Improving Therapy of Pharmacoresistant Epilepsies: The Role of Fenfluramine

Abstract

Epilepsy is among the most common neurological chronic disorders, with a prevalence of 0.5–1%. Despite the introduction of new antiepileptic drugs during recent years, about one third of the epileptic population remain drug-resistant. Hence, especially in the pediatric population limited by different pharmacokinetics and pharmacodynamics and by ethical and regulatory issues it is needed to identify new therapeutic resources. New molecules initially used with other therapeutic indications, such as fenfluramine, are being considered for the treatment of pharmacoresistant epilepsies, including Dravet Syndrome (DS) and Lennox-Gastaut Syndrome (LGS). Drug-refractory seizures are a hallmark of both these conditions and their treatment remains a major challenge. Fenfluramine is an amphetamine derivative that was previously approved as a weight loss drug and later withdrawn when major cardiac adverse events were reported. However, a new role of fenfluramine has emerged in recent years. Indeed, fenfluramine has proved to be a promising antiepileptic drug with a favorable risk–benefit profile for the treatment of DS, LGS and possibly other drug-resistant epileptic syndromes. The mechanism by which fenfluramine provide an antiepileptic action is not fully understood but it seems to go beyond its pro-serotoninergic activity. This review aims to provide a comprehensive analysis of the literature, including ongoing trials, regarding the efficacy and safety of fenfluramine as adjunctive treatment of pharmacoresistant epilepsies.

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“…Fenfluramine has been shown to offer significant improvement in DS patients, possibly via multiple mechanisms of action (47). For example, fenfluramine acts to increase serotonin release by inhibiting its reuptake while also inhibiting several classes of serotonin receptors such as 5HT-1D and 5HT-2A/C (48).…”

“…The functional deficit in the patient-derived SSs could be rescued to some extent by acute application of fenfluramine as assessed by two-photon calcium imaging (Figure 4G-H). Fenfluramine has been shown to offer significant improvement in DS patients, possibly via multiple mechanisms of action (47). For example, fenfluramine acts to increase serotonin release by inhibiting its reuptake while also inhibiting several classes of serotonin receptors such as 5HT-1D and 5HT-2A/C (48).…”

“…These serotonin receptors are G-protein coupled receptors that have multiple downstream targets including potassium channels and Ca 2+ signaling pathways (49), thus are capable of modulating neuronal excitability. Sigma 1 receptors, another main target of fenfluramine, can modulate various voltage- and ligand-gated ion channels at the postsynapse to indirectly influence synaptic function (47). It has also been demonstrated that serotonin can modulate GABAA receptors and inhibitory neurotransmission in hiPSC-derived neurons (50).…”

Optimal dose of fenfluramine in adjuvant treatment of drug-resistant epilepsy: evidence from randomized controlled trials

“…Apart from DS and LGS, studies on FFA for the treatment of other DREs are also ongoing ( 15 ). A small sample size study of FFA for CDD conducted by Devinsky et al ( 14 ) recruited six patients with CDD and initially demonstrated that 0.4 mg/kg/d and 0.7 mg/kg/d FFA decreased seizure frequency with no distinct adverse effects.…”

“…No serious adverse effects, such as lethal cardiac disease, were observed in any of these studies. Meanwhile, another study applying FFA as an adjunct to the treatment of five different types of developmental and epileptic encephalopathies (DEEs) (SYNGAP1 Encephalopathy, STXBP1 Encephalopathy With Epilepsy, Inv Dup ( 15 ) Encephalopathy, Multifocal or Bilateral Malformations of Cortical Development, Continuous Spike and Waves During Slow Sleep) is also enrolling patients in a non-controlled clinical trial (NCT05232630), which focuses on assessing seizure frequency, intensity, and duration before and after FFA treatment. Moreover, “non-epileptic outcomes,” such as variations in cognitive activity, level of alertness, impulsivity/self-control, gait stability, and other alterations may also be detected during the interview and physical examination.…”