Epilepsy Research Findings: July 2018

This month’s promising epilepsy news includes the FDA approval of the cannabidiol-based drug EPIDIOLEX® for the treatment of seizures associated with Dravet Syndrome and Lennox-Gastaut Syndrome, two forms of epilepsy that are challenging to treat. This decision brings hope to families facing these difficult diagnoses. In addition, a report discusses epilepsy genetics and the utility of next-generation sequencing in the diagnosis of early-life epilepsies.

In more sobering news, a study shows that the incidence of Sudden Unexpected Death in Epilepsy (SUDEP), once thought to be greater in adults than in children, may be the same in both populations. However, we have included a report discussing the recent discovery of a potential biomarker for SUDEP, which could lead to preventative measures for this devastating occurrence.

Summaries of all highlighted studies follow below. I’ve organized the findings into four categories: Treatment Advances, Diagnostic Advances, Research Discoveries, and Also Notable.

Treatment Advances

First Prescription Formulation of Cannabidiol (CBD) Approved for Lennox-Gastaut Syndrome 

The US Food and Drug Administration (FDA) approved EPIDIOLEX® (cannabidiol/CBD) for the treatment of seizures associated with Lennox-Gastaut Syndrome (LGS) in patients two years of age or older. EPIDIOLEX® is the first prescription pharmaceutical formulation of highly purified CBD and the first in its class of antiepileptic drugs.

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New Technique Fine-Tunes Treatment for Severe Epilepsy Cases 

An advance by researchers will enable surgeons to more precisely target areas of the brain which cause debilitating symptoms in a subset of epilepsy patients. The technology, called magnetoencephalography or MEG, measures small amounts of magnetic-electrical activity on the surface of epileptic brain areas, and researchers have developed a novel way to employ it.

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Treating Refractory Epilepsy with Transcutaneous Vagal Nerve Stimulation 

This study found that transcutaneous vagal nerve stimulation (t-VNS) had no or minimal side effects and significantly reduced seizures in about one third of the enrolled patients.

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Sunovion Announces Health Canada Approval of Aptiom (eslicarbazepine acetate) as Monotherapy to Treat Partial-Onset Seizures in Adults with Epilepsy

Health Canada approved the use of Aptiom (eslicarbazepine acetate) as monotherapy for partial-onset seizures in adults with epilepsy.

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Diagnostic Advances

Next-Generation Sequencing May Improve Pediatric Epilepsy Treatment

Next-generation sequencing can improve treatment efficacy and reduce hospitalization in children with drug-resistant epilepsy, according to a study published in CNS Neuroscience & Therapeutics.

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Prediction Method for Epileptic Seizures Developed 

Scientists have proposed a generalized, patient-specific seizure-prediction method that can alert epilepsy sufferers of the likelihood of a seizure within 30 minutes, according to a paper published in Neural Networks.

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Research Discoveries

Incidence of Sudden Unexpected Death in Epilepsy in Children is Similar to Adults

SUDEP may be more common in children than widely reported, with the incidence rate of definite/probable SUDEP in children being similar to rates reported in adults.

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Heart Rate Variability in Epilepsy: A Potential Biomarker of Sudden Unexpected Death in Epilepsy Risk

These findings suggest that autonomic dysfunction is associated with SUDEP risk in patients with epilepsy due to sodium channel mutations. The relationship of heart rate variability to SUDEP merits further study; heart rate variability may eventually have potential as a biomarker of SUDEP risk. This would allow for more informed counseling of patients and families, and also serve as a useful outcome measure for research aimed at developing therapies and interventions to reduce SUDEP risk.

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Also Notable

Comparative Effectiveness of Levetiracetam vs Phenobarbital for Infantile Epilepsy

This study reports that levetiracetam may have superior effectiveness compared with phenobarbital for initial monotherapy of nonsyndromic epilepsy in infants. If 100 infants who received phenobarbital were instead treated with levetiracetam, 44 would be free from monotherapy failure instead of 16 by the estimates in this study. Randomized clinical trials are necessary to confirm these findings.

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Variability in Gene-Sequencing Panels Could Mean Missed Early-Life Epilepsy Diagnoses

Variability among next-generation sequencing (NGS) panels for early-life epilepsies could cause some confirmed epilepsy genes to be missed, researchers report. NGS panels have demonstrated utility for diagnosing genetic variants linked to early-life epilepsies, but little is known about the variability in genes tested among clinically available NGS panels.

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Generic Antiepileptic Drugs — Safe or Harmful in Patients with Epilepsy?

Sufficient evidence indicates that most generic antiepileptic drugs (AEDs) are bioequivalent to innovator AEDs; they do not pose a relevant risk for patients with epilepsy. However, some patients are reluctant towards variations in color and shape of their AEDs which may result in nonadherence. This report recommends administering generics when a new AED is initiated. Switches from brand to generic AEDs for cost reduction and between generics, which is rarely required, generally seem to be safe, but should be accompanied by thorough counseling of patients on low risks.

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Health Care Expenditures Among Elderly Patients with Epilepsy in the United States

Epilepsy is common among elderly individuals, and health care expenditures among this growing group are two times higher than in those without epilepsy.

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Open-Label Use of Highly Purified CBD (Epidiolex®) in Patients with CDKL5 Deficiency Disorder and Aicardi, Dup15q, and Doose Syndromes

OBJECTIVE: We studied our collective open-label, compassionate use experience in using cannabidiol (CBD) to treat epilepsy in patients with CDKL5 deficiency disorder and Aicardi, Doose, and Dup15q syndromes.

METHODS: We included patients aged 1-30?years with severe childhood-onset epilepsy who received CBD for ?10?weeks as part of multiple investigator-initiated expanded access or state access programs for a compassionate prospective interventional study: CDKL5 deficiency disorder (n?=?20), Aicardi syndrome (n?=?19), Dup15q syndrome (n?=?8), and Doose syndrome (n?=?8). These patients were treated at 11 institutions from January 2014 to December 2016.

RESULTS: The percent change in median convulsive seizure frequency for all patients taking CBD in the efficacy group decreased from baseline [n?=?46] to week 12 (51.4% [n?=?35], interquartile range (IQR): 9-85%) and week 48 (59.1% [n?=?27], IQR: 14-86%). There was a significant difference between the percent changes in monthly convulsive seizure frequency during baseline and week 12, ?2(2)?=?22.9, p?=?0.00001, with no difference in seizure percent change between weeks 12 and 48. Of the 55 patients in the safety group, 15 (27%) withdrew from extended observation by week 144: 4 due to adverse effects, 9 due to lack of efficacy, 1 withdrew consent, and 1 was lost to follow-up.

SIGNIFICANCE: This open-label drug trial provides class III evidence for the long-term safety and efficacy of CBD administration in patients with treatment-resistant epilepsy (TRE) associated with CDKL5 deficiency disorder and Aicardi, Dup15q, and Doose syndromes. Adjuvant therapy with CBD showed similar safety and efficacy for these four syndromes as reported in a diverse population of TRE etiologies. This study extended analysis of the prior report from 12?weeks to 48?weeks of efficacy data and suggested that placebo-controlled randomized trials should be conducted to formally assess the safety and efficacy of CBD in these epileptic encephalopathies.

Open-label use of Highly Purified CBD (Epidiolex®) in Patients with CDKL5 Deficiency Disorder and Aicardi, Dup15q, and Doose Syndromes

OBJECTIVE: Researchers studied their collective open-label, compassionate use experience in using cannabidiol (CBD) to treat epilepsy in patients with CDKL5 deficiency disorder and Aicardi, Doose, and Dup15q syndromes.

METHODS: The study included patients aged 1-30?years with severe childhood-onset epilepsy who received CBD for ?10?weeks as part of multiple investigator-initiated expanded access or state access programs for a compassionate prospective interventional study: CDKL5 deficiency disorder (n?=?20), Aicardi syndrome (n?=?19), Dup15q syndrome (n?=?8), and Doose syndrome (n?=?8). These patients were treated at 11 institutions from January 2014 to December 2016.

RESULTS: The percent change in median convulsive seizure frequency for all patients taking CBD in the efficacy group decreased from baseline [n?=?46] to week 12 (51.4% [n?=?35], interquartile range (IQR): 9-85%) and week 48 (59.1% [n?=?27], IQR: 14-86%). There was a significant difference between the percent changes in monthly convulsive seizure frequency during baseline and week 12, ?2(2)?=?22.9, p?=?0.00001, with no difference in seizure percent change between weeks 12 and 48. Of the 55 patients in the safety group, 15 (27%) withdrew from extended observation by week 144: 4 due to adverse effects, 9 due to lack of efficacy, 1 withdrew consent, and 1 was lost to follow-up.

SIGNIFICANCE: This open-label drug trial provides class III evidence for the long-term safety and efficacy of CBD administration in patients with treatment-resistant epilepsy (TRE) associated with CDKL5 deficiency disorder and Aicardi, Dup15q, and Doose syndromes. Adjuvant therapy with CBD showed similar safety and efficacy for these four syndromes as reported in a diverse population of TRE etiologies. This study extended analysis of the prior report from 12?weeks to 48?weeks of efficacy data and suggested that placebo-controlled randomized trials should be conducted to formally assess the safety and efficacy of CBD in these epileptic encephalopathies.

Research Sheds Light on Composition of Cannabis Used to Treat Children with Epilepsy

study has found Australian parents who turned to medicinal cannabis to treat children with epilepsy overwhelmingly (75%) considered the extracts as “effective”. Contrary to parental expectations, extracts generally contained low doses of cannabidiol (CBD) – commonly considered to be a key therapeutic element and that has been successfully used in recent clinical trials to treat epilepsy.

The research, which commenced two years ago by the University of Sydney’s Lambert Initiative for Cannabinoid Therapeutics, not only sheds light on the composition of cannabis used in the community but also reveals the legal, bureaucratic, and cost issues faced by families who relied on the products, as well as demonstrating the barriers to accessing medicinal cannabis.

The study found that the main psychoactive ingredient in cannabis, tetrahydrocannabidiol (THC), and the closely related compound THCA, were present in most extracts, although the quantity was generally not enough to produce intoxicating effects. Just over half the extracts were associated with a seizure reduction of 75%-100%, which reinforces observations from animal studies and case reports of anticonvulsant effects of THC and THCA. As well, 65% were associated with other beneficial effects like improved cognition (35%) and language skills (24%).

First Prescription Formulation of Cannabidiol (CBD) Approved for Lennox-Gastaut Syndrome

The LGS Foundation is pleased to announce that the US Food and Drug Administration (FDA) has approved EPIDIOLEX® (cannabidiol / CBD) for the treatment of seizures associated with Lennox-Gastaut syndrome (LGS) in patients two years age or older. EPIDIOLEX® is the first prescription pharmaceutical formulation of highly purified CBD and the first in its class of anti-epileptic drugs.

“Today’s announcement gives individuals with Lennox-Gastaut Syndrome and their families much-needed hope,” says LGS Foundation Executive Director Christina SanInocencio. “Lennox-Gastaut syndrome is a devastating form of epilepsy and despite currently available FDA-approved medications and a poly-therapy approach to treatment, the majority of individuals with LGS will continue to have life-long, debilitating seizures, along with cognitive impairment and abnormal waves on the EEG (electroencephalogram).”

Cannabidiol (CBD) is a compound derived from the cannabis plant that does not produce a “high” and has been an increasing focus of medical research in epilepsy. Recently, study results from the clinical trial of EPIDIOLEX® published in the New England Journal of Medicine showed to significantly reduce the number of seizures in patients with Lennox-Gastaut Syndrome.

Along with the FDA’s approval for EPIDIOLEX® for seizures associated with Lennox-Gastaut syndrome, the approval is also indicated for another form of rare epilepsy that begins in childhood called Dravet syndrome.

The adult motor phenotype of Dravet syndrome is Associated with Mutation of the STXBP1 Gene and Responds Well to Cannabidiol Treatment

Dravet syndrome is a terrible disease generally caused by mutations of the SCN1A gene. Recently others genes such as STXBP1 have been involved in the pathogenesis of the disease. The STXBP1 mutation in patients with Dravet Syndrome may additionally causes several parkinsonian features usually attributed to carriers of the SCN1A mutation. Management continues to be difficult; that is why Cannabidiol emerged as valid option for treatment of this condition.

Inadequate Regulation Contributes to Mislabeled Online Cannabidiol Products

Researchers from the University of Pennsylvania, Veterans Affairs San Diego, RTI international, Americans for Safe Access, Palo Alto University, and Johns Hopkins University analyzed the content of 84 cannabidiol (CBD) products purchased on the internet and compared the results to their advertised concentrations. Products were mislabeled with 26% containing less CBD than labeled and 43% containing more, indicating a high degree of variability and poor standardization of online products.

Notably, the oil-based products were more likely to be accurate (45% compared to 25% for tincture and 12.5% for vaporization liquid) and had a smaller percentage of deviation. Oil based products also had a higher range of concentration. In addition to CBD mislabeling, ?-9-tetrahydrocannabibolic acid (THC) was detected in 21% of samples. This study also notes that products containing THC could have sufficient enough concentrations to produce intoxication in children.

Results of Phase 3 Study of Cannabidiol Oral Solution in Lennox-Gastaut Syndrome Show Significant Reduction in Drop Seizures

GW Pharmaceuticals plc along with its U.S. subsidiary Greenwich Biosciences announced the publication of results from a Phase 3 study of cannabidiol oral solution (Epidiolex®) in patients with Lennox-Gastaut syndrome (LGS), a rare, severe and difficult-to-treat form of childhood-onset epilepsy. In this study, both evaluated doses of cannabidiol oral solution significantly reduced the monthly frequency of drop seizures compared to placebo in highly treatment-resistant patients when added to existing treatment.

“This publication in The New England Journal of Medicine marks another landmark for GW Pharmaceuticals with data again published by a top-tier, peer-reviewed journal. It offers further evidence for cannabidiol oral solution as a potential future treatment option for patients with this devastating condition,” said Justin Gover, GW’s Chief Executive Officer. “We are now in the latter stages of the FDA’s review of our New Drug Application and look forward to a decision from FDA in late June. If approved, we expect to make this important potential new medicine available to U.S. patients with LGS in the second half of the year.”

FutureNeuro and GreenLight Medicines Partner to Develop Treatments for Epilepsy

A new partnership between FutureNeuro, the SFI Research Centre for Chronic and Rare Neurological diseases based at RCSI, and GreenLight Medicines, an indigenous Irish biopharmaceutical company, has been formed to develop new cannabis-based treatments for drug resistant epilepsies, and in particular, childhood epilepsies.

The research will explore how cannabidiol (CBD) and other non-psychoactive molecules from the cannabis plant can reduce seizures. It will also look at optimizing the effectiveness of this new approach to treat epilepsy.

“This project has strong alignment with FutureNeuro’s strategic goal to bring novel treatments to patients in Ireland with difficult to control epilepsy” said Professor David Henshall, academic supervisor on the project and FutureNeuro Director. [Dr. Henshall is a former CURE grantee]

Dr. Colin Doherty, National Clinical Lead for Epilepsy and a Principal Investigator at the FutureNeuro Centre said, “The use of cannabis to treat epilepsy offers a tantalising new horizon for severe disabling seizures. The mechanism by which CBD exerts its antiepileptic effects is currently unknown, and this impactful research will help to provide clinical evidence of its long-term efficacy, as well as data on any long-term side effects.”

Epilepsy Research Findings: May 2018

This month I would like to share with you several promising treatment and diagnostic advances, and research discoveries. The FDA recently recommended supporting the approval of the New Drug Application for cannabidiol-based drug Epidiolex and also approved Medtronic’s deep brain stimulation therapy for drug-resistant epilepsy. Recent research has also provided the promise of new genetic insight for children with epileptic encephalopathy, and has brought us closer to understanding how to repair a “leaky” blood-brain barrier associated with epilepsy. In contrast to these exciting results, we have also learned that individuals with epilepsy are at an increased risk of dying from suicide and accidents, and a new study has highlighted the high direct costs associated with epilepsy for children with the disorder.

Summaries of all highlighted studies follow below. I’ve organized the findings into four categories: Treatment Advances, Diagnostic Advances, Research Discoveries, and Also Notable.

TREATMENT ADVANCES

GW Pharmaceuticals and U.S. Subsidiary Greenwich Biosciences Announces FDA Advisory Committee Unanimous Recommendation of Support for Epidiolex

GW Pharmaceuticals plc, along with its U.S. subsidiary Greenwich Biosciences, announced that the Peripheral and Central Nervous System Drugs Advisory Committee of the U.S. Food and Drug Administration unanimously recommended supporting the approval of the New Drug Application (NDA) for the investigational cannabidiol oral solution (CBD), also known as Epidiolex®, for the adjunctive treatment of seizures associated with Lennox-Gastaut syndrome (LGS) and Dravet syndrome in patients two years of age and older. If approved, Epidiolex would be the first pharmaceutical formulation of purified, plant-based CBD.

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Medtronic Receives FDA Approval for Deep Brain Stimulation Therapy for Medically Refractory Epilepsy

Medtronic plc, the global leader in medical technology, announced that the U.S. Food and Drug Administration has granted premarket approval for Medtronic’s Deep Brain Stimulation (DBS) therapy as adjunctive treatment for reducing the frequency of partial-onset seizures in individuals 18 years of age or older who are refractory or drug-resistant to three or more antiepileptic medications. DBS therapy for epilepsy delivers controlled electrical pulses to a target in the brain called the anterior nucleus of the thalamus, which is part of a network involved in seizures.

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Zynerba Pharmaceuticals Announces Twelve Month Data from STAR 2 Study in Patients with Focal Seizures

Zynerba Pharmaceuticals, Inc reported new longer term open label clinical data from its STAR 2 Study in patients with focal seizures. “The data continues to suggest that focal seizures may be reduced with longer-term exposure to transdermally-delivered CBD,” said Dr. Liza Squires, Zynerba’s Chief Medical Officer. “In this population of patients, the use of ZYN002 for an additional 12 months in STAR 2 was well tolerated and appeared to result in clinically meaningful seizure reductions both across and within the originally randomized STAR 1 groups.”

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Zynerba Pharmaceuticals Initiates Open-Label Phase 2 Trial of ZYN002 in Developmental and Epileptic Encephalopathies

Zynerba Pharmaceuticals announced that it has initiated the Phase 2 BELIEVE 1 clinical trial, an open label study to assess the safety and efficacy of ZYN002 administered as a transdermal gel to children and adolescents with developmental and epileptic encephalopathy.

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DIAGNOSTIC ADVANCES

New Testing Provides Better Information for Parents of Children with Epileptic Encephalopathy

Advances in genetic testing offer new insights to parents who have a child with a rare but serious form of epilepsy, epileptic encephalopathy. New ways of sequencing the human genome mean geneticists and genetic counselors have much more to say to parents who wonder if future children might carry the disease, says Dr. Heather Mefford, Associate Professor of Pediatrics (genetic medicine) at University of Washington School of Medicine and Deputy Scientific Director of the Brotman Baty Institute for Precision Medicine, co-senior author of findings published in the New England Journal of Medicine.

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RESEARCH DISCOVERIES

Repairing a Leaky Blood-Brain Barrier in Epilepsy

In a study of rodent brain capillaries published in the Journal of Neuroscience, Björn Bauer and colleagues identified a seizure-triggered pathway that contributes to blood-brain barrier dysfunction in epilepsy. The blood-brain barrier is a filtering mechanism that lets nutrients into the brain but keeps toxins out. Understanding how a “leaky” blood-brain barrier can lead to seizures is necessary to develop strategies to plug the leak.

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Hope for New Treatment of Severe Epilepsy

Researchers at Lund University in Sweden succeeded in reducing epileptic activity in the hippocampus. In many severe cases of epilepsy, this is the part of the brain where epileptic seizures start. The researchers used a method known as chemogenetics, which enables them to reduce activity in the specific areas and nerve cells involved in an epileptic seizure, whereas other parts and cells in the body remain unaffected. This is in contrast to current drugs that affect more or less all parts and cells of the body, potentially leading to side-effects.

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Epilepsy Does Not Impact Likelihood of Pregnancy

Women with epilepsy, without previous infertility and related disorders, were as likely to conceive as their counterparts without epilepsy, according to findings recently published in JAMA Neurology. Dr. Page B. Pennell and colleagues found that 60.7% of women with epilepsy became pregnant versus 60.2% of the control group without epilepsy.

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Increased Risk of Suicide and Accidental Death Found for People with Epilepsy

A new study has shown that people diagnosed with epilepsy in England and Wales are at increased risk of dying from suicide and accidents. Though the risks of dying from suicide and accidents for people with epilepsy are low in absolute terms (0.3-0.5%), they are higher than in people without epilepsy, says Dr. Hayley Gorton from The University of Manchester.

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ALSO NOTABLE

What Modern Day Challenges Affect Epilepsy Treatment?

Researchers recently published an article in The Lancet Neurology discussing the difficulties facing seizure detection in patients with epilepsy. In a recent study, Christian Elger and Christian Hoppe determined that a key challenge facing patients is that over 50% of patients under-report the number of seizures they experience, which has a serious impact on how well doctors are able to determine what treatments are most suitable for them. This also calls into question much of the previously published research on epilepsy treatments.

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Study Finds a High Direct Cost of Epilepsy in Children

A study of children aged 17 years using data from the Medical Expenditure Panel Survey-Household Component found that medical expenditure among children with epilepsy is high. The high expenditure is essentially driven not only by inpatient expenditure but also by home healthcare, outpatient, and medication healthcare expenditures.

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