Improvement was statistically significant for Cognition and the Global Executive Composite score, where approximately twice as many patients achieved clinically meaningful improvement.
Research from a phase 3 Study 1601 (NCT03355209) presented at the 2021 American Academy of Neurology (AAN) Annual Meeting, April 17-22, showed that treatment with fenfluramine (Fintepla; Zogenix) oral solution had a positive impact on everyday executive function for children and young adults with Lennox-Gastaut syndrome (LGS).1
Kim Bishop, PhD, principal drug development and psychologist, Global Pharma Consultancy, and lead investigator of the study, assessed the impact of fenfluramine using the Behavior Rating Inventory of Executive Function (BRIEF) scale throughout a 14-week study period. After completion of both baseline and end of-study BRIEF assessments, researchers mapped the BRIEF ratings to the current BRIEF 2 parent form, a shorter, 63-item version that incorporated a 1400 sample normative population and statistics to support interpretation.
Patients with LGS between 6 to 18 years old showed improvements in each of the 4 BRIEF 2 indexes following treatment with fenfluramine (n = 92) compared to placebo (n = 45). More specifically, for the fenfluramine group, there was a 24% improvement in Behavior (placebo, 13%; P = .118), 19% improvement in Emotions (placebo, 16%; P = .665), 27% improvement in Cognition (placebo, 13%; P = .665), and 25% improvement in Global Executive Composite (GEC) overarching summary score (placebo, 11%; P = .034).
"Fintepla-treated children and young adults with LGS showed improved overall self-regulation, with specific improvements in regulation of attention and cognition after 14 weeks in a phase 3 double-blind randomized controlled trial,” Bishop said in a statement. “Better self-regulation can have a positive impact on children’s everyday functioning and reduce caregiver burden.”
The study authors concluded that the improvements may be a result of improved seizure control and/or fenfluramine’s mechanism of action at 5-HT and sigma-1 receptors, both of which have been implicated as having positive effects on memory, learning, and executive function. When asked about the robust effect of fenfluramine over the 14-week study period, Bishop told NeurologyLive “we were pleasantly surprised. We did not see any treatment effects during the randomized controlled trials when the program began. We thought it would take longer-term treatment to see any effects in these domains.”
In the presentation, it was noted that future work will include evaluations of the impact of fenfluramine on everyday executive function on long-term (≥1 year) outcomes, in adults older than 18 years and children 5 years and younger, as well as associations between seizure frequency and/or type.
More results from this study were presented at the American Epilepsy Society Annual Meeting in December 2020, which showed that the trial met its primary end point.2 Treatment with fenfluramine 07 mg/kg/day achieved –19.9% estimated median difference from placebo (ESM; Hodges-Lehmann estimate) in monthly drop in seizure frequency (MDSF) from baseline (P = .001). The data was comparable to the magnitude previously demonstrated in other completed LGS randomized controlled trials (range, –14.8% to –21.6%).
The ESM in MDSF from baseline for those in the fenfluramine 0.2 mg/kg/day group did not reach statistical significance (–10.5%; P = .09). However, more investigators and caregivers rated patients “much improved” or “very much improved” on clinical global impression of improvement (CGI-I) for both doses compared with placebo.
There has been much speculation on whether fenfluramine becomes the next FDA-approved treatment for patients with LGS. These rumbling stem from the increasing amount of data in addition to the drug becoming approved for patients with Dravet syndrome in June 2020.3
Arnold Gammaitoni, PharmD, vice president, Medical and Scientific Affairs, Zogenix, told NeurologyLive, “Our plan is to submit an sNDA to the FDA in the third quarter of this year for LGS. That’s the rough timeline. Right now, we’re in the process of data collection and preparation of the regulatory filings.”
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