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

Abstract

Treatment and diagnosis of developmental and epileptic encephalopathies have entered a new era [[1]Cross J.H. Epilepsy in 2020—a new dawn.Lancet Neurol. 2021; 20: 8-10Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar]. In this new environment, widespread availability of genetic testing speeds time to precise diagnosis; networked epilepsy centers offer improved access to appropriate medical care in the USA and in the EU; new medications are demonstrating unprecedented treatment outcomes; and targeted gene therapy approaches are on the horizon. Overall, newly available treatment options are advancing patient care from symptomatic treatment to disease modification [[2]Cross J.H. Lagae L. The concept of disease modification.Eur J Paediatr Neurol. 2020; 24: 43-46Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar]. In many ways, aspects of the management of Dravet syndrome have pioneered this emergent paradigm shift. Dravet syndrome is a treatment-resistant developmental and epileptic encephalopathy characterized by a high burden of seizures and debilitating outcomes in motor, cognitive, and behavioral domains [[3]Dravet C. The core Dravet syndrome phenotype.Epilepsia. 2011; 52: 3-9Crossref PubMed Scopus (299) Google Scholar]. Until recently, treatment options were limited, and most patients retained a high seizure burden even with polypharmacy, with little positive impact on non-seizure-related outcomes [[4]Lagae L. Brambilla I. Mingorance A. Gibson E. Battersby A. Quality of life and comorbidities associated with Dravet syndrome severity: a multinational cohort survey.Dev Med Child Neurol. 2018; 60: 63-72Crossref PubMed Scopus (66) Google Scholar]. Stiripentol and cannabidiol became the first drugs approved for Dravet syndrome in the USA (both in 2018) and in the EU (2007 and 2019, respectively) [[5]Wheless J.W. Fulton S.P. Mudigoudar B.D. Dravet syndrome: a review of current management.Pediatr Neurol. 2020; 107: 28-40Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar]. In 2020, fenfluramine was approved for Dravet syndrome by both agencies based on the results of 3 independent pivotal trials, each of which demonstrated monthly convulsive seizure frequency reductions of 54% to 65% in comparison to placebo, even in patients who were concurrently receiving stiripentol [6Sullivan J, Lagae L, Cross JH, Devinsky O, Guerrini R, Knupp KG, et al. Fenfluramine (FINTEPLA) in Dravet syndrome: results of a third randomized, placebo-controlled clinical trial (Study 3) [poster]. Presented at: American Epilepsy Society Virtual Meeting 2020.Google Scholar, 7Nabbout R. Mistry A. Zuberi S. Villeneuve N. Gil-Nagel A. Sanchez-Carpintero R. et al.Fenfluramine for treatment-resistant seizures in patients with Dravet syndrome receiving stiripentol-inclusive regimens: a randomized clinical trial.JAMA Neurol. 2020; 77: 300https://doi.org/10.1001/jamaneurol.2019.4113Crossref PubMed Scopus (63) Google Scholar, 8Lagae L. Sullivan J. Knupp K. Laux L. Polster T. Nikanorova M. et al.Fenfluramine hydrochloride for the treatment of seizures in Dravet syndrome: a randomised, double-blind, placebo-controlled trial.Lancet (London, England). 2019; 394: 2243-2254Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar]. For the first time, it became possible for a large percentage of patients to achieve profound reductions in convulsive seizure frequency; ≥75% reduction in monthly convulsive seizure frequency (MCSF) was achieved by 48% to 50% of patients on stiripentol-free regimens versus 2% to 4% of those receiving placebo (Studies 1 and 3), and in 35% of patients on stiripentol-inclusive regimens versus 2% of patients taking placebo (Study 2). The longest mean seizure-free interval was between 29.7 and 32.9 days for the most effective fenfluramine dose compared with 10.6 to 13.4 days for placebo [7Nabbout R. Mistry A. Zuberi S. Villeneuve N. Gil-Nagel A. Sanchez-Carpintero R. et al.Fenfluramine for treatment-resistant seizures in patients with Dravet syndrome receiving stiripentol-inclusive regimens: a randomized clinical trial.JAMA Neurol. 2020; 77: 300https://doi.org/10.1001/jamaneurol.2019.4113Crossref PubMed Scopus (63) Google Scholar, 8Lagae L. Sullivan J. Knupp K. Laux L. Polster T. Nikanorova M. et al.Fenfluramine hydrochloride for the treatment of seizures in Dravet syndrome: a randomised, double-blind, placebo-controlled trial.Lancet (London, England). 2019; 394: 2243-2254Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar]. Compared to other therapies, fenfluramine appears to be achieving responder rates at the ≥75% level that were previously observed at the ≥50% level. In pivotal studies for cannabidiol, for example, the proportion of patients who achieved ≥50% reduction in MCSF was 43% to 49% compared with placebo response rates of 26% to 27% [9Miller I, Devinsky O, Auvin S, Thiele E, Polster T, Laux L, et al. Efficacy and tolerability with FINTEPLA (fenfluramine) in adult patients with Dravet syndrome: a case series of patients participating in phase 3 studies [poster]. Presented at: American Epilepsy Society Virtual Meeting 2020.Google Scholar, 10Devinsky O. Cross J.H. Laux L. Marsh E. Miller I. Nabbout R. et al.Trial of cannabidiol for drug-resistant seizures in the Dravet syndrome.N Engl J Med. 2017; 376: 2011-2020Crossref PubMed Scopus (668) Google Scholar]. The number needed to treat (NNT) with fenfluramine to achieve either ≥50% or ≥75% reduction in MCSF was between 2 and 3, compared with NNTs of 4 to 6 to achieve ≥50% levels in comparable Class I level-of-evidence clinical trials of antiseizure medications for Dravet syndrome (e.g., cannabidiol), and NNTs of 8 to 20 in a meta-analysis of antiepileptic drugs for treatment-refractory partial epilepsy [10Devinsky O. Cross J.H. Laux L. Marsh E. Miller I. Nabbout R. et al.Trial of cannabidiol for drug-resistant seizures in the Dravet syndrome.N Engl J Med. 2017; 376: 2011-2020Crossref PubMed Scopus (668) Google Scholar, 11Costa J, Fareleira F, Ascencao R, Borges M, Sampaio C, Vaz-Carneiro A. Clinical comparability of the new antiepileptic drugs in refractory partial epilepsy: a systematic review and meta-analysis. Epilepsia 2011;52:1280-91.Google Scholar, 12Miller I. Scheffer I.E. Gunning B. Sanchez-Carpintero R. Gil-Nagel A. Perry M.S. et al.Dose-ranging effect of adjunctive oral cannabidiol vs placebo on convulsive seizure frequency in Dravet syndrome: a randomized clinical trial.JAMA Neurol. 2020; 77: 613https://doi.org/10.1001/jamaneurol.2020.0073Crossref PubMed Scopus (59) Google Scholar, 13Moretz D. Drug class update with new drug evaluations: antiepileptics. Oregon State University/Oregon Health Authority, Salem, OR2019Google Scholar, 14Sullivan J. Perry M.S. Wheless J.W. Galer B. Gammaitoni A. Fenfluramine responder analyses and numbers needed to treat: translating epilepsy trial data into clinical practice.Eur J Paediatr Neurol. 2021; 31: 10-14Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar]. Unlike the pharmacodynamic tolerance or tachyphylaxis exhibited by some antiepileptic drugs (e.g., some benzodiazepines) [[15]Vinkers C.H. Olivier B. Mechanisms underlying tolerance after long-term benzodiazepine use: a future for subtype-selective GABAA receptor modulators?.Adv Pharmacol Sci. 2012; 2012416864PubMed Google Scholar], long-term open-label extension studies up to 3 years demonstrate that fenfluramine provided sustained reductions in convulsive seizure frequency [16Sullivan J. Scheffer I.E. Lagae L. Nabbout R. Pringsheim M. Talwar D. et al.Fenfluramine HCl (Fintepla®) provides long-term clinically meaningful reduction in seizure frequency: analysis of an ongoing open-label extension study.Epilepsia. 2020; 61: 2396-2404Crossref PubMed Scopus (18) Google Scholar, 17Scheffer I, Devinsky O, Perry MS, Wheless J, Thiele E, Farfel G, et al. Efficacy and tolerability of adjunctive FINTEPLA (fenfluramine hydrochloride) in an open-label extension study of Dravet syndrome patients treated for up to 3 years. Presented at: American Epilepsy Society Virtual Meeting 2020.Google Scholar]. Fenfluramine not only showed a clinical response that was unprecedented in the pediatric clinical trial target patient population (ages 2–18 years), it also showed continued efficacy in patients who reached their 18th birthday during the clinical trials and in those who were adults when treated as part of early access programs [9Miller I, Devinsky O, Auvin S, Thiele E, Polster T, Laux L, et al. Efficacy and tolerability with FINTEPLA (fenfluramine) in adult patients with Dravet syndrome: a case series of patients participating in phase 3 studies [poster]. Presented at: American Epilepsy Society Virtual Meeting 2020.Google Scholar, 18Perry MS, Knupp KG, Wirrell E, Sullivan J, Franz D, Burkholder D, et al. Fenfluramine (FINTEPLA) provides comparable clinical benefit in adults and children with Dravet syndrome: real-world experience from the US Early Access Program [poster]. Presented at: American Epilepsy Society Virtual Meeting 2020.Google Scholar]. Fenfluramine has demonstrated a positive benefit-risk profile in Dravet syndrome and has been generally well tolerated in clinical trials. The most common adverse events were reported as decreased appetite, fatigue, diarrhea, and pyrexia. Fenfluramine treatment for developmental and epileptic encephalopathies has not resulted in any cases of pulmonary arterial hypertension (PAH) or valvular heart disease (VHD), which had previously led to withdrawal from the market when fenfluramine was used at higher doses as an anorectic agent to treat obese adult patients [[19]Lai W.W. Galer B.S. Wong P.C. Farfel G. Pringsheim M. Keane M.G. et al.Cardiovascular safety of fenfluramine in the treatment of Dravet syndrome: analysis of an ongoing open-label safety extension study.Epilepsia. 2020; 61: 2386-2395Crossref PubMed Scopus (16) Google Scholar]. The long-term safety profile continues to be investigated in patients with Dravet syndrome and other developmental and epileptic encephalopathies. Ongoing open-label long-term extension studies to 3 years of daily fenfluramine treatment have reported no observations of PAH or VHD in any patient at any time (N = 330; median treatment duration: ∼631 days; range: 81–1086 days; dose range: 0.2–0.7 mg/kg/day; maximum: 26 mg/day for patients on stiripentol-free regimens, 17 mg/day max for patients on stiripentol-containing regimens) [[17]Scheffer I, Devinsky O, Perry MS, Wheless J, Thiele E, Farfel G, et al. Efficacy and tolerability of adjunctive FINTEPLA (fenfluramine hydrochloride) in an open-label extension study of Dravet syndrome patients treated for up to 3 years. Presented at: American Epilepsy Society Virtual Meeting 2020.Google Scholar]. Treatment of a small number of patients for 6–27 years (N = 12; mean treatment duration: 16.1 years) also did not result in clinically significant echocardiographic findings [[20]Ceulemans B, Schoonjans AS, Marchau F, Paelinck BP, Lagae L. Five-year extended follow-up status of 10 patients with Dravet syndrome treated with fenfluramine. Epilepsia 2016;57:e129-e34.Google Scholar]. However, solely based on historical reports from the use of higher doses of fenfluramine for treatment of adult obesity, the recent approval of fenfluramine by the FDA includes a Risk Evaluation and Mitigation (REMS) program, with a requirement for serial echocardiogram monitoring every 6 months and medical providers must be enrolled in the program to prescribe [[21]FINTEPLA® (fenfluramine) [prescribing information]. Zogenix, Inc.: Emeryville, CA; 2020.Google Scholar]. Fenfluramine has also set new standards for achieving clinically important results in patient-reported outcomes. A recent study highlighted that the unpredictability of seizures, along with their frequency and severity, was a key concern of caregivers [[22]Berg A.T. Kaiser K. Dixon-Salazar T. Elliot A. McNamara N. Meskis M.A. et al.Seizure burden in severe early-life epilepsy: perspectives from parents.Epilepsia Open. 2019; 4: 293-301Crossref PubMed Scopus (20) Google Scholar]. Improving the interval between seizures improves quality of life not only for the patient but also for the entire family unit, including parents and siblings [22Berg A.T. Kaiser K. Dixon-Salazar T. Elliot A. McNamara N. Meskis M.A. et al.Seizure burden in severe early-life epilepsy: perspectives from parents.Epilepsia Open. 2019; 4: 293-301Crossref PubMed Scopus (20) Google Scholar, 23Villas N. Meskis M.A. Goodliffe S. Dravet syndrome: characteristics, comorbidities, and caregiver concerns.Epilepsy Behav. 2017; 74: 81-86Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar, 24Bailey L.D. Schwartz L. Dixon-Salazar T. Meskis M.A. Galer B.S. Gammaitoni A.R. et al.Psychosocial impact on siblings of patients with developmental and epileptic encephalopathies.Epilepsy Behav. 2020; 112: 107377https://doi.org/10.1016/j.yebeh.2020.107377Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar]. Further, reducing the frequency of prolonged acute convulsive seizures has the potential to improve quality of life by preventing episodes of status epilepticus and associated long-term, irreversible neurological sequelae [[25]Kirkham F.J. Vigevano F. Raspall-Chaure M. Wilken B. Lee D. Le Reun C. et al.Health-related quality of life and the burden of prolonged seizures in noninstitutionalized children with epilepsy.Epilepsy Behav. 2020; 102: 106340https://doi.org/10.1016/j.yebeh.2019.04.058Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar]. Beyond seizures, a survey study of caregivers reported that cognitive impairment is one of their top 3 concerns [[23]Villas N. Meskis M.A. Goodliffe S. Dravet syndrome: characteristics, comorbidities, and caregiver concerns.Epilepsy Behav. 2017; 74: 81-86Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar]; later interview-based studies confirmed that cognitive and behavioral functioning had global impact on the child [26Nabbout R. Auvin S. Chiron C. Irwin J. Mistry A. Bonner N. et al.Development and content validation of a preliminary core set of patient- and caregiver-relevant outcomes for inclusion in a potential composite endpoint for Dravet syndrome.Epilepsy Behav. 2018; 78: 232-242Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar, 27Nabbout R. Auvin S. Chiron C. Thiele E. Cross H. Scheffer I.E. et al.Perception of impact of Dravet syndrome on children and caregivers in multiple countries: looking beyond seizures.Dev Med Child Neurol. 2019; 61: 1229-1236Crossref PubMed Scopus (17) Google Scholar]. Some of these aspects are captured quantitatively by the Clinical Global Impression of Improvement (CGI-I), a metric that assesses patients across all aspects of clinical presentation. When considering a new treatment option, clinicians counsel patients on possible side effects, including lethargy, somnolence, and other negative cognitive outcomes known to be caused by antiepileptic drugs [[28]Park S.P. Kwon S.H. Cognitive effects of antiepileptic drugs.J Clin Neurol. 2008; 4: 99https://doi.org/10.3988/jcn.2008.4.3.99Crossref PubMed Scopus (134) Google Scholar]. Fenfluramine did not worsen cognitive outcomes in safety assessments but, surprisingly, in analyses prespecified in the protocol, appeared to improve measures of executive functioning, a construct of cognition, in the short term (14 weeks) [[8]Lagae L. Sullivan J. Knupp K. Laux L. Polster T. Nikanorova M. et al.Fenfluramine hydrochloride for the treatment of seizures in Dravet syndrome: a randomised, double-blind, placebo-controlled trial.Lancet (London, England). 2019; 394: 2243-2254Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar]. Furthermore, another, post hoc analysis recently evaluated the longest assessment of executive function in the largest number of patients with Dravet syndrome published to date (N = 58; 1 year). Improvements in aspects of executive function at 1 year were reported, as measured by the Behavior Rating Inventory of Executive Function 2 (BRIEF®2) instrument [[29]Bishop KI, Isquith PK, Gioia GA, Gammaitoni AR, Farfel G, Galer BS, et al. Improved everyday executive functioning following profound reduction in seizure frequency with fenfluramine: analysis from a phase 3 long-term extension study in children/young adults with Dravet syndrome. Epilepsy Behav 2021;121:108024.Google Scholar]. The mechanisms of action of fenfluramine in reducing convulsive seizure activity are the subject of active investigation. Although fenfluramine has long been recognized as a potent serotonin-releasing agent with agonist activity at 5-HT2A, 5-HT2B, and 5-HT2C receptors, recent evidence supports activity at 5-HT7 and 5-HT4 receptors and positive modulatory activity at σ1 receptors [30Sourbron J. Smolders I. de Witte P. Lagae L. Pharmacological analysis of the anti-epileptic mechanisms of fenfluramine in scn1a mutant zebrafish.Front Pharmacol. 2017; 8: 191Crossref PubMed Scopus (66) Google Scholar, 31Martin P. de Witte P.A.M. Maurice T. Gammaitoni A. Farfel G. Galer B. Fenfluramine acts as a positive modulator of sigma-1 receptors.Epilepsy Behav. 2020; 105: 106989https://doi.org/10.1016/j.yebeh.2020.106989Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar, 32Faingold CL, Tupal S. The action of fenfluramine to prevent seizure-induced death in the DBA/1 mouse SUDEP model is selectively blocked by an antagonist or enhanced by an agonist for the serotonin 5-HT4 receptor [abstract]. Presented at: American Epilepsy Society Annual Meeting; December 6-10, 2019; Baltimore, MD.Google Scholar]. Reports in a zebrafish model of Dravet syndrome demonstrate that fenfluramine restores dendritic arborization, suggesting its potential for disease modification [[33]Tiraboschi E. Martina S. van der Ent W. Grzyb K. Gawel K. Cordero-Maldonado M.L. et al.New insights into the early mechanisms of epileptogenesis in a zebrafish model of Dravet syndrome.Epilepsia. 2020; 61: 549-560Crossref PubMed Scopus (22) Google Scholar]. Serotonergic and/or σ1 receptor-related mechanisms may mediate not only seizure frequency reduction but also non-seizure outcomes, including cognitive outcomes and prevention of sudden unexpected death in epilepsy (SUDEP) [31Martin P. de Witte P.A.M. Maurice T. Gammaitoni A. Farfel G. Galer B. Fenfluramine acts as a positive modulator of sigma-1 receptors.Epilepsy Behav. 2020; 105: 106989https://doi.org/10.1016/j.yebeh.2020.106989Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar, 32Faingold CL, Tupal S. The action of fenfluramine to prevent seizure-induced death in the DBA/1 mouse SUDEP model is selectively blocked by an antagonist or enhanced by an agonist for the serotonin 5-HT4 receptor [abstract]. Presented at: American Epilepsy Society Annual Meeting; December 6-10, 2019; Baltimore, MD.Google Scholar, 34Tupal S. Faingold C.L. Fenfluramine, a serotonin-releasing drug, prevents seizure-induced respiratory arrest and is anticonvulsant in the DBA/1 mouse model of SUDEP.Epilepsia. 2019; 60: 485-494PubMed Google Scholar]. It is unclear whether these mechanisms are specific to the unique SCN1A genetic etiology of Dravet syndrome or to the neuropathophysiology inherent in specific convulsive seizure subtypes. Early evidence in Lennox-Gastaut syndrome, for example, suggests that fenfluramine is uniquely effective in controlling convulsive seizures (e.g., generalized tonic-clonic seizures) in patients with this diagnosis [[35]Knupp KG, Scheffer I, Ceulemans B, Sullivan J, Nickels KC, Miller I, et al. Efficacy and safety of FINTEPLA (fenfluramine) for the treatment of seizures associated with Lennox-Gastaut syndrome: a randomized, double-blind, placebo-controlled clinical trial. Presented at: American Epilepsy Society Virtual Meeting 2020.Google Scholar]. These novel aspects of fenfluramine treatment for both clinical and patient-centered outcomes have effectively raised the bar for assessment of future therapies. Definitions of minimally effective and optimal seizure control in patients with Dravet syndrome will need to be re-evaluated when future treatment paradigms are discussed. New standards may be set for reduction in seizure burden and patient-centered outcomes that will guide conversations between clinicians and patients and their families in clinical decision-making. As treatment algorithms are developed [36Scheffer I.E. Berkovic S. Capovilla G. Connolly M.B. French J. Guilhoto L. et al.ILAE classification of the epilepsies: position paper of the ILAE Commission for Classification and Terminology.Epilepsia. 2017; 58: 512-521Crossref PubMed Scopus (1787) Google Scholar, 37Wirrell E.C. Laux L. Donner E. Jette N. Knupp K. Meskis M.A. et al.Optimizing the diagnosis and management of Dravet syndrome: recommendations from a North American consensus panel.Pediatr Neurol. 2017; 68: 18-34.e3Abstract Full Text Full Text PDF PubMed Scopus (124) Google Scholar], these newer treatments are likely to be considered as early second-line treatment [[38]Cross J.H. Caraballo R.H. Nabbout R. Vigevano F. Guerrini R. Lagae L. Dravet syndrome: treatment options and management of prolonged seizures.Epilepsia. 2019; 60: S39-S48PubMed Google Scholar]. Fenfluramine is currently labeled for treatment at a minimum age of 2 years [[21]FINTEPLA® (fenfluramine) [prescribing information]. Zogenix, Inc.: Emeryville, CA; 2020.Google Scholar], with pivotal trials conducted in patients at a mean age of ∼9 years [[8]Lagae L. Sullivan J. Knupp K. Laux L. Polster T. Nikanorova M. et al.Fenfluramine hydrochloride for the treatment of seizures in Dravet syndrome: a randomised, double-blind, placebo-controlled trial.Lancet (London, England). 2019; 394: 2243-2254Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar]. However, disease onset most often occurs before 1 year of age, and minimizing seizure burden from an early stage in the disease could result in a better long-term prognosis for cognitive outcomes and other non-seizure comorbidities (1) as a direct result of seizure control [8Lagae L. Sullivan J. Knupp K. Laux L. Polster T. Nikanorova M. et al.Fenfluramine hydrochloride for the treatment of seizures in Dravet syndrome: a randomised, double-blind, placebo-controlled trial.Lancet (London, England). 2019; 394: 2243-2254Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar, 29Bishop KI, Isquith PK, Gioia GA, Gammaitoni AR, Farfel G, Galer BS, et al. Improved everyday executive functioning following profound reduction in seizure frequency with fenfluramine: analysis from a phase 3 long-term extension study in children/young adults with Dravet syndrome. Epilepsy Behav 2021;121:108024.Google Scholar, 39Gavrilovic A. Toncev G. Boskovic Matic T. Vesic K. Ilic Zivojinovic J. Gavrilovic J. Impact of epilepsy duration, seizure control and EEG abnormalities on cognitive impairment in drug-resistant epilepsy patients.Acta Neurol Belg. 2019; 119: 403-410Crossref PubMed Scopus (12) Google Scholar, 40Seidenberg M. O'Leary D.S. Berent S. Boll T. Changes in seizure frequency and test-retest scores on the Wechsler Adult Intelligence Scale.Epilepsia. 1981; 22: 75-83Crossref PubMed Scopus (66) Google Scholar, 41Helmstaedter C. Witt J.A. Hoppe C. Evaluating the mediating role of executive functions for antiepileptic drugs' effects on IQ in children and adolescents with epilepsy.Epilepsy Behav. 2019; 96: 98-103Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar, 42Dodrill C.B. Progressive cognitive decline in adolescents and adults with epilepsy.Prog Brain Res. 2002; 135: 399-407Crossref PubMed Scopus (124) Google Scholar, 43O'Reilly H. Eltze C. Bennett K. Verhaert K. Webb R. Merrett A. et al.Cognitive outcomes following epilepsy in infancy: a longitudinal community-based study.Epilepsia. 2018; 59: 2240-2248Crossref PubMed Scopus (8) Google Scholar], (2) as the result of better engagement in other early intervention and education programs to support cognitive and social development [23Villas N. Meskis M.A. Goodliffe S. Dravet syndrome: characteristics, comorbidities, and caregiver concerns.Epilepsy Behav. 2017; 74: 81-86Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar, 26Nabbout R. Auvin S. Chiron C. Irwin J. Mistry A. Bonner N. et al.Development and content validation of a preliminary core set of patient- and caregiver-relevant outcomes for inclusion in a potential composite endpoint for Dravet syndrome.Epilepsy Behav. 2018; 78: 232-242Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar, 27Nabbout R. Auvin S. Chiron C. Thiele E. Cross H. Scheffer I.E. et al.Perception of impact of Dravet syndrome on children and caregivers in multiple countries: looking beyond seizures.Dev Med Child Neurol. 2019; 61: 1229-1236Crossref PubMed Scopus (17) Google Scholar], and (3) due to the inherent pharmacological activity of fenfluramine [30Sourbron J. Smolders I. de Witte P. Lagae L. Pharmacological analysis of the anti-epileptic mechanisms of fenfluramine in scn1a mutant zebrafish.Front Pharmacol. 2017; 8: 191Crossref PubMed Scopus (66) Google Scholar, 31Martin P. de Witte P.A.M. Maurice T. Gammaitoni A. Farfel G. Galer B. Fenfluramine acts as a positive modulator of sigma-1 receptors.Epilepsy Behav. 2020; 105: 106989https://doi.org/10.1016/j.yebeh.2020.106989Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar, 33Tiraboschi E. Martina S. van der Ent W. Grzyb K. Gawel K. Cordero-Maldonado M.L. et al.New insights into the early mechanisms of epileptogenesis in a zebrafish model of Dravet syndrome.Epilepsia. 2020; 61: 549-560Crossref PubMed Scopus (22) Google Scholar]. As Dravet is diagnosed earlier and earlier, the question arises as to whether fenfluramine could be utilized in younger patients (before the age of 2 years). Although developmental delay has been considered to be associated with seizure burden, evidence now suggests that mutations in SCN1A encoding the α1 subunit of Nav1.1 likely contribute to cognitive outcomes independently of seizures [5Wheless J.W. Fulton S.P. Mudigoudar B.D. Dravet syndrome: a review of current management.Pediatr Neurol. 2020; 107: 28-40Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar, 44Nabbout R. Chemaly N. Chipaux M. Barcia G. Bouis C. Dubouch C. et al.Encephalopathy in children with Dravet syndrome is not a pure consequence of epilepsy.Orphanet J Rare Dis. 2013; 8: 176https://doi.org/10.1186/1750-1172-8-176Crossref PubMed Scopus (102) Google Scholar]. As highlighted above, ongoing studies are evaluating the pharmacological role of serotonergic and/or σ1 receptor targets in the antiseizure and neuroprotective mechanisms of fenfluramine [30Sourbron J. Smolders I. de Witte P. Lagae L. Pharmacological analysis of the anti-epileptic mechanisms of fenfluramine in scn1a mutant zebrafish.Front Pharmacol. 2017; 8: 191Crossref PubMed Scopus (66) Google Scholar, 31Martin P. de Witte P.A.M. Maurice T. Gammaitoni A. Farfel G. Galer B. Fenfluramine acts as a positive modulator of sigma-1 receptors.Epilepsy Behav. 2020; 105: 106989https://doi.org/10.1016/j.yebeh.2020.106989Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar]. Assessing how cognitive outcomes are affected by seizure burden versus non-seizure effects of the underlying SCN1A mutations will be necessary when clinicians consider how patients respond to future treatments [[44]Nabbout R. Chemaly N. Chipaux M. Barcia G. Bouis C. Dubouch C. et al.Encephalopathy in children with Dravet syndrome is not a pure consequence of epilepsy.Orphanet J Rare Dis. 2013; 8: 176https://doi.org/10.1186/1750-1172-8-176Crossref PubMed Scopus (102) Google Scholar]. As our understanding of disease pathogenesis for developmental and epileptic encephalopathies with defined genetic etiology improves, precision medicine and targeted gene therapy approaches offer the possibility of reaching even higher levels of therapeutic efficacy. Treatment efficacy of fenfluramine in patients with Dravet syndrome may be attributable to the high proportion of patients who share a common genetic etiology, given that 70% to 85% of patients with Dravet syndrome present with mutations in the SCN1A gene [[5]Wheless J.W. Fulton S.P. Mudigoudar B.D. Dravet syndrome: a review of current management.Pediatr Neurol. 2020; 107: 28-40Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar]. In the new genomic era, targeted gene therapy approaches that augment or restore gene function show the most promise for greatest efficacy. Targeted Augmentation of Nuclear Gene Output (TANGO) technology and CRISPR-Cas9 gene activation approaches have shown efficacy in seizure reduction and SUDEP prevention in mouse models [45Han Z. Chen C. Christiansen A. Ji S. Lin Q. Anumonwo C. et al.Antisense oligonucleotides increase Scn1a expression and reduce seizures and SUDEP incidence in a mouse model of Dravet syndrome.Sci Transl Med. 2020; 12: eaaz6100https://doi.org/10.1126/scitranslmed.aaz6100Crossref PubMed Google Scholar, 46Colasante G. Lignani G. Brusco S. Di Berardino C. Carpenter J. Giannelli S. et al.dCas9-based Scn1a gene activation restores inhibitory interneuron excitability and attenuates seizures in Dravet syndrome mice.Mol Ther. 2020; 28: 235-253Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar]. Stoke Therapeutics has initiated trials in patients with Dravet syndrome using the TANGO technology platform (http://stoketherapeutics.com). Whereas CRISPR technology is a powerful tool for gene editing, TANGO and other strategies aim to increase expression of the functional copy of the SCN1A gene. Encoded Therapeutics is exploring upregulation of SCN1A expression in GABAergic inhibitory neurons via an adeno-associated viral vector delivery system that has been shown to reverse key phenotypes in a mouse model of Dravet syndrome (EX101; http://encoded.com) [[47]Young AN, Tanenhaus A, Chen M, McLaughlin J, Belle A, Li J, et al. A GABA-selective AAV vector-based approach to up-regulate endogenous Scn1a expression reverses key phenotypes in a mouse model of Dravet syndrome. Oral presentation at: American Society of Gene & Cell Therapy Annual Meeting; April 29-May 2, 2019; Washington, DC.Google Scholar]. Tevard Biosciences has developed an mRNA stabilization approach using a viral vector to enhance expression of the functional SCN1A gene copy (http://tevard.com). As new antiepileptic drugs and gene therapies come onto the market and into the therapeutic pipeline, these treatments should be evaluated against the demonstrated efficacy of fenfluramine. These expectations will continue to set standards for all future therapies, including targeted and gene therapies. Fenfluramine has raised the bar for evaluating the efficacy of future therapies in Dravet syndrome, both for seizures and for critically important patient-centered outcomes. Not only does the unprecedented level of seizure control demonstrated with fenfluramine treatment set a new standard for what can be achieved in Dravet syndrome, it also provides important insights into treatment for other developmental and epileptic encephalopathies. The convergence of genomic and precision medicine, diagnostics, and treatment strategies in recent years has led to re-envisioned achievable efficacy for various epilepsy syndromes. There is still a long way to go before the ultimate goal of seizure freedom and normal cognitive functioning becomes a reality, but recent advances will have important implications for research, diagnosis, and treatment of epilepsy syndromes moving forward.