Rethinking the Disease Model: Etiology Over Symptom

For years, the medically urgent dimension of Dravet syndrome was the seizures -- the hospitalizations, the status epilepticus, the constant threat of SUDEP. Newer, Dravet-targeted antiseizure medications have improved seizure control, but even patients who achieve meaningful or complete seizure reduction continue to experience the developmental delays, behavioral challenges, motor decline, and sleep disturbances that define the disease. This reality has forced a reckoning with how the field conceptualizes what it is actually treating.

Dr. Schreiber opens by addressing the intractability of the disease even with the best available therapies. Despite multiple antiseizure medications, the vast majority of patients continue to have medically refractory seizures, and even among those who achieve seizure freedom, the full developmental burden of Dravet persists. He notes that natural history studies show a plateau effect -- children gain skills very slowly and fall progressively further behind their neurotypical peers over time -- while motor problems emerge as an additional dimension of decline as patients age.

Dr. Wirrell highlights two natural history studies that helped reframe the disease model. The BUTTERFLY study, which followed children ages 2 to 18 without intervention beyond standard medications, showed minimal gains on the Vineland Adaptive Behavior Scales, confirming the trajectory of developmental stagnation in the absence of a disease-modifying approach. The ENDEAVOR study added a critical piece: language impairment was detectable as early as 18 months and was independent of seizure control, directly implicating the underlying SCN1A channelopathy rather than seizure burden as the driver of developmental deficits.

Dr. Wheless frames the conceptual leap this represents for the field. Understanding the genetic underpinning of Dravet is one thing; recognizing that therapeutic strategies can now be aimed upstream at that genetic abnormality, rather than at the downstream symptoms, is a different kind of advance. He argues that if the underlying cause can be addressed -- and addressed early -- the opportunity exists to meaningfully improve not just seizure control but the full developmental and neurological trajectory of these children. This thinking, he notes, will extend beyond Dravet to other monogenic epilepsies as well.

In the next episode, the panelists explain how zorevunersen works at the molecular level and why its mechanism represents a fundamentally different approach than any antiseizure medication currently available for Dravet syndrome.