New Prospective Data on Patients With Dravet Syndrome Inform Outcome Measurements in Trials

Joseph Sullivan, MD

Data from the BUTTERFLY study suggest that over the course of 12 months, patients with Dravet syndrome (DS) who were being treated with antiseizure medications (ASMs) experienced small improvements in receptive communication, with most deemed either unchanged or slightly improved on measurements of cognition. The study investigators noted that these data—including the lack of significant changes—will help inform outcome measurements for future trials in DS.¹

The data were presented as a poster by Joseph Sullivan, MD, a professor of neurology at UCSF Weill Institute for Neurosciences, at the 2022 American Epilepsy Society Annual Meeting, held December 2 to 6, in Nashville, Tennessee. Sullivan and colleagues wrote that the small improvements in communication “appear to be driven by younger patients.” On the Vineland Adaptive Behavior Scales-III (VABS-III), the least squares (LS) mean change from baseline to 12 months was 5.49 (95% CI, 0.56-10.41; P = .030) for receptive communication. The LS mean change for expressive communication was 2.37 (95% CI, –0.10 to 4.85; P = .060), and for interpersonal relationships was 2.99 (95% CI, –1.22 to 7.20; P = .16), with gross and fine motor scores changing by 1.90 points (95% CI, –3.24 to 7.05 P = .45) and 3.59 points (95% CI, –1.93 to 9.11; P = .19), respectively.

On the cohort's Bayley Scales of Infant Development-III (BSID-III) scores, the LS mean change in cognitive scores was –1.08 (95% CI, –3.53 to 1.37; P = .37). The LS mean change on BSID-III receptive communication and expressive communication scores were 3.68 (95% CI, 0.48-6.89; P = .027) and 3.23 (95% CI, –1.66 to 8.11; P = .18), respectively.

Sullivan and colleagues noted that, “Most patients performed in the dynamic range of Gillette [Functional Assessment Questionnaire] at baseline with little change observed in mean total scores over 12 months.” On the Behavior Rating Inventory of Executive Function-Preschool version (BRIEF-P) global executive composite scale, many patients performed on the higher end, which Sullivan et al wrote “suggest[ed] difficulties with executive function; little change was observed in. BRIEF-P scores across all scales over 12 months.” Global executive composite scores ranged from 63 to 189. Gillette FAQ total scores ranged from 0 to 66.

BUTTERFLY, conducted by Stoke Therapeutics, is an observational study aimed at collecting information about the mental development, behavior, movement, communication skills, seizure frequency, and sleep patterns of young people with DS.^1,2 The primary objective is to assess neurodevelopmental change from baseline to 24 months, with secondary outcomes of the number of countable convulsive seizures per 4 weeks prior to visits and the change from baseline in clinical status, quality of life, and executive function.

Those included in the trial were between the ages of 2 and 18 years (divided into 3 age groups of 12 patients each: 2-7 years, 8-12 years, and 13-18 years) and 61% (n = 22) of them were girls. The mean age of seizure onset was 5.1 months (range, 2-12), with all patients experiencing 1 or more convulsive seizure types and 86% (n = 31) experiencing generalized tonic-clonic seizures.

All told, patients were on a mean of 3.5 ASMs (SD, 1.56), with clobazam (Onfi; Lundbeck) being the most common (64%; n = 23). Across the 4-week baseline period, the median 28-day convulsive seizure frequency was 10.0 (95% CI, 5.0-16.0) among 26 individuals, including 24 who experienced generalized tonic-clonic seizures at a frequency of 7.2 (95% CI, 4.0-12.0).

“DS is a severe and progressive genetic epilepsy,” Sullivan and colleagues wrote, also noting that there are limited prospective long-term data for the disease. “Available therapies do not adequately control seizures in 90% of [patients with DS], and they do not address other comorbidities of the disease, including intellectual disability, ataxia/motor abnormalities, behavioral problems, speech impairment, sleep disturbances, and a high risk for sudden unexpected death.”

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REFERENCES
1. Sullivan J, Wirrell E, Knupp KG, et al. Twelve-month analysis of BUTTERFLY: An observational study to investigate cognition and other non-seizure comorbidities in children and adolescents with Dravet syndrome (DS). Presented at: AES Annual Meeting; December 2-6, 2022; Nashville, TN, and virtual.
2. The BUTTERFLY Study. Stoke Therapeutics website. Updated March 15, 2019. Accessed December 3, 2022. https://www.stoketherapeutics.com/wp-content/uploads/2021/09/Stoke-BUTTERFLY-A4-Info-for-Website-PDF_V01-USA_02Apr2019.pdf