Impact of fenfluramine on the expected SUDEP mortality rates in patients with Dravet syndrome

Cross, J. Helen; Galer, Bradley S.; Gil‐Nagel, Antonio; Devinsky, Orrin; Ceulemans, Berten; Lagae, Lieven; Schoonjans, An‐Sofie; Donner, Elizabeth; Wirrell, Elaine; Kothare, Sanjeev V.; Agarwal, Anupam; Lock, Michael; Gammaitoni, Arnold R.

doi:10.1016/j.seizure.2021.10.024

Cited by 49 publications

(56 citation statements)

References 38 publications

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“…Thankfully, some of these recent DS‐specific therapy trials have also demonstrated improvements in non‐seizure‐related outcomes such as executive function, 20 and it remains to be seen whether earlier use of “DS‐specific” ASMs will have more favorable impact on long‐term outcomes. Although a recent study suggested that fenfluramine may be associated with reduced risk of SUDEP, 21 further research is needed.…”

Section: Discussionmentioning

confidence: 99%

International consensus on diagnosis and management of Dravet syndrome

et al. 2022

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Objective: This study was undertaken to gain consensus from experienced physicians and caregivers regarding optimal diagnosis and management of Dravet syndrome (DS), in the context of recently approved, DS-specific therapies and emerging disease-modifying treatments.Methods: A core working group was convened consisting of six physicians with recognized expertise in DS and two representatives of the Dravet Syndrome Foundation. This core group summarized the current literature (focused on clinical presentation, comorbidities, maintenance and rescue therapies, and evolving disease-modifying therapies) and nominated the 31-member expert panel (ensuring international representation), which participated in two rounds of a Delphi process to gain consensus on diagnosis and management of DS.Results: There was strong consensus that infants 2-15 months old, presenting with either a first prolonged hemiclonic seizure or first convulsive status epilepticus with fever or following vaccination, in the absence of another cause, should undergo genetic testing for DS. Panelists agreed on evolution of specific comorbidities with time, but less agreement was achieved on optimal management. There was also agreement on appropriate first-to third-line maintenance therapies, which included the newly approved agents. Whereas there was agreement for recommendation of disease-modifying therapies, if they are proven safe and efficacious for seizures and/or reduction of comorbidities, there was less consensus for when these should be started, with caregivers being more conservative than physicians.Significance: This International DS Consensus, informed by both experienced global caregiver and physician voices, provides a strong overview of the impact of DS, therapeutic goals and optimal management strategies incorporating the recent therapeutic advances in DS, and evolving disease-modifying therapies. K E Y W O R D Scannabidiol, developmental and epileptic encephalopathy, disease-modifying treatment, fenfluramine, SCN1A, stiripentol Note: Bold and all-capital text indicates Strong consensus; bold and italic text indicates Moderate consensus; nonbold and italic text indicates no consensus.

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Section: Discussionmentioning

confidence: 99%

International consensus on diagnosis and management of Dravet syndrome

et al. 2022

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“…Status epilepticus and SUDEP events, as the primary causes of premature death in DS (5,6), are of paramount importance; however, RCTs in DS could never be powered adequately for these outcomes. In a recently published pooled analysis of 732 people with DS treated with fenfluramine across RCTs, open-label extension studies and early access programs, the observed incidence rates of all-cause and SUDEP mortality (both 1.7 per 1000 patient years) were substantially lower than those reported in the literature with SoC therapy (15.8 and 9.3 per 1000 person-years, respectively), which the authors attributed largely to the substantial additional reductions in convulsive seizure frequency observed with fenfluramine (24). But in the absence of comparative data it is not possible to estimate an indirect treatment effect on these outcomes in the current study.…”

Section: Discussionmentioning

confidence: 82%

Comparative effectiveness of fenfluramine versus cannabidiol in their licensed indications for the treatment of seizures in Dravet Syndrome: a systematic review and network meta-analysis

Linley

Schwenkglenks

Hawkins³

et al. 2022

Preprint

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Purpose: Fenfluramine and cannabidiol are licensed as add-on therapies for the treatment of seizures in Dravet syndrome (DS); however, there are no comparative trials of these therapies. We assessed the comparative effectiveness of fenfluramine (with/without concomitant stiripentol) versus cannabidiol (with/irrespective of concomitant clobazam, using robust indirect comparison methods. Methods: We systematically searched for randomised controlled trials (RCTs) of licensed regimens published up to 30 November 2021. Outcomes of interest were placebo-adjusted reductions from baseline in monthly convulsive seizure frequency (MCSF), the odds of achieving >25%, >50%, >75% and 100% reductions from baseline in MCSF, and the odds of experiencing serious treatment-emergent adverse events (TEAEs). Comparative efficacy and safety were assessed using Bayesian network meta-analysis (NMA). PROSPERO registration: CRD42021296141. Results: We identified five relevant placebo-controlled RCTs (three for fenfluramine; two for cannabidiol; N=667). All licensed regimens of fenfluramine and cannabidiol significantly reduced MCSF compared with standard of care. When indirectly comparing fenfluramine 0.7mg/kg/day (without concomitant stiripentol) and fenfluramine 0.4mg/kg/day (with concomitant stiripentol) versus cannabidiol 10mg/kg/day, irrespective of clobazam use, the mean differences in placebo-adjusted reduction from baseline in MCSF were 47.3% (95%CrI: 18.9, 64.7) and 35.1% (1.0, 57.5), respectively, and versus cannabidiol 10mg/kg/day plus clobazam were 37.2% (2.0, 59.7) and 23.5% (-20.2, 51.3), respectively. For these outcomes, and for the proportion of patients achieving >25%, >50% and >75% reductions in MCSF, Bayesian treatment ranking indicated >99% probability that fenfluramine is the most effective therapy versus <1% probability for cannabidiol 10 or 20mg/kg/day (maximum recommended dose), with/irrespective of concomitant clobazam. Fenfluramine regimens had lower odds of serious TEAEs. Conclusion: NMA using RCT data indicates fenfluramine provides superior convulsive seizure control compared to cannabidiol across all licensed dose regimens and is comparatively well-tolerated. Fenfluramine may meet the need for a highly effective and tolerable add-on therapy to control seizures in DS.

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“…The overall importance of 5‐HT in SUDEP can be related to the 5‐HT‐dependent regulation of breathing and sleep arousal to keep normal blood CO 2 and pH values 152 . Recently, Cross and colleagues showed that the all‐cause and SUDEP mortality rates during FA treatment of patients with DS significantly decreased (1.7/1000 person‐years), compared to literature reports (9.3‐15.8/1000 person‐years) 153 …”

Section: Resultsmentioning

confidence: 98%

Serotonin receptors in epilepsy: Novel treatment targets?

Sourbron

Lagae

2022

Epilepsia Open

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Despite the availability of over 30 antiseizure medications (ASMs), there is no “one size fits it all,” so there is a continuing search for novel ASMs. There are divergent data demonstrating that modulation of distinct serotonin (5‐hydroxytryptamine, 5‐HT) receptors subtypes could be beneficial in the treatment of epilepsy and its comorbidities, whereas only a few ASM, such as fenfluramine (FA), act via 5‐HT. There are 14 different 5‐HT receptor subtypes, and most epilepsy studies focus on one or a few of these subtypes, using different animal models and different ligands. We reviewed the available evidence of each 5‐HT receptor subtype using MEDLINE up to July 2021. Our search included medical subject heading (MeSH) and free terms of each “5‐HT subtype” separately and its relation to “epilepsy or seizures.” Most research underlines the antiseizure activity of 5‐HT1A,1D,2A,2C,3 agonism and 5‐HT6 antagonism. Consistently, FA, which has recently been approved for the treatment of seizures in Dravet syndrome, is an agonist of 5‐HT1D,2A,2C receptors. Even though each study focused on a distinct seizure/epilepsy type and generalization of different findings could lead to false interpretations, we believe that the available preclinical and clinical studies emphasize the role of serotonergic modulation, especially stimulation, as a promising avenue in epilepsy treatment.

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Impact of fenfluramine on the expected SUDEP mortality rates in patients with Dravet syndrome

Cited by 49 publications

References 38 publications

International consensus on diagnosis and management of Dravet syndrome

International consensus on diagnosis and management of Dravet syndrome

Comparative effectiveness of fenfluramine versus cannabidiol in their licensed indications for the treatment of seizures in Dravet Syndrome: a systematic review and network meta-analysis

Serotonin receptors in epilepsy: Novel treatment targets?

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