16th International Epilepsy Colloqium

Associate Professor

Prof. Dr.

Prof. Dr. med.

PD Dr. med.

Univ.-Prof. Dr. med.

Real-world experience of cannabidiol in conjunction with clobazam for the treatment of seizures associated with Lennox-Gastaut syndrome and Dravet syndrome: Results from a retrospective multicentre study in Germany

Treatment of drug refractory epilepsy

Introduction: Lennox–Gastaut syndrome (LGS) and Dravet syndrome (DS) are rare and debilitating forms of epilepsy, characterised by recurrent, severe, drug-resistant seizures starting in infancy or early childhood, an increased risk of sudden unexpected death in epilepsy (SUDEP), and neurodevelopmental impairments. A non-psychotropic, plant-derived, highly purified formulation of cannabidiol (CBD; Epidyolex®, 100 mg/mL oral solution) has been approved in the EU for use in patients aged ≥2 years for the adjunctive treatment of seizures associated with LGS or DS in conjunction with clobazam (CLB), or for the adjunctive treatment of seizures associated with tuberous sclerosis complex. A retrospective, multicentre study was conducted to evaluate the real-world use of CBD oral solution in patients with drug-resistant epilepsies.Methods: We performed a retrospective chart review of patients with drug-resistant epilepsies and treated with CBD at six epilepsy centres in Germany. We analysed patient and treatment characteristics, seizure outcomes, treatment retention rates (percentage of patients remaining on CBD treatment at time of assessment) and adverse events (AEs) for up to 12 months. Here, we present data for patients treated concomitantly with CBD and CLB.Results: We identified 126 patients (102 LGS; 24 DS) with a mean (standard deviation; SD) age of 23.2 (15.8) years and a mean (SD) age of epilepsy onset of 3 (3.7) years (Table 1). Patients were highly refractory to ASMs, with a median number of prior ASMs of 6 (range: 1–24), and concomitant ASMs of 3 (range: 1–7). During treatment with CBD+CLB, the most common concomitant ASMs were valproate (n=70, 55.6%), lamotrigine (n=38, 30.2%), brivaracetam (n=26, 20.6%), lacosamide (n=22, 17.5%), perampanel (n=22, 17.5%) and rufinamide (n=20, 15.9%). The median target CBD dose was 11.1 mg/kg/day in the total population (17.8, 15.8 and 9.7 mg/kg/day in the &lt;6 years, 6–17 years and ≥18 years subgroups, respectively). A ≥50% reduction in total seizures was achieved by 47.5% of patients at 3 months (35.7–52.6% across age groups) and by 45.5% of patients at 12 months (44.4–46.2% across age groups) (Table 2). Of the patients who experienced generalized tonic-clonic seizures (GTCS) at baseline, a ≥50% reduction in GTCS was achieved by 63.0% of patients at 3 months (60.7–66.7% across age groups) and 56.9% of patients at 12 months (50.0–75.0% across age groups) (Table 2). Median seizure days per month significantly decreased from 30 (range: 0.5–30) to 15 (range: 0–30) in the 3-month period before and after CBD+CLB treatment (p&lt;0.001). Treatment retention rates were 89.7%, 80.7% and 69.8% at 3, 6, and 12 months, respectively, and were similar across paediatric and adult groups (Table 2). Overall, 32 (25.4%) patients discontinued over the 12-month period, due to lack of treatment effectiveness (n=17, 13.5%), AEs (n=7, 5.6%), both treatment effectiveness and AEs (n=5, 4.0%) or other (n=3, 2.4%). Conclusion: In patients with severe drug refractory LGS or DS, treatment with CBD+CLB demonstrated a reduction in seizure frequency and sustained treatment retention for up to 12 months across age groups in real-world clinical practice.

Poster

Comparative effectiveness of fenfluramine versus cannabidiol in Dravet syndrome: a numbers needed to treat indirect comparison analysis

Introduction: Dravet syndrome (DS), a developmental and epileptic encephalopathy, presents with treatment-resistant seizures, including convulsive seizures; high convulsive seizure frequency increases risk of premature death. Cannabidiol and fenfluramine, the most recently FDA- and EMA-approved adjunctive treatments for DS, were compared using a numbers needed to treat (NNTs) analysis to quantify the number of individuals needing treatment to observe a positive outcome.Objectives: To determine the effectiveness of fenfluramine and cannabidiol in an indirect comparison model.Materials &amp; Methods: Data identified from a published systematic literature review of 3 randomized controlled trials (RCTs) of DS patients comparing fenfluramine (0.4 mg/kg/d with stiripentol or 0.7 mg/kg/d without stiripentol) vs placebo and 2 RCTs comparing cannabidiol (10 or 20 mg/kg/d irrespective of clobazam) vs placebo were analyzed (Metalnsight web-based tool). Reduction in monthly convulsive seizure frequency (MCSF) from baseline of ≥50% (MCSF50) and ≥75% (MCSF75) was measured. A Bayesian network meta-analysis (NMA) model with fixed effects was conducted to estimate odds ratios of MCSF response for fenfluramine and cannabidiol vs placebo. Using an estimated placebo response rate for the network, NNTs vs placebo were calculated using NMA-adjusted MCSF rates.Results: NMA-adjusted MCSF50 response rates were 17%, 29%, 33%, 86%, and 84% under placebo, cannabidiol 10 and 20 mg/kg/d, and fenfluramine 0.4 and 0.7 mg/kg/d, respectively; NNTs (credible interval) comparing each treatment (cannabidiol 10 and 20 mg/kg/day, fenfluramine 0.4 and 0.7 mg/kg/day) vs placebo were 8.0 (3.5, 144.3), 6.3 (3.5, 18.2), 1.5 (1.2, 2.4), and 1.5 (1.3, 1.9). NMA-adjusted MCSF75 response rates were 6%, 27%, 14%, 67%, and 66%; NNTs were 4.8 (2.3, 14.1), 11.7 (4.7, 63.6), 1.6 (1.1, 5.5), and 1.7 (1.2, 3.0).Conclusions: Results suggest that, within an indirect comparison model, fenfluramine is more likely to achieve MCSF reduction than cannabidiol as fewer patients need to be treated for one person to benefit. These results are subject to the limitations of indirect comparison methodology and limited available data.Supported by: UCB Pharma.

Safety and Effectiveness of Adjunctive Fenfluramine in an Open-Label Extension Study of Patients With Dravet Syndrome

Introduction: Phase 3 and interim open-label extension (OLE) studies have shown profound, durable reductions in median monthly convulsive seizure frequency (MCSF) in patients with Dravet syndrome (DS) treated with fenfluramine (FFA). We report results from the final OLE analysis of FFA use in a large cohort of patients with DS.Objectives: To describe the long-term safety and effectiveness of FFA in patients with DS treated for 3 yearsMaterials &amp; Methods: Safety was reported for patients who received ≥1 dose FFA. Key effectiveness endpoint in the modified intent-to-treat (mITT) group (from core study with baseline seizure frequency measured) was change in MCSF from core baseline vs overall OLE. Caregivers and investigators rated patients on the Clinical Global Impression-Improvement (CGI-I) scale. Descriptive statistics and Wilcoxon test for MCSF percent change from baseline were used.Results: As of 27-Jan-2023, 375 patients had enrolled; 374 received &gt;=1 dose FFA. Table 1 shows demographics and exposure. In the mITT population (n=324), median percent MCSF change from baseline over the entire OLE was -66.8%, PConclusions: This final analysis of patients with DS treated with FFA (median 2.3y) demonstrates sustained and clinically meaningful reduction in seizures and known safety profile. Supported by: UCB Pharma.

Prof.

Status Epilepticus in Shiraz, Iran: Clinical Features, Outcomes, and Economic Impact at a Referral Center

Clinical and translational research

Introduction: Status Epilepticus (SE) is a common neurological emergency (1), with outcomes and prognosis significantly affected by treatment strategies (2). Intensive care may be necessary for some patients (3) highlighting the need for timely appropriate interventions to mitigate mortality, adverse outcomes, and costs(4).Objectives: To explore the causes, outcomes, and associated costs in patients with SE to improve the quality of care through enhancements in facilities and treatment strategies.Materials &amp; Methods: This study examined SE patients admitted to Namazi Hospital in Shiraz, Iran, between 2021 and 2022. Data included medical record reviews and cost assessments. Categorical variables were reported as count (percent), and data analysis utilized the Mann-Whitney U test.Results: In this study, 130 SE patients were (77; 59% males) hospitalized aged neonates to 92 years (median: 7; IQR: 34.25). Of them, 81(62%) had epilepsy, onset from neonatal to 75 years, with nearly half before age one. Notably, 14 (17.2%) patients with epilepsy (PWE) were not taking anti-epileptic drugs (AEDs), and 30 (27%) had prior SE episodes. Most cases (88.5%) had SE on admission, while the others faced SE during hospitalization. The presumed cause of SE was an exacerbation of pre-existing epilepsy (75 cases; 57.6%), frequently due to poor drug compliance (22 cases; 17%). Cerebrovascular lesions and hypoxia were other common causes; 12 cases had unknown etiology. Fifty-seven patients (43.8%) were hospitalized in the intensive care unit (ICU) in their admission course. The mortality rate was 17% (22 cases), with three (2.3%) in a vegetative state and 20 (15.3%) with varying degrees of mild to severe disabilities. The others (85 cases; 65%) recovered back to their previous health status. Hospital stays ranged from 1 to 184 days (median: 8; IQR:15). ICU-admitted patients had significantly longer stays compared to non-ICU patients (p &lt; 0.001). Daily costs varied from 0.59 to 3971 USD (median:57.06; IQR:45.72). ICU admission incurred higher daily costs compared to non-ICU admission (p &lt; 0.001).Conclusion: Findings emphasize need for improved management strategies to reduce SE incidence, enhance treatment adherence among PWE, and optimize resource allocation in hospital settings to improve patient outcomes and mitigate economic burdens.Figure 1: Outcome of patients with Status EpilepticusTable 1: Presumed primary etiologies for Status Epilepticus. Patients may have had more than one etiology.References:Knake S, Rosenow F, Vescovi M, Oertel WH, Mueller HH, Wirbatz A, et al. Incidence of status epilepticus in adults in Germany: a prospective, population-based study. Epilepsia. 2001;42(6):714-8. doi: 10.1046/j.1528-1157.2001.01101.x. PubMed PMID: 11422324.Trinka E, Höfler J, Zerbs A. Causes of status epilepticus. Epilepsia. 2012;53 Suppl 4:127-38. Epub 2012/09/14. doi: 10.1111/j.1528-1167.2012.03622.x. PubMed PMID: 22946730.Bleck TP. Intensive care unit management of patients with status epilepticus. Epilepsia. 2007;48 Suppl 8:59-60. Epub 2008/03/11. doi: 10.1111/j.1528-1167.2007.01352.x. PubMed PMID: 18330002.Moghaddasi M, Joodat R, Ataei E. Evaluation of Short-term Mortality of Status Epilepticus and Its Risk Factors. J Epilepsy Res. 2015;5(1):13-6. Epub 2015/07/15. doi: 10.14581/jer.15003. PubMed PMID: 26157668; PubMed Central PMCID: PMC4494989.

Lecture hall 1

Poster session

Short presentations – Pharmacology

Poster session
Short presentations – Pharmacology

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Chairs

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Poster sessionShort presentations – Pharmacology

Appointment

Chairs

Programme

Poster session
Short presentations – Pharmacology