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(Abst. 2.438), 2019

Profound Reduction in Seizure Frequency (≥75%) Leads to Improved Everyday Executive Function: Analysis From a Phase 3 Study of ZX008 (Fenfluramine HCl) in Children/Young Adults With Dravet Syndrome
Authors: #N/A, PharmaWrite; Kim I. Bishop, Global Pharma Consultancy, LLC; Peter K. Isquith, Boston's Children Hospital; Gerard Gioia, Children's National Health System; Glenn Morrison, Zogenix, Inc.; Arnold R. Gammaitoni, Zogenix, Inc.; Douglas Haney, Zogenix, Inc.; Rima Nabbout, Hôpital Universitaire Necker; Elaine C. Wirrell, Mayo Clinic; Tilman Polster, Mara Hospital; Joseph E. Sullivan, Benioff Children’s Hospital
Content: Rationale:

Patients with Dravet syndrome (DS) often experience cognitive impairment, including executive function deficits. Although convulsive seizure frequency (CSF) and severity are believed to exacerbate cognitive impairment over time, few long-term studies are available to confirm this conclusion. In a recent phase 3 study, adjunctive fenfluramine (FFA) significantly reduced CSF and improved executive function, an important aspect of behavioral, emotional and cognitive functioning, after 14 weeks in patients with DS. The objective of this analysis was to evaluate: (1) overall relationship between changes in CSF and executive function and (2) impact of reducing CSF by comparing subsets of patients who experienced profound (>=75%) vs minimal (<25%) reductions after 1 year of add-on FFA in an open-label extension (OLE) study.


Patients (ages 2-18 years, inclusive) with DS entered the OLE of a double-blind, parallel-group, placebo-controlled phase 3 clinical study (Study 1, NCT02682927, NCT02826863; Study 1503 OLE, NCT02823145) and completed an additional year of FFA. Upon OLE entry, all patients were administered FFA titrated to effect (dose range: 0.2-0.7 mg/kg/day FFA, administered as 2.5 mg/mL FFA HCl; max, 17 mg/26 mg with/without stiripentol). Percent difference in CSF per 28 days was calculated from baseline in the double-blind study through the end of OLE Year 1. Executive function was evaluated with the Behavior Rating Inventory of Executive Function (BRIEF) completed by caregivers at baseline and Year 1 for patients age 5-18 years. Scores on the BRIEF were updated to the more current version, BRIEF2. Association between BRIEF2 Behavior Regulation Index (BRI), Emotion Regulation Index (ERI), Cognitive Regulation Index (CRI), and Global Executive Composite (GEC) scores, was assessed statistically by calculating Spearman's Rho correlation coefficients. Lower scores on the BRIEF2 indexes/composite indicate better executive functioning. Clinically meaningful change in BRIEF2 indexes/composite scores from baseline to Year 1, defined as improvement in Reliable Change Index (RCI) >95%, was compared statistically for the <25% vs >=75% CSF reduction groups using Fisher's exact test (2-sided, P<0.05).


At analysis, 53 patients in the OLE had completed >=1 year of FFA and had both baseline and Year 1 BRIEF2 data (median age: 10 years; 57% male). Median % change from pre-randomization baseline in CSF was -71.0% (range, -99.7%-55.0%) in this group of patients. Responder analysis showed that 24/53 (45%) patients achieved a >=75% reduction in CSF and 11/53 (21%) had <25% reduction. Change in CSF correlated significantly with ERI (P=0.032) and GEC (P=0.034), with a trend for CRI (P=0.066). Change in CSF was not significantly associated with BRI (P=0.137). A significantly higher percentage of patients in the profound (>=75%) responder group experienced significant, clinically meaningful improvements (>=10-point change, RCI >95%) on ERI and GEC (P<0.05) (Figure).


This analysis found a significant association between decrease in CSF and improvement in executive function. Additionally, profound (>=75%) reduction in CSF resulted in significantly more patients experiencing clinically meaningful improvements in executive function, suggesting that higher levels of CSF reduction for prolonged periods of time (>=1 year) may improve some of the everyday executive function deficits experienced by patients with DS.

 Funding: Zogenix
Figure 1