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.”

Clinical Trial: Anxiety and Depression in Epilepsy – A Pilot Treatment Study

Brief Summary: As a potential solution to address high rates of depression and anxiety seen in epilepsy patients and poor mental health care access, this trial aims to carry out treatment for depression and anxiety directly in our epilepsy clinic. Patients that meet eligibility criteria, including significant symptoms of depression and/or anxiety, will be enrolled in the intervention. The intervention will consist of an initial prescription for an FDA-approved medication to treat depression/anxiety and telephone-based chronic care management plan for repeated symptom measurement and side effect surveillance. The purpose of this pre-piloting limited study is to streamline recruitment, intervention and outcome assessment process in preparation for a randomized, controlled pilot of the intervention.

Estimated study start date: May 2018
Estimated study completion date: January 2019

Eligibility Criteria

Ages Eligible for Study: 18 Years and Older (Adult, Senior)
Sexes Eligible for Study: All
Accepts Healthy Volunteers: No

Inclusion Criteria:

  • Provision of signed and dated informed consent form
  • Stated willingness to comply with all study procedures and availability for the duration of the study
  • Age 18 or older
  • Ability to take oral medication and the willing to adhere to the intervention regimen
  • Minimum of 1 prior clinic visit at the Comprehensive Epilepsy Center
  • Adequate cognition (MoCA score of 20 or greater)
  • Diagnosis of epilepsy: EEG with documented seizure or epileptiform discharges OR non-epileptiform EEG and seizure remission with antiseizure drug OR treating epileptologist’s leading clinical impression is epilepsy
  • NDDI-E score greater than 15 and/or GAD-7 score greater than or equal to 10

 

Exclusion Criteria:

  • Pregnancy or lactation
  • Known allergic reactions to escitalopram or venlafaxine
  • Comorbid psychogenic nonepileptic seizures
  • Prior psychiatric hospitalization
  • Prior suicide attempt
  • History of manic or psychotic symptoms (past manic episode (SCID-I), or psychotic symptom screen positive)
  • Current treatment by a psychiatrist or counselor/theraptist
  • Active suicidality at the time of screening
  • Current treatment with buspirone or an SSRI/SNRI/atypical antidepressant (specifically bupropion, fluoxetine, levomilnacipran, citalopram, milnacipran, desvenlafaxine, mirtazapine, duloxetine, paroxetine, escitalopram, sertraline, fluvoxamine, venlafaxine, vilazodone, vortioxetine)

Briviact Approved for Pediatric Patients With Partial-Onset Seizures

The Food and Drug Administration (FDA) has approved Briviact (brivaracetam; UCB) tablets and oral solution as monotherapy and adjunctive therapy in the treatment of partial-onset seizures in patients aged ?4 years. Briviact injection, however, is still only indicated to treat partial-onset seizures in patients aged ?16 years.

The expanded approval was supported by extrapolated efficacy data from placebo-controlled studies in adults with partial-onset seizures. Additional pharmacokinetic and open-label safety studies in patients aged 4 to <16 years were also conducted and the data showed a similar drug-response relationship between adults and pediatric patients. In addition, the safety and tolerability of Briviact was similar in patients aged 4–16 years compared with adults. Somnolence, sedation, dizziness, fatigue, nausea, and vomiting were the the most common adverse reactions seen in adult and pediatric patients.

Briviact exhibits a high and selective affinity for synaptic vesicle protein 2A (SV2A) in the brain. When initiating treatment, gradual dose escalation is not required; weight-based dose adaptations have been established for pediatric patients.

Rush is First to Use Microburst Vagus Nerve Stimulation for Drug-Resistant Epilepsy

Epilepsy patients who have not responded to standard drug treatments may benefit from a new therapy that delivers high frequency bursts of electrical stimulation, called microbursts, to the brain. Rush University Medical Center in Chicago is the first health care provider in the world to provide this treatment, known as microburst vagus nerve stimulation.

The treatment is akin to a heart pacemaker. A surgeon places an electronic pulse generator under the skin in the chest and attaches it to the left vagus nerve, which runs down the side of the body from the stem of the brain through the neck and chest to the abdomen.

The device sends regular electrical pulses through the vagus nerve to the brain to prevent epileptic seizures from occurring. The stimulator’s settings can be changed according to each patient’s needs using a special programming wand, with no additional surgery needed.

The study consists of two groups of patients with epilepsy, enrolling up to 40 patients in total at approximately 15 sites in the United States. The first group will include 20 patients with primary generalized tonic-clonic seizures. The second group will consist of 20 patients with partial onset seizures, including complex partial seizures with or without secondary generalization.

Each patient will participate in the study for a minimum of 15 months. The study will measure the percent change in seizure frequency and occurrence of stimulation-related adverse events in comparison to a patient’s baseline. Activation of various areas of the brain in response to stimulation will be assessed using functional magnetic resonance imaging or fMRI. Patients also will be evaluated to assess changes from baseline in seizure severity, quality of life, antiepileptic drug use, suicidality and adverse events.

Genetic Literacy Series: Primer Part 2—Paradigm Shifts in Epilepsy Genetics

This is the second of a 2?part primer on the genetics of the epilepsies within the Genetic Literacy Series of the Genetics Commission of the International League Against Epilepsy.

In Part 1, we covered types of genetic variation, inheritance patterns, and their relationship to disease. In Part 2, we apply these basic principles to the case of a young boy with epileptic encephalopathy and ask 3 important questions: (1) Is the gene in question an established genetic etiology for epilepsy? (2) Is the variant in this particular gene pathogenic by established variant interpretation criteria? (3) Is the variant considered causative in the clinical context? These questions are considered and then answered for the clinical case in question.

A Population?Based Cost?Effectiveness Study of Early Genetic Testing in Severe Epilepsies of Infancy

Significance: Severe epilepsies occur in 1 in 2000 infants, with the etiology identified in two?thirds, most commonly malformative. Early use of targeted whole exome sequencing (WES) yields more diagnoses at lower cost. Early genetic diagnosis will enable timely administration of precision medicines, once developed, with the potential to improve long?term outcome.

Objective: The severe epilepsies of infancy (SEI) are a devastating group of disorders that pose a major care and economic burden on society; early diagnosis is critical for optimal management. This study sought to determine the incidence and etiologies of SEI, and model the yield and cost?effectiveness of early genetic testing.

Methods: A population?based study was undertaken of the incidence, etiologies, and cost?effectiveness of a whole exome sequencing–based gene panel (targeted WES) in infants with SEI born during 2011?2013, identified through electroencephalography (EEG) and neonatal databases. SEI was defined as seizure onset before age 18 months, frequent seizures, epileptiform EEG, and failure of ?2 antiepileptic drugs. Medical records, investigations, MRIs, and EEGs were analyzed, and genetic testing was performed if no etiology was identified. Economic modeling was performed to determine yield and cost?effectiveness of investigation of infants with unknown etiology at epilepsy onset, incorporating targeted WES at different stages of the diagnostic pathway.

Results: Of 114 infants with SEI (incidence = 54/100 000 live births/y), the etiology was determined in 76 (67%): acquired brain injuries (n = 14), focal cortical dysplasias (n = 14), other brain malformations (n = 17), channelopathies (n = 11), chromosomal (n = 9), metabolic (n = 6), and other genetic (n = 5) disorders. Modeling showed that incorporating targeted WES increased diagnostic yield compared to investigation without targeted WES (48/86 vs 39/86). Early targeted WES had lower total cost ($677 081 U.S. dollars [USD] vs $738 136 USD) than late targeted WES. A pathway with early targeted WES and limited metabolic testing yielded 7 additional diagnoses compared to investigation without targeted WES (46/86 vs 39/86), with lower total cost ($455 597 USD vs $661 103 USD), lower cost per diagnosis ($9904 USD vs $16 951 USD), and a dominant cost?effectiveness ratio.

Study: Yield of EEG Monitoring in Children with Developmental Disabilities is High

PURPOSE: The purpose of this study was to investigate the yield of a 2-hour electroencephalography (EEG) monitoring (awake and sleep) in children with developmental disabilities and without any clinically apparent seizures.

METHODS: In this retrospective study, I investigated all children below 9?years of age who had developmental disabilities and were referred to Shiraz Comprehensive Epilepsy center for electroencephalographic investigation from June 2017 until January 2018. Exclusion criteria included any past history of neonatal seizures, febrile or afebrile seizures, and parental suspicion for seizures. We systematically obtained a brief clinical history and performed a 2-hour, awake and asleep EEG monitoring for all patients.

RESULTS: Thirty-two patients (23 males and 9 females) met all the inclusion and exclusion criteria; mean age (±standard deviation) was 4.1 (±2.1) years. Nineteen patients (59%) had an abnormal EEG: 15 patients (47%) had epileptiform discharges, and four children had abnormal background activity with no epileptiform discharges.

CONCLUSION: Considering the high diagnostic yield of an awake and asleep EEG monitoring, as it was observed in the current study, this test on a screening basis can be reasonably justified in all children with developmental disabilities.

Study: Improving Staff Response to Seizures on the Epilepsy Monitoring Unit with Online EEG Seizure Detection Algorithms

OBJECTIVE: User safety and the quality of diagnostics on the epilepsy monitoring unit (EMU) depend on reaction to seizures. Online seizure detection might improve this. While good sensitivity and specificity is reported, the added value above staff response is unclear. We ascertained the added value of two electroencephalograph (EEG) seizure detection algorithms in terms of additional detected seizures or faster detection time.

METHODS: EEG-video seizure recordings of people admitted to an EMU over one year were included, with a maximum of two seizures per subject. All recordings were retrospectively analyzed using Encevis EpiScan and BESA Epilepsy. Detection sensitivity and latency of the algorithms were compared to staff responses. False positive rates were estimated on 30 uninterrupted recordings (roughly 24?h per subject) of consecutive subjects admitted to the EMU.

RESULTS: EEG-video recordings used included 188 seizures. The response rate of staff was 67%, of Encevis 67%, and of BESA Epilepsy 65%. Of the 62 seizures missed by staff, 66% were recognized by Encevis and 39% by BESA Epilepsy. The median latency was 31?s (staff), 10?s (Encevis), and 14?s (BESA Epilepsy). After correcting for walking time from the observation room to the subject, both algorithms detected faster than staff in 65% of detected seizures. The full recordings included 617?h of EEG. Encevis had a median false positive rate of 4.9 per 24?h and BESA Epilepsy of 2.1 per 24?h.

CONCLUSIONS: EEG-video seizure detection algorithms may improve reaction to seizures by improving the total number of seizures detected and the speed of detection. The false positive rate is feasible for use in a clinical situation. Implementation of these algorithms might result in faster diagnostic testing and better observation during seizures.

Study: Efficacy and Safety of Ketogenic Diet for Treatment of Pediatric Convulsive Refractory Status Epilepticus

CONCLUSIONS: This series suggests efficacy and safety of ketogenic diet (KD) for treatment of pediatric convulsive refractory status epilepticus (RSE).

PURPOSE: To describe the efficacy and safety of ketogenic diet for convulsive refractory status epilepticus.

METHODS: RSE patients treated with KD at the 6/11 participating institutions of the pediatric Status Epilepticus Research Group from January-2011 to December-2016 were included. Patients receiving KD prior to the index RSE episode were excluded. RSE was defined as failure of ?2 anti-seizure medications, including at least one non-benzodiazepine drug. Ketosis was defined as serum beta-hydroxybutyrate levels >20?mg/dl (1.9?mmol/l). Outcomes included proportion of patients with electrographic (EEG) seizure resolution within 7?days of starting KD, defined as absence of seizures and ?50% suppression below 10??V on longitudinal bipolar montage (suppression-burst ratio ?50%); time to start KD after onset of RSE; time to achieve ketosis after starting KD; and the proportion of patients weaned off continuous infusions 2 weeks after KD initiation. Treatment-emergent adverse effects (TEAEs) were also recorded.

RESULTS: Fourteen patients received KD for treatment of RSE (median age 4.7 years, interquartile range [IQR] 5.6). KD was started via enteral route in 11/14 (78.6%) patients. KD was initiated a median of 13?days (IQR 12.5) after the onset of RSE, at 4:1 ratio in 8/14 (57.1%) patients. Ketosis was achieved within a median of 2?days (IQR 2.0) after starting KD. EEG seizure resolution was achieved within 7?days of starting KD in 10/14 (71.4%) patients. Also, 11/14 (78.6%) patients were weaned off their continuous infusions within 2 weeks of starting KD. TEAEs, potentially attributable to KD, occurred in 3/14 (21.4%) patients, including gastro-intestinal paresis and hypertriglyceridemia. Three month outcomes were available for 12/14 (85.7%) patients, with 4 patients being seizure-free, and 3 others with decreased seizure frequency compared to pre-RSE baseline.

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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