Progress Report on New Antiepileptic Drugs: A Summary of the Fourteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XIV). II. Drugs in More Advanced Clinical Development

The Fourteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XIV) took place in Madrid, Spain, on May 13?16, 2018 and was attended by 168 delegates from 28 countries. The conference provided a forum for professionals involved in basic science, clinical research, regulatory affairs, and clinical care to meet and discuss the latest advances related to discovery and development of drugs and devices aimed at improving the management of people with epilepsy.

This progress report provides a summary of findings on investigational compounds for which data from both preclinical studies and studies in patients were presented. The compounds reviewed include anakinra, cannabidiol, cannabidivarin, fenfluramine, ganaxolone, medium?chain fatty acids, padsevonil, and the valproic derivatives valnoctamide and sec?butylpropylacetamide. On June 25, 2018, the US Food and Drug Administration approved a standardized formulation of cannabidiol oral solution for the treatment of seizures associated with Lennox-Gastaut syndrome and Dravet syndrome in patients 2 years and older.

The report shows that there continues to be a steady flow of potential antiepileptic drugs progressing to clinical development. Many of these compounds show innovative mechanisms of action, and some have already been tested in placebo?controlled randomized controlled trials, with promising efficacy and safety results.

Pilot Study: Rapamycin has Positive Effects on Seizures in Tuberous Sclerosis Complex in Years 1-2 but Effects Decline After Year 2

PURPOSE: The purpose of this study was to evaluate the long-term results of eight cases diagnosed with tuberous sclerosis complex (TSC) and receiving rapamycin therapy because of epileptic seizures and/or accompanying TSC findings.

METHOD: Rapamycin therapy was initiated at a dose of 1.5?mg/m2. Seizure frequency, electroencephalographic (EEG) findings, renal and cranial imaging findings, and cutaneous lesions over 3- to 6-month periods during follow-up and treatment were evaluated.

RESULTS: Four girls and four boys aged 4-16?years at the start of rapamycin therapy and now aged 9-24?years were evaluated. Duration of rapamycin therapy was 1-5?years, and the monitoring period after commencement of rapamycin therapy lasted 5-8?years. Positive effects were observed at 9-12?months in three out of six cases of renal angiomyolipoma (AML) and in the second year of treatment in one. An increase in AML dimensions was observed in three cases after treatment was stopped. Seizure control was established in the first year of rapamycin therapy in all cases. An increased frequency of seizures was observed in three cases after the second year of treatment. No seizure recurrence was determined in the second year of treatment with rapamycin in five out of eight cases. Recurrence of seizure was observed in 6-12?months after the discontinuation of rapamycin in three cases.

CONCLUSION: Rapamycin therapy exhibits positive effects on epileptic seizures in cases of TSC in 1-2 ?years but these positive effects on seizure control of rapamycin therapy decline after the second year. Larger case series are still needed to determine the duration and effectiveness of treatment in childhood.

High Vigabatrin Dosage is Associated with Lower Risk of Infantile Spasms Relapse Among Children with Tuberous Sclerosis Complex

After initially successful treatment of infantile spasms, the long-term cumulative risk of relapse approaches 50%, and there is no established protocol to mitigate this risk. Although vigabatrin may be an effective means to prevent relapse, there is little guidance as to ideal duration and dosage. Using a cohort of children with infantile spasms and tuberous sclerosis complex (TSC), we evaluated the potential association of post-response VGB treatment and the rate of infantile spasms relapse. Patients with infantile spasms and clinical response to vigabatrin were identified among a multicenter prospective observational cohort of children with TSC. For each patient we recorded dates of infantile spasms onset, response to vigabatrin, relapse (if any), and quantified duration and dosage of vigabatrin after response. Time to relapse as a function of vigabatrin exposure was evaluated using survival analyses.

We identified 50 children who responded to VGB. During a median follow-up of 16.6 months (IQR 10.3-22.9), 12 (24%) patients subsequently relapsed after a median of 7.8 months (IQR 3.1-9.6). Relapse occurred after VGB discontinuation in four patients, and during continued VGB treatment in the remaining eight cases. In survival analyses, risk of relapse was unaffected by the presence or absence of VGB treatment (HR 0.31, 95%CI 0.01-28.4, P?=? 0.61), but weighted-average dosage was associated with marked reduction in relapse risk: Each 50 mg/kg/d increment in dosage was associated with 61% reduction in risk (HR 0.39, 95%CI 0.17 – 0.90, P?=? 0.026).

This study suggests that the risk of infantile spasms relapse in TSC may be reduced by high-dose vigabatrin treatment.

Neurelis Files New Drug Application with the FDA for VALTOCO™ (Diazepam Nasal Spray), An Investigational Treatment for Pediatric, Adolescent, and Adult Epilepsy Patients

Neurelis, Inc. announced that the company has submitted a New Drug Application (NDA) with the U.S. Food and Drug Administration (FDA) for VALTOCOTM (diazepam nasal spray) as a treatment for epilepsy patients six years and older who experience increased bouts of seizure activity, also known as cluster or acute repetitive seizures. Earlier this year, the FDA provided conditional acceptance for use of the name “VALTOCO” for the product previously referred to in clinical development as “NRL-1”.

VALTOCO, Neurelis’ lead product candidate, is a proprietary formulation of diazepam incorporating the unique combination of a vitamin E-based solution and Intravail® absorption enhancement. The FDA previously granted Neurelis both Orphan Drug designation for VALTOCO in November of 2015 and Fast Track designation in December of 2016. There are over 3.4 million people with epilepsy in the United States with approximately 200,000 new patients diagnosed each year. Despite the availability of chronic, daily oral medications to control epilepsy, a significant number of these patients continue to experience seizures. Of these uncontrolled patients, about 170,000 are at risk for cluster or acute repetitive seizures.

Study Reveals New Therapeutic Target for Pediatric Tumor-Associated Intractable Epilepsy

Featuring the work of CURE Grantee Dr. Jeong Ho Lee

Pediatric brain tumors are characterized by frequent complications due to intractable epilepsy compared to adult brain tumors. However, the genetic cause of refractory epilepsy in pediatric brain tumors has not been elucidated yet, and it is difficult to treat patients because the tumors do not respond to existing antiepileptic drugs and debilitate children’s development.

A research team led by Professor Jeong Ho Lee of the Graduate School of Medical Science and Engineering has recently identified a neuronal BRAF somatic mutation that causes intrinsic epileptogenicity in pediatric brain tumors. Their research results were published online in Nature Medicine on September 17.

Seizure Outcomes Best With Complete Resective Surgery In Pediatric Patients With Polymicrogyria

Abstract

OBJECTIVE: Polymicrogyria (PMG) is a common malformation of cortical development. Many patients with PMG will have medically refractory epilepsy but the role of epilepsy surgery is unclear. The objective of this study was to assess the efficacy of surgical resection/disconnection in achieving seizure control in pediatric patients with PMG.

METHODS: A retrospective review of children undergoing epilepsy surgery for PMG between 2002 and 2017 at The Hospital for Sick Children in Toronto, Canada, was performed.

RESULTS: A total of 12 children aged 6 months to 17.8 years (median 8.8 years) underwent resective surgery (7 children) or functional hemispherectomy (5 children). Gross total resection or complete disconnection of PMG was carried out in 7 of 12 children. Follow-up duration was between 1 and 9 years (median 2.1 years). Nine children remained seizure-free at last follow-up. Complete resection or disconnection of PMG led to seizure freedom in 6 of 7 patients (86%), whereas subtotal resection produced seizure freedom in 3 of 5 patients (60%).

SIGNIFICANCE: We present one of the largest surgical series of pediatric polymicrogyria patients. Seizure outcomes were best with complete resection/disconnection of polymicrogyria. However, tailored resections based on electroclinical and neuroradiologic data can produce good outcomes and remain an appropriate strategy for patients with extensive polymicrogyria.

Diagnostic Efficacy And Study Quality Of Home Video Telemetry And Inpatient Video Telemetry For Epilepsy Are Similar In Pediatric Patients

Abstract

PURPOSE: Home Video Telemetry (HVT) combines ambulatory EEG with simultaneous video recording. No previous reports have compared HVT and inpatient video telemetry (IVT) in a purely paediatric population. This study compares HVT and IVT in this group in terms of diagnostic efficacy, recording quality and acceptability to parents/carers.

METHODS: 33 HVT and 29 IVT patients aged 1-17 years were included. Information regarding patient demographics, ictal capture, diagnostic utility, recording quality (e.g. video clarity, EEG artefacts) and parent/carer preferences was documented. Difficulties using HVT equipment were recorded.

RESULTS: 62% of IVT patients and 64% of HVT patients had typical attacks during the recording. 59% of IVT and 70% of HVT recordings were considered to have answered the referral question. Study quality was similar in both groups. In HVT studies the rate of equipment difficulties was 52%; problems included camera positioning and failure to turn on the infrared button at night. Diagnostic information was lost in 15% of patients. 76% of parents/carers of HVT patients would choose this investigation again.

CONCLUSIONS: The diagnostic efficacy and study quality of home video telemetry and inpatient video telemetry are similar in paediatric patients. Home video telemetry is acceptable to most parents/carers. User error may compromise the investigation in a minority of cases but did not impact on diagnostic utility. Adoption of home video telemetry investigation could provide an accessible and economic alternative to inpatient video telemetry.

Status Epilepticus Associated with Significant Mortality and Cost

Abstract

PURPOSE: To summarize the epidemiology, morbidity, mortality, and costs of status epilepticus (SE) in the pediatric population.

METHOD: Review of the medical literature.

RESULTS: The overall incidence of pediatric SE is roughly 20 per 100,000 children per year, with overall mortality of 3%. Underlying etiology is the biggest risk factor for SE, with symptomatic (acute > remote) etiologies associated with worse outcomes. The most common cause of SE in children is febrile SE, though this entity occurs primarily in early childhood. After a first episode, the risk of recurrence is similar to the risk after a first unprovoked seizure (25-40%). SE is expensive, regularly costing more than $10,000 per episode and often more than $100,000 for refractory cases.

CONCLUSION: Status epilepticus is not an uncommon neurologic emergency and depending on the associated etiology can carry significant morbidity, mortality, and cost especially if treatment is not performed in a timely manner.

Trend Of Increased Subsequent Epilepsy In Children With Recurrent Febrile Seizures: A Retrospective Matched Cohort Study.

Abstract

PURPOSE: Trends of epilepsy in children were correlated with febrile seizure (FS) in a previous retrospective study. In the present study, the authors obtained relevant data from a nationwide cohort database to investigate trends in subsequent epilepsy in children with a history of recurrent FS.

METHODS: A total of 10,210 children with FS comprised the cohort. The diagnosis date was used as the index date. A comparison cohort was randomly matched with each case based on age, sex, urbanization level, parents’ occupation, and index date. Cox proportional hazard regression was performed to estimate the hazard ratio and confidence interval of FS-associated epilepsy.

RESULTS: This retrospective cohort study included 7729 children with FS and a comparison cohort of 30,916 children. The incidence of epilepsy was 11.4-fold higher in the FS cohort than in the comparison cohort (5.67 vs. 0.49 per 1000 person-years, respectively). Compared with the comparison cohort, the epilepsy incidence rate ratio increased in children with admissions for FS, from 8.62 at 1 admission to 26.2 at ?2 admissions (95% CI 6.80-10.9, and 19.78-34.8, respectively; p for trend < 0.0001).

CONCLUSION: Febrile seizures may increase the risk for subsequent epilepsy in children. Recurrent febrile seizures increased the cumulative incidence of epilepsy.