Improved everyday executive functioning following profound reduction in seizure frequency with fenfluramine: Analysis from a phase 3 long-term extension study in children/young adults with Dravet syndrome

Abstract

Objective: Individuals with Dravet syndrome (DS) experience frequent pharmacoresistant seizures beginning in infancy. Most exhibit poor neurodevelopmental outcomes including motor function difficulties, behavior problems, and cognitive impairment. Cognitive deficits in children with DS have been associated with seizure frequency and antiseizure medication (ASM) use.Recent research in children and young adults with DS has begun to examine the role of executive functions (EFs), as these include higher-order cognitive functions and may mediate the relationship between risk factors and cognitive impairment. Current conceptualizations, however, of EFs involve the broader self-regulation of cognitive, behavioral, and emotional domains. We explored relationships between reduction in convulsive seizure frequency and everyday EFs in a subset of children and young adults with DS treated with adjunctive fenfluramine for 1 year. Methods: This is a post-hoc analysis of data from children and young adults with Dravet syndrome aged 5-18 years who participated in a phase 3 randomized, placebo-controlled clinical trial (core study) followed by completion of at least 1 year of fenfluramine treatment in an open-label extension (OLE) study. Eligible children and young adults started the OLE study at 0.2 mg/kg/day fenfluramine and were titrated to optimal seizure control and tolerability (maximum daily dose: 26 mg/day). Parents/caregivers documented convulsive seizure frequency per 28 days (i.e., monthly convulsive seizure frequency [MCSF]) by electronic diary. A parent/caregiver for each child also completed the Behavior Rating Inventory of Executive Function (BRIEF Ò ) parent form, a questionnaire capturing parents'/caregivers' perceptions of everyday EF that was included as a safety measure to assess treatment-related adverse effects on EF during the trial. Ratings on BRIEF Ò were mapped to the current edition, the BRIEF Ò 2 parent form, and were used to calculate T-scores for the Behavior Regulation Index (BRI), Emotion Regulation Index (ERI), Cognitive Regulation Index (CRI), and Global Executive Composite (GEC). Change in BRIEF Ò 2 T-scores from baseline in the core study to Year 1 of the OLE study was calculated. Spearman's rho correlation coefficients assessed associations between change in BRIEF Ò 2 indexes/composite T-scores and percentage change in MCSF. Children and young adults were divided into 2 groups based on percentage of MCSF reduction achieved from pre-randomization baseline in the core study to Year 1 of the OLE study: <50% and !50% MCSF reduction. Changes in the distribution of BRIEF Ò 2 indexes/composite T-scores were compared between MCSF reduction groups using Mann-Whitney U tests. The proportions of children and young adults in these groups who showed clinically meaningful improvement in everyday EF, defined as

An Emerging Role for Sigma-1 Receptors in the Treatment of Developmental and Epileptic Encephalopathies

“…Sigma1Rs have long been associated with seizure-related conditions-from amphetamine-induced seizures to epileptic encephalopathies [49][50][51]-but one of the newer, intriguing possibilities of Sigma1R functionality may involve mediation of non-seizure comorbidities associated with DEE pathophysiology. The observation that administration of fenfluramine remediated cognitive deficits in mouse models via Sigma1R activity paralleled clinical findings showing that fenfluramine treatment resulted in clinically meaningful improvements in executive function over time in children and young adults with Dravet syndrome or Lennox-Gastaut syndrome [12,14]. Taken together, these findings have led to further investigation into potential Sigma1R activity in other aspects of DEE neuropathophysiology.…”

“…In a small population of patients with Dravet syndrome treated with fenfluramine, the Emotional Regulation Index of the BRIEF ® 2 instrument used to assess cognitive function showed improvement after 1 year. This effect was most pronounced in patients experiencing clinically meaningful (≥50%) or profound (≥75%) reductions in monthly convulsive seizure frequency (Supplemental Table S1) [12]. The mechanism for these observed improvements in affective behavior is unclear, but modulation of Sigma1R pharmacology by fenfluramine may contribute.…”

“…An unexpected finding was that treatment appeared to improve aspects of everyday executive function in patients with both Dravet syndrome and Lennox-Gastaut syndrome as measured by scores on the Behavior Rating Index of Executive Function (BRIEF ® ) and BRIEF ® 2 (2nd edition) [8,14]. Improvements were noted at Year 1 of fenfluramine treatment in patients with Dravet syndrome [12]. These findings are concordant with earlier evidence of modest improvements in intellectual functioning after fenfluramine among children with mental retardation or autism [119,120].…”

“…Patients with DEEs also present with developmental delay; profound cognitive impairment; impairments in motor function, speech, and language; and growth abnormalities [1][2][3]. The drug fenfluramine, originally described only in terms of serotonin (5-hydroxytryptamine, 5-HT) pharmacology [4][5][6], recently has demonstrated efficacy in treating DEEs in multiple phase 3 trials [7][8][9][10] (Supplemental Table S1 [7][8][9][10][11][12][13][14][15][16][17]). The profound effects of fenfluramine on seizures as demonstrated in clinical trials cannot be explained by serotonergic activity alone, as other serotonergic drugs have only marginal or inconsistent effects on seizure frequency [18][19][20][21].…”

Efficacy and safety of fenfluramine in the treatment of Dravet syndrome - literature review

“…Seventy-eight percent (78%) of children and young adults treated with adjunctive fenfluramine for 1 year in the OLE study achieved ≥50% reduction in MCSF, for a magnitude of efficacy associated with a significantly greater likelihood of experiencing clinically meaningful improvement in emotion regulation and cognitive regulation [16].…”