Poster Number: 3.303

Rationale:

Early onset SCN2A DEE is a rare, fatal disorder characterized by developmental delay or regression, frequent, epileptic seizures, typically beginning within days of birth, that are difficult to control with standard-of-care ASMs. Clinical studies with a gapmer SCN2A ASO addressing the primary genetic driver show significant seizure reduction, amongst other benefits. However, persistent network hyperexcitability in a developmentally altered brain may remain. Adjunctive precision sodium channel modulation could further stabilize excitability and enhance clinical outcomes.

Elsunersen is an intrathecally-administered ASO in development for early onset SCN2A DEE, with recent clinical experience demonstrating well-tolerated, significant and sustained seizure reduction. Relutrigine is a sodium channel functional state modulator, demonstrating robust and sustained seizure reduction in patients with a diverse set of DEE patients. Here, we describe the first complementary emergency use case of elsunersen and relutrigine in an infant with severe early onset SCN2A DEE and refractory status epilepticus (SE).

Methods:

A preterm infant (29+4 weeks gestation; birthweight 1400g) diagnosed prenatally with a pathogenic SCN2A variant presented with life-threatening SE and only partial effect of high-dose sodium channel blockers (SCBs). Following confirmation of gain-of-function status, treatment with elsunersen commenced at 7 weeks, with 25 monthly doses administered to date (174.5mg total). Two years later, treatment with relutrigine commenced (0.5mg/kg daily dose).

Results: Elsunersen treatment in combination with best standard-of-care ASMs (mainly SCBs) was well-tolerated with no drug-related severe or serious adverse events. Early dosing led to SE cessation and revealed a temporal association with seizure reduction. Seizure frequency remained stable with ongoing dosing; maintained after tapering phenytoin at 14 months, with no neurodevelopmental worsening. Two years after ASO commencement, and aiming for further seizure reduction, the treatment strategy was adjusted to include relutrigine. Three weeks after relutrigine commencement, parents and nursing staff reported moderate-to-significant improvement including fewer, less severe seizures, with no new safety findings. Continued improvement in clinical status following 2 months of relutrigine treatment permitted a previously unattainable reduction in carbamazepine dosage.

Conclusions:

Preliminary first-in-human findings highlight the potential for complementary use of elsunersen and relutrigine for early onset SCN2A DEE, which we hypothesize is due to targeting both the root genetic cause and downstream network hyperexcitability characteristic of this disease.

Funding:

Elsunersen and relutrigine made available under emergency use provisions from Praxis Precision Medicines.