Linda Laux, MD – Ann and Robert H Lurie Children’s Hospital of Chicago, Chicago, IL, USA
Antonio Gil-Nagel, MD, PhD – Ruber International Hospital, Madrid, Spain
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. Certain pathogenic variants in voltage-gated sodium channel (NaV) genes can increase NaV activity leading to the neuronal hyperexcitability observed in severe DEEs.
Tailored for pediatric needs, relutrigine is a next-generation, functionally selective, precision NaV modulator with demonstrated superior selectivity for disease-state NaV hyperexcitability. Preclinical and emerging clinical data suggest a wide therapeutic window and potential for superior safety and efficacy over current standard-of-care for 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 and a minimum of 0.25 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 was generally well tolerated. AEs were mostly mild to moderate, with no study drug-related SAEs. No dose reduction was required and >50% of participants increased dosing to 1 mg/kg/day. Relutrigine demonstrated 46% placebo-adjusted reduction in motor seizures during the double-blind portion of the study, with significant reductions observed over single 28-day (27%, n=8 vs 1.6% placebo, n=7) and OLE (75%, n=8) periods. At the time of submission, 33% of patients were seizure-free (longest follow-up >200 days), with ~30-70% improvements reported by clinicians and caregivers across multiple domains on CGI-I and CgGI-I, respectively.
Conclusions:
Relutrigine is poised to be a first-line, best-in-class treatment for all DEEs, demonstrating well-tolerated, robust, short- and long-term improvement in motor seizures alongside marked seizure freedom. A registration-enabling EMBOLD cohort extension has been initiated, with Praxis seeking regulatory advice on advancing relutrigine development in other DEEs.
Funding: Praxis Precision Medicines.