Abstracts

Rationale: Dravet syndrome (DS) is a severe and progressive genetic developmental and epileptic encephalopathy that typically begins in the first year of life. It is characterized by frequent, prolonged, and refractory seizures, intellectual disability, ataxia/motor abnormalities, behavioral problems, speech impairment, sleep disturbances, and a high risk of sudden unexpected death. There remains a need for therapy to reduce seizure frequency (SF) and improve non-seizure comorbidities. There is a lack of prospective long-term data regarding the progression of substantial non-seizure comorbidities in patients with DS. This fully enrolled study evaluates neurodevelopmental and adaptive functioning, SF, gait performance, quality of life, and sleep in patients with DS.

Methods: This 24-month (mo), multicenter, longitudinal, prospective study includes patients aged 2-18 years (yrs) with genetically confirmed DS whose seizures are not controlled by their current antiepileptic drugs (AEDs). Primary endpoints assess neurodevelopment and adaptive functioning over 6 visits.

Results: 36 patients enrolled across 3 age groups (n=12/group): 2-7, 8-12, and 13-18 yrs; 61% were female, 94% were white, and 14% were Latino. Across all patients, mean age of seizure onset was 0.4 yrs (range 0.2-1.0 yrs, n=36). Over the 4-week baseline period, mean convulsive SF was 14.4 (95% CI 8.1 to 20.7, n=26) per 28 days, including 24 patients who had generalized tonic-clonic seizures with a mean SF of 9.1 (95% CI 5.5 to 12.7) per 28 days. There was a mean change of 19.4% (95% CI -12.6% to 51.4%, n=22) in total convulsive SF from baseline to mo 3. Only 2 patients (5.6%) were free of convulsive seizures during the 4-week baseline and/or 3-mo follow-up. At baseline, VABS-III adaptive behavior composite (ABC) across all groups was 45.2 (95% CI 38.2 to 52.1, n=33) versus neurotypical mean score=100, SD=15. There was an ABC mean change of -1.9 (95% CI –5.9 to 2.1, p=0.3289, n=23) from baseline to mo 3. The mean baseline ABC was highest in the 2-7 yrs group, 62.8 (95% CI 52.3 to 73.3, n=12) compared to 37.9 (95% CI 31.4 to 44.5, n=12) and 31.3 (95% CI 19.3 to 43.3, n=9) in the 8-12 and 13-18 yrs groups, respectively. At baseline, BSID-III developmental quotient (DQ) across all groups was 21 (95% CI 12 to 29, n=15). There was a DQ mean change of 1 (95% CI -3 to 9, n=6, p=0.5887) from baseline to mo 3. The mean baseline DQ was highest in the 2-7 yrs group, 29 (95% CI 7 to 51, n=6). Complete 3-mo interim analysis will be presented for all endpoints.

Conclusions: Patients enrolled in BUTTERFLY appear representative of patients with DS. Despite use of multiple AEDs, most patients experienced ongoing convulsive seizures and showed substantially decreased neurocognitive abilities compared to neurotypical children of same chronological age. Data suggest SF and neurodevelopment and adaptive functioning remain relatively stable over 3 mo. This long-term prospective study will provide valuable insights on the course of seizure and non-seizure manifestations in patients with DS.

Funding: Please list any funding that was received in support of this abstract.: Stoke Therapeutics.