Authors :
Erik Andersen, MBChB – Department of Pediatrics and Child Health, University of Otago, Wellington, NZ
Katherine Howell, MBBS, PhD – Department of Neurology, Royal Children's Hospital, Melbourne, Australia
Silvana Frizzo, MD – Praxis Precision Medicines, Boston, MA, USA
Presenting Author: Brian Spar, 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
Geza Berecki, PhD – The Florey Institute of Neuroscience and Mental Health, Melbourne, Australia
Steven Petrou, PhD – Praxis Precision Medicines, Boston, MA, USA
Marcio Souza, PharmD, MBA – Praxis Precision Medicines, Boston, MA, USA
Rationale:
Developmental and epileptic encephalopathies (DEEs) are devastating neurological disorders presenting in infancy and early childhood, characterized by severe, frequent seizures and increased mortality, as well as developmental delay, intellectual disability, and other comorbidities. 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 (PRAX-562) is a next-generation sodium channel functional state modulator with demonstrated superior selectivity for disease-state sodium channel hyperexcitability currently in development for DEEs. Preclinical and clinical data have demonstrated potential for relutrigine to be a first- and best-in-class treatment for DEEs. Here we describe its first emergency use case in an infant with SCN2A-DEE and refractory status epilepticus (SE).
Methods:
An 11-month-old patient with SCN2A-DEE began receiving relutrigine in February 2024 at age 4 months, on a named patient, emergency-use basis following a medical history of refractory seizures with multiple episodes of SE requiring ICU hospital admissions and IV medications to resolve the clinical status.
In the 7 days preceding relutrigine treatment initiation, the patient had been in SE on three separate occasions and was receiving clobazam (2 mg/kg/day), lacosamide (12.4 mg/kg/day) and phenytoin (3.7 mg/kg/d) without any impact on seizure frequency and severity. Other ASMs trialed in the first months of life without response included: levetiracetam 80 mg/kg/day, carbamazepine 25 mg/kg/day, vigabatrin up to 100 mg/kg/day, topiramate 10 mg/kg/day, and sodium valproate 40 mg/kg/day.
Results:
Following weaning off phenytoin, treatment with relutrigine commenced at a starting dose of 0.5 mg/kg/day, with increasing increments of 0.5 mg/kg every two to four weeks, up to a dose of 3 mg/kg/day as of August 2024. Thus far, the patient has been receiving relutrigine once a day over a period of 6 months.
Since relutrigine treatment initiation, there has been a marked reduction in episodes of SE and hospital admissions. The patient has also demonstrated a reduction in seizure frequency and severity, as well as a decrease in emergency medications administered. In addition, the patient has been more alert and awake, responding to, and looking towards, familiar voices.
Over the course of treatment thus far, relutrigine has been well-tolerated and there have been no clinically significant findings on fortnightly blood draws, urine or ECG analysis, and no drug-related or severe adverse events.
Conclusions:
Relutrigine is poised to be a first- and best-in-class treatment for DEEs, with early clinical experience indicating safety and marked seizure reduction, including cessation of previous SE. Ongoing follow up will determine long-term effects on seizure frequency and intensity, and associated comorbidities.
Funding:
Relutrigine was made available under an emergency use provision from Praxis Precision Medicines.