Dual Activity of Fenfluramine (Fintepla®) as a Serotonin Receptor Agonist and Positive Sigma-1 Receptor Modulator: Implication for Disease Modification in Developmental and Epileptic Encephalopathies
Abstract number :
3.393
Submission category :
1. Basic Mechanisms / 1D. Mechanisms of Therapeutic Interventions
Year :
2021
Submission ID :
1886506
Source :
www.aesnet.org
Presentation date :
12/6/2021 12:00:00 PM
Published date :
Nov 22, 2021, 06:56 AM
Authors :
Arnold Gammaitoni, PharmD - Zogenix, Inc.; Thadd Reeder, PhD - Zogenix, Inc.; Parthena Martin, PhD, DABT - Zogenix, Inc.; Jo Sourbron, PhD, PharmD, MSc, MD - University Hospital KU Leuven; Peter de Witte, MD - Laboratory for Molecular Biodiscovery; Bradley Galer, MD - Zogenix, Inc.
Rationale: Developmental and epileptic encephalopathies (DEEs) are characterized by high seizure burden, neurodevelopmental delay, and motor impairment. For many families, dealing with behavioral, emotional, and cognitive impairments can be as challenging as dealing with seizures. Fenfluramine (FFA), recently approved in the US and EU for treatment of Dravet syndrome (DS), targets multiple serotonin (5HT) receptors and the Sigma-1 receptor (Sigma1R). This unique dual mechanism of action (MOA) not only may account for FFA’s efficacy in reducing the frequency of convulsive seizures in patients with DS and Lennox-Gastaut syndrome (LGS), but also may have effects on sudden unexpected death in epilepsy (SUDEP) and observed improvements in executive functions in both conditions. Here, we report the results of a systematic review comparing the MOAs of all antiseizure medications (ASMs) currently approved, in development, or used off-label to treat DS or LGS.
Methods: A systematic review of PubMed was performed using the search string ("antiseizure medication" or "antiepileptic drug") and (epilept* encephalop* or Dravet or Lennox* or SMEI or scn1a) with unlimited date range. MOAs for ASMs summarized in recent expert opinion or review articles and in the UpToDate database for management of LGS or DS were investigated by cross-referencing PubMed.
Results: The search string returned 314 articles (245 relevant): 16 ASMs were used clinically to manage DS (3 approved, 13 used off-label, and 5 in development), and 31 ASMs were used to manage LGS (8 approved in the EU and/or US, 17 used off-label, and 6 in development). MOAs had predominantly sodium channel, calcium channel, and gamma-aminobutyric acid (GABA)ergic targets. Besides FFA, no other ASM acts on the combination of serotonin and Sigma1R pathways. Preclinical studies in two animal models demonstrated that FFA reduced seizure activity, improved aspects of cognition (eg, learning and memory), restored dendritic arborization, and reduced the incidence of SUDEP. These effects have been shown through FFA’s ability to interact with multiple serotonin receptors, including 5HT1D, 5HT2A, 5HT2C, and 5HT4, along with positive modulatory activity at Sigma1R. A conceptual model supports Sigma1R positive modulatory activity in diminishing glutamatergic activity, while 5-HT activity increases GABAergic, inhibitory input, thereby restoring the balance between inhibitory GABAergic signaling and excitatory glutamatergic signaling and reducing seizure activity.
Conclusions: This systematic review aligns all currently used ASMs by MOA and demonstrates that FFA is the only ASM currently used for DEE treatment with the dual MOA of acting within both serotonergic and Sigma1R pathways. This unique MOA may explain FFA’s efficacy in both seizure and non-seizure outcomes for DEEs.
Funding: Please list any funding that was received in support of this abstract.: Zogenix.
Basic Mechanisms