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(Abst. 2.454), 2018

Improved Everyday Executive Function With Fenfluramine HCl Oral Solution (Fintepla®): Results From a Phase 3 Study in Children and Young Adults With Dravet Syndrome
Authors: Kim I. Bishop, Global Pharma Consultancy, LLC; Gerard A. Gioia, Children’s National Health System; Peter K. Isquith, Boston Children's Hospital, Harvard Medical School; Arnold Gammaitoni, Zogenix, Inc.; Gail Farfel, Zogenix, Inc.; Bradley Galer, Zogenix, Inc.; Arun Mistry, Zogenix, Inc.; Michael Lock, Zogenix, Inc.; and Glenn Morrison, Zogenix, Inc.
Content: Rationale: Fenfluramine HCl has demonstrated superior efficacy compared with placebo for the reduction in frequency of convulsive seizures in children and young adults (2-18 years old) with Dravet syndrome (DS) in two recently completed Phase 3 double-blind, placebo-controlled clinical trials. Patients with epileptic encephalopathies, such as DS, also have impairment in cognition and neurodevelopment, which is believed to be in part due to the frequency of poorly treated seizures. Here we provide an analysis of the impact of fenfluramine on caregiver-reported everyday executive functioning of their children with DS in a Phase 3 placebo-controlled trial. Methods: Patients 2-18 years old with DS were randomly assigned to placebo, fenfluramine 0.2 mg/kg/day, or fenfluramine 0.8 mg/kg/day following a 6-week baseline period to establish convulsive seizure frequency. The Behavior Rating Inventory of Executive Function (BRIEF®2) was administered to caregivers of all patients ≥5 years old during baseline and after 14 weeks of treatment. Reliable change index scores (RCIs) were calculated to evaluate whether any change from baseline to end of study in individual scores was clinically meaningful (>90% certainty of improvement and 80% certainty of worsening). Raw scores were converted to T scores for this analysis. Results: A total of 77 patients (n=28, fenfluramine 0.8 mg/kg/day; n=24, fenfluramine 0.2 mg/kg/day; and n=25, placebo) were assessed with BRIEF2. Forty-seven percent were female, and 71% were from English-speaking countries. Both fenfluramine groups showed clinically meaningful improvement on the Behavior Regulation and Emotion Regulation Indexes compared with those in the placebo group (P<0.02). A significantly greater proportion of patients receiving fenfluramine treatment showed benefit on the Plan/Organize scale of the Cognitive Regulation Index compared with the placebo group (P<0.04). There were no significant differences in adverse changes (worsening) among the treatment groups. Conclusions: Patients in the fenfluramine 0.2 mg/kg and 0.8 mg/kg groups showed significant and clinically meaningful improvements in behavior regulation, emotion regulation, and planning and organization. Theoretical and empirical models support that improved emotional control and behavioral regulation serve as “building blocks” to then enable higher level cognitive regulation functions. Children and young adults must be able to inhibit impulses, modulate emotions, and adapt flexibly to changes before they can demonstrate or develop cognitive regulatory functions, including working memory, planning, and organization. The impact of behavior and emotion regulation might be expected to enable improvements in the higher level cognitive regulation with longer-term treatment and will be examined in the long-term extension study of fenfluramine. Funding: Zogenix, Inc.PI, GG, KB all contributed equally to this work.