Authors :
Matias Wagner, MD – Ludwig Maximilians University Hospital, Munich, Germany
Ingo Borggraefe, MD – Ludwig Maximilians University Hospital, Munich, Germany
James Wheless, BScPharm, MD, FAAP, FACP, FAAN, FAES – LeBonheur Children’s Hospital
Christopher Troedson, MBBS – The Children’s Hospital at Westmead, Sydney, Australia
Katherine Howell, MBBS, PhD – Department of Neurology, Royal Children's Hospital, Melbourne, Australia
Silvana Frizzo, MD – Praxis Precision Medicines, Boston, MA, USA
Robert Horton, MBS – Praxis Precision Medicines, Boston, MA, USA
Henry Jacotin, MD – Praxis Precision Medicines, Boston, MA, USA
Dharit Patel, MBBS, MPH – Praxis Precision Medicines, Boston, MA, USA
William Motel, PhD – Praxis Precision Medicines, Boston, MA, USA
Brian Spar, BS – Praxis Precision Medicines, Boston, MA, USA
Presenting Author: Steven Petrou, PhD – Praxis Precision Medicines, Boston, MA, USA
Marcio Souza, PharmD, MBA – Praxis Precision Medicines, Boston, MA, USA
Rationale:
Early onset SCN2A developmental and epileptic encephalopathy (SCN2A-DEE) is a rare, severe disorder caused by gain-of-function (GoF) mutations in the SCN2A gene encoding the voltage-gated sodium channel NaV1.2. Patients are at high risk of premature death and present with frequent epileptic seizures, typically beginning within days of birth, and often difficult to control with standard-of-care anti-seizure medications.
Preclinical findings suggest that gapmer ASOs that down regulate SCN2A expression may alter the disease course in patients. Elsunersen is an intrathecally administered ASO in development for early onset GoF SCN2A-DEE, with emerging clinical data highlighting its potential to be disease modifying. We provide clinical updates from 4 patients currently receiving elsunersen under an Emergency Use Program.
Methods:
Elsunersen has been administered in Germany since March 2023 for treatment of a preterm infant (29+4 weeks gestation) diagnosed prenatally with a pathogenic SCN2A variant. The patient was in constant, life-threatening status epilepticus (SE), with only partial effect of high-dose sodium channel blockers. Elsunersen treatment commenced at age 6 weeks, with 15 doses administered to date (94.5 mg total).
An 8-year-old patient with GoF SCN2A-DEE has been receiving elsunersen in Australia since December 2023, following a history of refractory seizures, global cerebral atrophy, global developmental delay, frequent oculogyric movement, and severe dystonia while awake. To date, 10 doses have been administered (22 mg total).
Two SCN2A-DEE patients from the completed EMBRAVE study were granted emergency access to continue receiving elsunersen in the US; receiving four and five 1-mg doses since April and March 2024, respectively.
Results:
There have been no reported drug-related severe or serious AEs following ongoing administration of any dose in the 4 patients, with both procedure and dosing well tolerated.
In the German patient, early dosing led to SE cessation and revealed a temporal association with seizure reduction. Seizure frequency remains stable with ongoing dosing; maintained after tapering phenytoin at age 14 months, with no worsening of neurodevelopment at age 18 months.
In the Australian patient, 2 weeks after the second dose, a 0.5 ml weekly reduction of ethosuximide was achieved, with facial myoclonus subsiding during waking hours. Significantly fewer clinical and electrographic seizures were noted, with several notable quality-of-life improvements communicated by caregivers and medical personnel.
Conclusions:
Together with EMBRAVE Part 1 findings, clinical experience in ongoing emergency use programs in the US, Germany, and Australia demonstrate a well-tolerated, consistent and meaningful therapeutic response to elsunersen. Ongoing follow up will determine long-term effect on seizures and associated comorbidities.
Funding:
Elsunersen made available under emergency use provisions from Praxis Precision Medicines.