Fenfluramine for seizures associated with Dravet syndrome and Lennox–Gastaut syndrome

ObjectiveTo assess the burden of Dravet syndrome (DS) and Lennox–Gastaut syndrome (LGS), including managing seizure and nonseizure symptoms, on patients and caregivers.MethodsData were drawn from the Adelphi Real World DS and LGS Disease Specific Programme™, a cross‐sectional survey in Asia (China, Japan), Europe (France, Germany, Italy, Spain, United Kingdom), and the United States of America between July 2022 and August 2023. Neurologists/pediatric neurologists reported demographics, clinical characteristics, and nonseizure symptoms for up to 10 consecutively consulting patients. Caregivers provided data on patient nonseizure symptoms, quality of life (QoL), satisfaction with treatment, and caregiver burden. Analyses were descriptive.ResultsPhysicians (n = 259) reported data on 547 patients with DS and 811 with LGS. Caregivers (n = 348) provided data on 157 patients with DS and 191 with LGS. In the previous 6 months, 51% of patients with DS experienced ≥1 seizure‐related injury and 61% experienced status epilepticus. For LGS, this was 50% and 43% of patients, respectively. Rates of moderate to very severe impairment in nonseizure symptoms were reported by physicians in learning/intellect (DS 69%; LGS 78%), verbal communication (DS 69%; LGS 71%), severity of developmental delay (DS 65%; LGS 68%), overall mental status (DS 57%; LGS 67%), and nonverbal communication (DS 61%; LGS 64%). Caregivers reported moderate to very severe impairment in learning/intellect (DS 53%; LGS 67%), severity of developmental delay (DS 52%; LGS 56%), verbal communication (DS 48%; LGS 48%), and nonverbal communication (DS 42%; LGS 45%). Caregivers reported nonseizure symptoms moderately to significantly impacted QoL for 56% of patients (DS 49%; LGS 61%); satisfaction with treatment rate was low for control over cognition/memory, verbal communication, and nonverbal communication impairment.SignificanceIn this study, considerable burden in DS and LGS management and care was driven by nonseizure symptoms, suggesting a need for treatments that manage the broad spectrum of disease symptoms.Plain Language SummaryWe asked doctors and caregivers to tell us about the symptoms that patients with Dravet syndrome and Lennox–Gastaut syndrome have. We asked how the symptoms affect the lives of the patients as well as the caregivers. We found that seizures have a big impact on the health and well‐being of patients and caregivers. We also found that other symptoms not caused by seizures have a big impact on patients and their caregivers.

Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS) are rare developmental and epileptic encephalopathies associated with seizure and nonseizure symptoms. A comprehensive understanding of how many individuals are affected globally, the diagnostic journey they face, and the extent of mortality associated with these conditions is lacking. Here, we summarize and evaluate published data on the epidemiology of DS and LGS in terms of prevalence, incidence, diagnosis, genetic mutations, and mortality and sudden unexpected death in epilepsy (SUDEP) rates. The full study protocol is registered on PROSPERO (CRD42022316930). After screening 2172 deduplicated records, 91 unique records were included; 67 provided data on DS only, 17 provided data on LGS only, and seven provided data on both. Case definitions varied considerably across studies, particularly for LGS. Incidence and prevalence estimates per 100 000 individuals were generally higher for LGS than for DS (LGS: incidence proportion = 14.5-28, prevalence = 5.8-60.8; DS: incidence proportion = 2.2-6.5, prevalence = 1.2-6.5). Diagnostic delay was frequently reported for LGS, with a wider age range at diagnosis reported than for DS (DS, 1.6-9.2 years; LGS, 2-15 years). Genetic screening data were reported by 63 studies; all screened for SCN1A variants, and only one study specifically focused on individuals with LGS. Individuals with DS had a higher mortality estimate per 1000 person-years than individuals with LGS (DS, 15.84; LGS, 6.12) and a lower median age at death. SUDEP was the most frequently reported cause of death for individuals with DS. Only four studies reported mortality information for LGS, none of which included SUDEP. This systematic review highlights the paucity of epidemiological data available for DS and especially LGS, demonstrating the need for further research and adoption of standardized diagnostic criteria.

Raising the bar: Fenfluramine sets new treatment standards for Dravet syndrome

What is this summary about? Lennox-Gastaut syndrome (LGS) and Dravet syndrome (DS) are rare forms of epilepsy that start in childhood and cause life-long disability. People with LGS and DS experience many seizure types and nonseizure-related problems with cognition (ability to think and understand), learning, behaviour and communication. People with LGS and DS depend on caregivers to assist with daily activities. Although many medications are available to treat seizures associated with LGS and DS, the effect on nonseizure outcomes is unclear. A highly purified (defined as a substance that has undergone a special process to remove impurities) oral (by mouth) solution of cannabidiol (CBD; Epidiolex®) from plants is approved by the United States (US) Food and Drug Administration (FDA) for the treatment of seizures associated with LGS, DS and tuberous sclerosis complex in people who are at least 1 year old. In clinical studies, treatment with CBD reduced the number of seizures. Common side effects (secondary, typically unintended effects of the medication) were increased liver enzyme levels, sleepiness, decreased appetite, diarrhea, fever, vomiting, tiredness, rash, problems with sleep and infections. CBD may also improve nonseizure outcomes, such as cognition, behavior and quality of life. The BEhavior, COgnition and More with Epidiolex® (BECOME) survey was designed to find out whether caregivers of people with LGS or DS taking CBD noticed changes in nonseizure and seizure outcomes. What are the key takeaways? Caregivers of people with LGS or DS taking CBD noticed improvements in cognition, language and communication, emotional and social functioning, physical functioning, sleep and ability to do daily activities, as well as a reduction in the number and severity of seizures. People with reduction in seizures were more likely to experience nonseizure benefits, but some people without seizure reduction also experienced improvements in nonseizure outcomes. Caregivers reported that both seizure and nonseizure effects were important when thinking about treatment options. What were the main conclusions reported by the researchers? The BECOME survey provides a unique caregiver perspective on nonseizure outcomes that may be affected by CBD. These results support further study of CBD for nonseizure outcomes in people with LGS or DS.

PurposeThis retrospective chart review study (GWEP20052) evaluated plant-derived highly purified cannabidiol (CBD; Epidyolex®; 100 mg/mL oral solution) use without clobazam as add-on therapy in patients aged ≥2 years with Lennox-Gastaut syndrome (LGS) or Dravet syndrome (DS) enrolled in a European Early Access Program. MethodsData were extracted from patient charts covering a period starting 3 months before CBD treatment and concluding after 12 months of CBD treatment, or sooner if a patient discontinued CBD or started clobazam. ResultsOf 114 enrolled patients, data were available for 107 (92 LGS, 15 DS) who received CBD without clobazam for ≥3 months. Mean age: 14.5 (LGS) and 10.5 (DS) years; female: 44% (LGS) and 67% (DS). Mean time-averaged CBD dose: 13.54 (LGS) and 11.56 (DS) mg/kg/day. Median change from baseline in seizure frequency per 28 days over 3-month intervals varied from −6.2% to −20.9% for LGS and 0% to −16.7% for DS. Achievement of ≥50% reduction in drop (LGS) or convulsive (DS) seizures at 3 and 12 months: LGS, 19% (n = 69) and 30% (n = 53); DS, 21% (n = 14) and 13% (n = 8). Retention on CBD without clobazam (enrolled set): 94%, 80%, 69%, and 63% at 3, 6, 9, and 12 months. Adverse event (AE) incidence was 31%, most commonly somnolence, seizure, diarrhea, and decreased appetite. Two patients discontinued CBD owing to AEs, and four patients with LGS experienced elevated liver enzymes. ConclusionResults support favorable effectiveness and retention of CBD without concomitant clobazam for up to 12 months in clinical practice.

<h3>Objective:</h3> To develop a post hoc analysis of soticlestat treatment efficacy by seizure type in patients with Dravet syndrome (DS) or Lennox–Gastaut syndrome (LGS) in ELEKTRA (NCT03650452), a phase 2, randomized, placebo-controlled study of adjunctive soticlestat (≤300 mg BID, weight-adjusted) in children aged 2–17 years with DS demonstrating ≥3 convulsive seizures/28 days, or with LGS demonstrating ≥4 drop seizures/28 days at baseline. <h3>Background:</h3> DS and LGS involve developmental delay and frequent epileptic activity. The published ELEKTRA study investigated efficacy and safety of soticlestat, a cholesterol 24-hydroxylase inhibitor, in children with DS or LGS. Primary endpoint was change in convulsive (DS) and drop (LGS) seizure frequencies. <h3>Design/Methods:</h3> Post hoc efficacy analyses determined percent change in seizure frequency from baseline, by seizure type. Patients’ caregivers recorded seizure number and type throughout the baseline and full (20-week) treatment periods, including generalized tonic–clonic, focal to bilateral tonic–clonic, focal with motor signs and atonic seizures. <h3>Results:</h3> Of 141 enrolled patients, 126 (89%) completed ELEKTRA. The modified intent-to-treat population received ≥1 doses of study drug and had ≥1 efficacy assessments (DS, n=51; LGS, n=88). Median seizure frequency changes from baseline in patients with DS receiving soticlestat (placebo): generalized tonic–clonic seizures, −27.2% [n=14] (19.5%, n=21); focal to bilateral tonic–clonic seizures, −73.9% [n=9] (8.4%, n=4). Median seizure frequency changes from baseline in patients with LGS receiving soticlestat (placebo): generalized tonic–clonic seizures, −33.4% [n=17] (−20.0%, n=11); focal seizures with motor signs, −64.3% [n=10] (−21.1%, n=7); atonic seizures, −33.9% [n=16] (−17.9%; n=13); focal to bilateral tonic–clonic seizures, −41.3% [n=6] (none observed). <h3>Conclusions:</h3> Reduced median frequency of specific seizure types was observed in patients receiving soticlestat as adjunctive therapy. Investigation of soticlestat adjunctive therapy for these seizure types in other epilepsies is warranted (phase 3 studies ongoing for DS and LGS). Study funded by Takeda Pharmaceutical Company Limited. <b>Disclosure:</b> Dr. Pathi Jagannatham has received personal compensation for serving as an employee of Takeda Pharmaceuticals. Dr. Pathi Jagannatham has received personal compensation for serving as an employee of GlaxoSmithKline. Dr. Pathi Jagannatham has stock in Takeda Pharmaceuticals. Dr. Pathi Jagannatham has stock in GlaxoSmithKline. Dr. Dlugos has received research support from NIH. The institution of Dr. Dlugos has received research support from The Epilepsy Study Consortium. Yasir Khan has nothing to disclose. Dr. Hsiao has received personal compensation for serving as an employee of Takeda Pharmaceutical Company. Dr. Hsiao has stock in Takeda Pharmaceutical Company. Dr. Benitez has received personal compensation for serving as an employee of Takeda . Mahnaz Asgharnejad, PharmD has received personal compensation for serving as an employee of Takeda Pharmaceuticals. Mahnaz Asgharnejad, PharmD has stock in GlaxoSmithKline. Mahnaz Asgharnejad, PharmD has stock in Takeda Pharmaceuticals.

BackgroundAutism spectrum disorder (ASD) in epilepsy has been a topic of increasing interest, which in general occurs in 15–35% of the patients with epilepsy, more frequently in those with intellectual disability (ID). Lennox-Gastaut syndrome (LGS) and Dravet syndrome (DS) are two typical forms of intractable epileptic encephalopathy associated with ID. We previously reported that ASD was diagnosed in 24.3% of patients with DS, higher in those with profound ID. Given the severe epilepsy and high frequency of ID in LGS, it is necessary to know whether ASD is a common psychomotor co-morbidity of LGS. This study evaluated the autistic behaviors and intelligence in patients with LGS and further compared that between LGS and DS, aiming to understand the complex pathogenesis of epilepsy-ASD-ID triad.MethodsA total of 50 patients with LGS and 45 patients with DS were enrolled and followed up for at least 3 years. The clinical characteristics were analyzed, and evaluations of ASD and ID were performed.ResultsNo patients with LGS fully met the diagnostic criteria for ASD, but three of them exhibited more or less autistic behaviors. Majority (86%) of LGS patients presented ID, among which moderate to severe ID was the most common. Early onset age and symptomatic etiology were risk predictors for ID. The prevalence of ASD in LGS was significantly lower than that in DS (0/50 vs. 10/45, p < 0.001), while the prevalence and severity of ID showed no significant difference between the two forms of epileptic encephalopathy.ConclusionsThis study demonstrated a significant difference in the co-morbidity of ASD between LGS and DS, although they had a similar prevalence and severity of ID, refuting the proposal that the prevalence of ASD in epilepsy is accounted for by ID. These findings suggest that the co-morbidity of ASD, ID, and epilepsy may result from multifaceted pathogenic mechanisms.

ObjectiveTo increase understanding of the impact of cannabidiol (CBD) on outcomes beyond seizure control among individuals with Dravet syndrome or Lennox-Gastaut syndrome.MethodsQualitative interviews were conducted with caregivers of individuals with Dravet syndrome or Lennox-Gastaut syndrome treated with plant-derived, highly purified CBD medicine (Epidiolex in the USA; Epidyolex in Europe; 100 mg/mL oral solution). Symptoms and impacts of Dravet syndrome and Lennox-Gastaut syndrome on individuals were explored, as were the effects of CBD. Data were analyzed using thematic analysis.ResultsTwenty-one caregivers of individuals with Dravet syndrome (n = 14) and Lennox-Gastaut syndrome (n = 7) aged 4-22 years participated. Health-related quality of life improvements associated with CBD included cognitive function, communication, behavior, mobility, and participation in daily activities. Seizure frequency reduction was commonly reported (n = 12), resulting in caregivers having greater freedom and family life being less disrupted. Adverse events were reported by 10 caregivers.ConclusionIn addition to reduced seizure frequency, CBD may have a wide range of beneficial effects beyond seizure control that warrant further investigation.

PRO58 QUALITY OF LIFE IN PATIENTS WITH DRAVET SYNDROME OR LENNOX GASTAUT SYNDROME IN THE UK: HIGHER SEIZURE FREQUENCY HAS A SUBSTANTIAL NEGATIVE IMPACT ON QUALITY OF LIFE

Epileptic encephalopathy is defined as a condition where the epileptic activity itself may contribute to the severe neurological and cognitive impairment seen, over and above that which would be expected from the underlying pathology alone. The epilepsy syndromes at high risk of this are a disparate group of conditions characterized by epileptic seizures that are difficult to treat and developmental delay. In this review, we discuss the ongoing debate regarding the significance of inter-ictal discharges and the impact of the seizures themselves on the cognitive delay or regression that is a common feature of these syndromes. The syndromes also differ in many ways and we provide a summary of the key features of the early-onset epileptic encephalopathies including Ohtahara and West syndromes in addition to later childhood-onset syndromes such as Lennox Gastaut and Doose syndromes. An understanding of the various severe epilepsy syndromes is vital to understanding the rationale for treatment. For example, the resolution of hypsarrhythmia in West syndrome is associated with an improvement in cognitive outcome and drives treatment choice, but the same cannot be applied to frequent inter-ictal discharges in Lennox Gastaut syndrome. We discuss the evidence base for treatment where it is available and describe current practice where it is not. For example, in West syndrome there is some evidence for preference of hormonal treatments over vigabatrin, although the choice and duration of hormonal treatment remains unclear. We describe the use of conventional and newer anti-epileptic medications in the various syndromes and discuss which medications should be avoided. Older possibly forgotten treatments such as sulthiame and potassium bromide also have a role in the severe epilepsies of childhood. We discuss hormonal treatment with particular focus on the treatment of West syndrome, continuous spike wave in slow wave sleep (CSWS)/electrical status epilepticus in slow wave sleep (ESES) and Landau Kleffner syndrome. The role of the ketogenic diet has in recent years come to the fore of the management of these severe epilepsies and we describe successful use in myoclonic astatic epilepsy, Lennox Gastaut syndrome and Dravet syndrome. It is important that resective epilepsy surgery is not ignored in the management of these children, particularly those with hemi-pathology who may present with ESES and respond well to hemispheric disconnection. Adjunctive and symptomatic surgical treatments such as vagal nerve stimulation and corpus callosotomy may improve seizure burden. Finally, it is vital that the identification and treatment of developmental, behavioural and psychiatric co-morbidities are not neglected and that a rational, holistic approach is taken to the management of epileptic encephalopathies.

Background and ImportanceCannabidiol is approved in Europe as adjunctive therapy for preventing seizures associated with Lennox-Gastaut Syndrome (LGS), Dravet Syndrome (DS), and Tuberous Sclerosis Complex (TSC) in patients with previous...

Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS) are rare treatment-resistant childhood epilepsies classed as developmental and epileptic encephalopathies. ELEKTRA investigated the efficacy and safety of soticlestat (TAK-935) as adjunctive therapy in children with DS or LGS (NCT03650452). ELEKTRA was a phase 2, randomized, double-blind, placebo-controlled study of soticlestat (≤300 mg twice daily, weight-adjusted) in children (aged 2-17 years) with DS, demonstrating three or more convulsive seizures/month, or with LGS, demonstrating four or more drop seizures/month at baseline. The 20-week treatment period comprised an 8-week dose-optimization period and a 12-week maintenance period. Efficacy endpoints included change from baseline in seizure frequency versus placebo. Safety assessments included incidence of treatment-emergent adverse events (TEAEs). ELEKTRA enrolled 141 participants; 126 (89%) completed the study. The modified intent-to-treat population included 139 participants who received one or more doses of study drug and had one or more efficacy assessments (DS, n=51; LGS, n=88). ELEKTRA achieved its primary endpoint: the combined soticlestat-treated population demonstrated a placebo-adjusted median reduction in seizure frequency of 30.21% during the maintenance period (p=.0008, n=139). During this period, placebo-adjusted median reductions in convulsive and drop seizure frequencies of 50.00% (p=.0002; patients with DS) and 17.08% (p=.1160; patients with LGS), respectively, were observed. TEAE incidences were similar between the soticlestat (80.3%) and placebo (74.3%) groups and were mostly mild or moderate in severity. Serious TEAEs were reported by 15.5% and 18.6% of participants receiving soticlestat and placebo, respectively. TEAEs reported in soticlestat-treated patients with ≥5% difference from placebo were lethargy and constipation. No deaths were reported. Soticlestat treatment resulted in statistically significant, clinically meaningful reductions from baseline in median seizure frequency (combined patient population) and in convulsive seizure frequency (DS cohort). Drop seizure frequency showed a nonstatistically significant numerical reduction in children with LGS. Soticlestat had a safety profile consistent with previous studies.

Fenfluramine (FFA), an antiseizure medication (ASM) with serotonergic and sigma‐1 receptor activity, is used to manage patients with developmental and epileptic encephalopathies (DEEs). It is approved in the US for treating seizures associated with Dravet syndrome (DS) and Lennox–Gastaut syndrome (LGS) in patients ≥2 years old and as add‐on therapy for seizures associated with DS and LGS in the EU, UK, and Japan in similarly aged patients. Consensus guidelines for treatment of DS have recommended FFA to be an early‐line ASM, and it has also shown efficacy in managing seizures associated with LGS. DS and LGS are DEEs associated with a range of seizure types, developmental impairments, and multiple comorbidities. Here we provide case vignettes describing 4 patients (3 DS and 1 LGS) aged 4–29 years old in whom up to 14 ASMs had previously failed, to illustrate real‐world practice issues encountered by neurologists. This review provides guidance on the use of FFA in the context of ASM polytherapy and drug–drug interactions (DDIs), behavioral issues, dose titration, and adverse events. Along with data from the clinical trial program, these case vignettes emphasize the low risk of DDIs, a generally well‐tolerated safety profile, and other seizure and nonseizure benefits (eg, improved cognition and sleep) associated with the use of FFA in DS or LGS.Plain Language SummaryFenfluramine is used to treat seizures in individuals with Dravet syndrome and Lennox–Gastaut syndrome, but there are a range of issues that clinicians may face when treating patients. This review highlights four patients from the authors’ everyday clinical work and offers guidance and practical considerations by neurologists with expertise in managing these complex conditions related to drug interactions, dosing, and side effects associated with fenfluramine.

The direct cost of seizure events in severe childhood-onset epilepsies: A retrospective claims-based analysis

Fenfluramine (FFA) is an antiseizure medication (ASM) with effectiveness in Dravet Syndrome (DS) and Lennox-Gastaut syndrome (LGS), but unknown effectiveness in other developmental epileptic encephalopathies (DEEs). This multicenter, retrospective study evaluated the efficacy and tolerability of FFA in children with DS, LGS and other DEEs within clinical practice. Data were extracted from patients' charts before and up to 6months after treatment. Fifty-four patients (median age 10years; 67% male) with DS (n = 17), LGS (n = 20), or other DEE (n = 17) were included. At three months following FFA treatment, the proportion of responders (≥ 50% reduction in seizure frequency) was significantly higher in patients with DS (94%) compared with LGS (50%; p = 0.003) and other DEEs (47%; p = 0.003). No significant difference in responder rates was observed between the LGS and other DEE groups. FFA efficacy was independent of dosage, concomitant ASMs, epilepsy duration, etiology, or specific comorbidities. FFA demonstrated effectiveness across all seizure types, with particular efficacy in tonic-clonic seizures. Responders experienced improvements in physician-assessed seizure intensity; 56-91% showed improvements in other Clinical Global Impression domains, including cognition, behavior, sleep, and seizure severity. Adverse events occurred in 56% of patients and were predominantly mild, with somnolence, anorexia, and irritability the most common. Treatment discontinuation due to AEs occurred in three patients (1 LGS, 2 other DEEs). FFA demonstrates effectiveness and tolerability in patients with DEEs in a real-world setting, and has potential as a broad-spectrum ASM, effective across a wide range of DEEs, seizure types, and patient profiles.