Comparative efficacy and safety of stiripentol, cannabidiol and fenfluramine as first‐line add‐on therapies for seizures in Dravet syndrome: A network meta‐analysis

Epilepsia Open, Journal Year: 2024, Volume and Issue: 9(2), P. 689 - 703

Published: March 1, 2024

Abstract Objectives Stiripentol, fenfluramine, and cannabidiol are licensed add‐on therapies to treat seizures in Dravet Syndrome (DS). There no direct or indirect comparisons assessing their full dose regimens, across different jurisdictions, as first‐line DS. Methods We conducted a systematic review frequentist network meta‐analysis (NMA) of randomized controlled trial (RCT) data for DS therapies. compared the proportions patients experiencing: reductions from baseline monthly convulsive seizure frequency (MCSF) ≥50% (clinically meaningful), ≥75% (profound), 100% (seizure‐free); serious adverse events (SAEs); discontinuations due AEs. Results identified relevant two placebo‐controlled RCTs each drug. Stiripentol 50 mg/kg/day fenfluramine 0.7 had similar efficacy achieving meaningful) (profound) MCSF (absolute risk difference [RD] stiripentol versus 1% [95% confidence interval: −20% 22%; p = 0.93] 6% [−15% 27%; 0.59], respectively), both were statistically superior ( < 0.05) regimens (10 20 mg/kg/day, with/irrespective clobazam) these outcomes. was seizure‐free intervals (RD 26% [CI: 8% 44%; 0.01]) cannabidiol. significant differences experiencing SAEs. The AEs lower stiripentol, although trials shorter. Significance This NMA RCT indicates therapy DS, is at least effective more than reducing seizures. No incidence SAEs between three agents observed, but may have These results inform clinical decision‐making continued development guidelines treatment people with Plain Language Summary study drugs (stiripentol, cannabidiol) used alongside other medications managing severe type epilepsy called found that similarly best drug stopping completely based on available data. All rates side effects, chance being stopped effects. information can help guide choices

Language: Английский

---

Practical considerations for the use of fenfluramine to manage patients with Dravet syndrome or Lennox–Gastaut syndrome in clinical practice

Epilepsia Open, Journal Year: 2024, Volume and Issue: 9(5), P. 1643 - 1657

Published: July 4, 2024

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

Language: Английский

---

Efficacy of Stiripentol Beyond Dravet Syndrome: A Retrospective Medical Record Review of Patients with Drug-Resistant Epilepsies

Neurology and Therapy, Journal Year: 2025, Volume and Issue: unknown

Published: May 3, 2025

Language: Английский

---

A comprehensive review of evolving treatment strategies for Dravet syndrome: Insights from randomized trials, meta-analyses, real-world evidence, and emerging therapeutic approaches

Epilepsy & Behavior, Journal Year: 2024, Volume and Issue: 162, P. 110171 - 110171

Published: Nov. 29, 2024

Language: Английский

---

Antiseizure medication prescribing in people with Dravet syndrome: An analysis of real‐time administrative data

Epilepsia Open, Journal Year: 2024, Volume and Issue: 10(1), P. 336 - 341

Published: Dec. 5, 2024

Since 2018, three new antiseizure medications (ASMs) received FDA approval for Dravet syndrome (DS) in the U.S: cannabidiol, stiripentol, and fenfluramine. Yet, uptake of these ASMs routine clinical practice is unknown. We use ICD-10 codes DS (implemented 2020) to estimate ASM receipt patients with DS. analyzed TriNetX Network, a real-time electronic health record-based dataset linked prescription data encompassing all 50 states U.S. After identifying care encounters 2021 2022 (via codes), we examined prescribing year following claim: 2023, respectively. retrieved 387 451 receiving claims 2022, Clobazam, diazepam, valproate, midazolam, clonazepam, levetiracetam, cannabidiol were most common used (29%-44%). Stiripentol fenfluramine was limited (7%-16%); two ASMs, considered second-line therapies DS, prescribed less often than third-line or beyond. Cannabidiol, rates remained nearly identical cohorts. Our suggests that fenfluramine, and, an extent, may be underused large, diverse, primarily U.S.-based population PLAIN LANGUAGE SUMMARY: In analysis routinely-collected U.S., found Syndrome (i.e., cannabidiol) has been since 2022. Even though stiripentol are treatments syndrome, they frequently medicines These findings raise concern underutilization United States.

Language: Английский

---

Addressing the problems of treatment failure in epilepsy: You cannot fix what you do not understand

Epilepsia, Journal Year: 2024, Volume and Issue: 65(8), P. 2248 - 2254

Published: June 15, 2024

"No seizures, no side effects" has been the mantra for epilepsy therapy discovery past several decades. Unfortunately, we are closer to achieving that goal today than when it was first uttered. The prevalence of treatment failure remains virtually unchanged despite many new medications available, and effects continue be a major cause failure.1-7 Perhaps one greatest obstacles face in reaching "promised land" seizure freedom devoid interfering consequences is really do not know why fail or present some patients but others. We often told learn from our mistakes, epilepsy, move on failures without ever learning drug failed other patients. One contributing may rooted how community identifies treatments. Fundamentally, chronic disease requires ongoing suppress seizures unpredictable occurrence. It also different causes types pathophysiology. At present, process relies primarily short-term acute testing (single doses, at most, weeks repeated dosing), with end point measurable effect duration severity single evoked doses produce gross motor behavior such as rotorod test.8-10 Complete suppression rarely seen, there consistent tests subtle effects. In clinic, success measured self-reported reduction number spontaneous epileptic seizures. From patient's perspective, true an all-or-none phenomenon, which determined over months years treatment. Significant incomplete less meaning patients, because their lives still compromised (sometimes devastated) by uncontrolled There reports improved control Dravet syndrome Lennox–Gastaut specific drugs (e.g., clobazam, stiripentol, fenfluramine), complete seen.11 A statistically significant frequency considered scientific success, want—or even need—total will only interfere put them increased risk accidental injury death automobile accidents). Side these treatments mentioned, generically, focus control. Although toxicity certainly "problem" patient, they contributor failure. current definition resistance specifies two otherwise well tolerated.12 reality most adjusted until quality life, failure.13, 14 If absence required designate compound failure, then can never called failures, commonly stopped result trials, withdrawal high 40% unblinded, open-dose adjustment allowed.3-5 have good explanation Moving forward identify basis so identified minimize chances longer term. topic cancer microbiological research years.15, 16 time become critical research. nothing this paper should criticism process. This designed potential successful purpose, reduced rate treatment.2, 17 hypothesizing outcomes come simply additional compounds (which continue); rather, understanding fail, particularly Until understand progress much more difficult. New approaches essential.18 Treatment uniform entity; instead, patterns see clinic.19 common pattern severity, life. another pattern, medicines discernable Still response controlled varying periods before return controlled. These observations mechanistic implications. To help possible underlying causes, propose include both (1) medicine occurrence (2) timeline reappearance following period confounding issue interpretation natural history disease; if untreated, would get better worse? mechanisms (patterns appearance breakthrough seizures) likely overlapping. categories proposing steps need develop picture histories epilepsies. concepts applied collective Examples be, "There carbamazepine, levetiracetam resulted change were lamotrigine" "Three seizures." suggest illustrations, here possible. apply individual's response. person medication respond very another.3-6, 20 Another response—or opposite response—to same medications. note appear after treatment, suggesting functional changes occurred brain time. significantly reduce occur. individual multiple types, (but all) suppressed (Figure 1A). could variations distribution alterations local pharmacokinetics levels circuits fall below threshold quickly. Little known about through pathology affects movement. Neither nor clinical affected 1B). suggests directed wrong target unable reach regions circuit. Seizures initially controlled, return, cases returning pretreatment dose 1C). cases, years. While patient receiving therapy, under again. related brain, either treatment-induced brain. derive subtype receptors channels, access key components Change generic source becoming control.21-23 particular situation pharmacokinetic cause. impair awareness function auras) person's life 1D). fits resistance, typically persistence auras, aggressive However, provide us information. As noted earlier, where go, goes involved spread actually begins.24 variant situation, autoimmune encephalitis metabolic disorder; Figure 1E). standard medical resolve addressed. category conventional cannot influence seizure-causing aspect disease. Some medication(s) tried subsequent medications.2, 3, 5, 25 successfully controls varies person. observation implications, differences sensitivity drugs. getting main others not. type carbamazepine generalized epilepsies). remain therapeutic level circuit surpassing 2). efficacy implies effective tissue achieved circuit, occur toxic reached outside differential sensitivities part factors sodium channel) having parts difference between thresholds given wide narrow direction. When talk people failing effects, efficacy, monolithic entity. "The couldn't tolerate three drugs." Most left binary classification. Failure next trial. symptoms contribute poor tolerance medication, classification might insight mechanisms. range broad. Motor, balance, coordination issues reported, blurring vision. sedation, cognitive slowing, behavior. Systemic consequences, including weight gain loss, treatment-associated issues. Headaches limited usefulness Allergic reactions prevent limit use drug, overall nervous system. Other broad "stopped taking medication" reported rates up 40%, what any drug. higher, accept exchange Just found useful classify epilepsies, model preclinical testing. commentary, described features epilepsy. emphasize multifactorial. minimum, defined terms reduction, persistent noninterfering) temporal (present beginning, relapse months). frames, along variable syndrome, require investigation, them. Much screening does actual rather behavioral surrogates hind-limb extension surrogate tonic component tonic–clonic seizure). Those protocols electrographic generally aimed acute, induced studies generate data evaluated reflect reality. Time usually recognized medication. modeling interplay laboratory critically needed. must establish tested clinic needs greater detail allow design translational focused problem, lead alignment worlds. Simply classifying into step examine who compare form did well. Would studying auras noninterfering/incomplete control? Animal models testable hypotheses. Table 1 highlights addressed going forward. Classify timelines (epidemiology). Identify targets locations. Define circuits. Evaluate regional neurological Examine contributions pharmacokinetics. Determine whether long-term exposure and/or alters structure importantly, approach needed perform relying results models. important agree emphasis aspects toxicity. Laboratory involve time- dependent protocols, define classes conditions suggested replicated. least shown repeat dosing, rapidly loses its doses.30, 31 demonstrate term seen Using existing researchers insights analyze time-dependent lose Without kinds studies, solutions problem evade us. epidemiological points made before, albeit ways. Calls ways identifying therapies 2 decades.32, 33 unfortunate make those calls. reasons drug-treatment None. E.H.B. receives support services International League Against Epilepsy University Virginia. F.E.D. equity interest previously received discounted equipment consultant fees Epitel. confirm read Journal's position ethical publication affirm report guidelines.

Language: Английский

---

Utilizing an acute hyperthermia‐induced seizure test and pharmacokinetic studies to establish optimal dosing regimens in a mouse model of Dravet syndrome

Epilepsia, Journal Year: 2024, Volume and Issue: unknown

Published: Aug. 30, 2024

The current standard of care for Dravet syndrome (DS) includes polytherapy after inadequate seizure control with one or more monotherapy approaches. Treatment guidelines are often based on expert opinions, and finding an optimal balance between adverse drug effects can be challenging. This study utilizes the efficacy pharmacokinetic assessment a second-line treatment regimen that combines clobazam sodium valproate add-on as proof-of-principle approach to establish effective therapeutic in DS mouse model.

Language: Английский

---

Use of Stiripentol in Patients with Dravet Syndrome: Common Practice Among Experts in Spain

Neurology and Therapy, Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 4, 2024

Despite considerable evidence for the efficacy and safety of stiripentol in Dravet syndrome (DS), some aspects use remain challenging clinical practice, such as dose titration adjustment concomitant antiseizure medications (ASMs) to prevent potential adverse effects. To (1) provide practical recommendations on initiation treatment patients with DS, (2) evaluate its effectiveness patient, (3) guide management drug interactions other monitoring. Six Spanish neurologists (the authors) expertise pediatric adult DS held a meeting early 2024 develop expert regarding based review literature their common experience. According these recommendations, can be administered any age, although vary according age group. Individualized ASMs, valproic acid clobazam or drugs specifically (i.e., fenfluramine), at during treatment, mitigate interactions, thereby increasing long-term tolerability treatment. In specific cases, doses > 50 mg/kg/day may contemplated, acute administration considered control refractory status epilepticus. Blood tests should performed before starting stiripentol, 3, 6, 12 months after then annually, except event effects, when additional testing necessary. Most effects adequately managed by adjusting medications. These easily adapted different countries, increase physicians' confidence monitoring thus facilitating effective improving outcomes. this article, six individuals (DS) developed academic experience syndrome. is rare severe form lifelong genetic epilepsy that first develops infancy, impairs neurologic psychomotor development, increases risk premature death. Stiripentol an medication which there but combination minimize practice. The presented here guidance assessment interaction It hoped will facilitate improve

Language: Английский

---

How Has the Treatment of Polish Children with Dravet Syndrome Changed? Future Perspectives

Biomedicines, Journal Year: 2024, Volume and Issue: 12(6), P. 1249 - 1249

Published: June 4, 2024

Background: This report focuses on the treatment histories of 21 patients diagnosed with Dravet syndrome (DRVT) under care Mother and Child Institute in Warsaw. paper aims to present typical schemes for drug-resistant epilepsy, as well highlight influence genetic diagnosis pharmacotherapeutic management an economic analysis hospitalization costs. will also summarize effectiveness latest drugs used DRVT. Methods: Clinical data were collected retrospectively from available medical records. The anticonvulsant was assessed based epileptic seizure diaries observations by caregivers pediatric neurologists. Results: study group (n = 21) consisted aged 3–26 years. Orphan dedicated introduced all due diagnosis, which significantly improved patients’ clinical conditions. breakthrough stiripentol (in 16/21) fenfluramine 3/21). Conclusions: In recent years, molecular genetics has rapidly developed Poland, along a steady increase knowledge among profession. Early precise provides opportunity target high efficacy.

Language: Английский

---

Fenfluramine treatment for Dravet syndrome: Long term real‐world analysis demonstrates safety and reduced health care burden

Epilepsia, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 30, 2024

Fenfluramine (FFA), stiripentol (STP), and cannabidiol (CBD) are approved add-on therapies for seizures in Dravet syndrome (DS). We report on the long-term safety health care resource utilization (HCRU) of patients with DS treated FFA under an expanded access program (EAP).

Language: Английский

---