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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Study of the Mozart Effect in Children with Epileptic Electroencephalograms

PURPOSE: To establish if listening to Mozart’s Sonata for two pianos in D major (K448) has an anti-epileptic effect on the EEGs (electroencephalograms) of children.

METHODS: Forty five children (2-18 years; mean 7 years 10 months) who had epileptiform activity on EEG were recruited from those attending for scheduled EEG investigations. Mozart’s Sonata for two pianos in D major (K448) and an age-appropriate control music were played during the EEG. There were five consecutive states during the record, each lasting 5?min; before Mozart music (baseline), during Mozart music, after Mozart music/before control music, during control music and after control music. Epileptic discharges were counted manually and the mean frequency of epileptic discharges calculated in each state.

RESULTS: A significant reduction (p?<?0.0005) in the frequency of epileptic discharges was found during listening to the Mozart music compared to the baseline. No evidence of a difference in mean epileptic discharges was found between the baseline and the other three states or between listening to the Mozart music and control music.

CONCLUSION: This study confirms an anti-epileptic effect of Mozart music on the EEG in children, which is not present with control music. The role of ‘Mozart therapy’ as a treatment for drug-resistant epilepsy warrants further investigation.

Engage Therapeutics Doses First Patient In Phase 2b Trial Of Epilepsy Seizure Rescue Therapy Staccato® Alprazolam

Engage Therapeutics, Inc. announced May 4th the dosing of the first patient in its multi-center, double-blind, randomized Phase 2b StATES (Staccato®AlprazolamTerminatesEpilepticSeizures) trial to investigate the safety and efficacy of Staccatoalprazolam in subjects with epilepsy that have a predictable seizure pattern.

The StATES trial (NCT03478982) will enroll 108 patients across 40 U.S.-based clinical sites. The primary endpoint is the cessation of seizure activity. Seizure episode severity, as well as the incidence of adverse events, will also be evaluated. Topline data is expected in the second half of 2019.Staccatoalprazolam, a single use, investigational epileptic seizure rescue therapy, combines the Staccato delivery technology, which is currently used in a U.S. Food and Drug Administration (FDA)-approved product, with alprazolam, an FDA-approved benzodiazepine. Together, this combination is novel for an epilepsy application in a patient population in need of innovative rescue options.

Greg Mayes, president, CEO and founder of Engage Therapeutics, said, “For individuals with epilepsy that have a predictable seizure pattern, currently available rescue treatments can only address the prevention of seizure activity once the first seizure ends, but Staccato alprazolam has the potential to be the first and only product that can abort an active seizure. We are excited by the enthusiastic response that this study has received from the epilepsy community and how quickly we have been able to advance this promising candidate to this point in development.”

CURE Discovery: Genetic Research Finds Potential Alternatives to Brain Surgery for Children with Cortical Dysplasia

A Potential Alternative is Already in Clinical Trial

Recent research by CURE grantee Dr. Jeong Ho Lee of the Korea Advanced Institute of Science and Technology has shed important light on the genetic mutations that lead to focal cortical dysplasia, a severe form of pediatric epilepsy that inadequately responds to available treatment options. Genetic mutations were found in the brain tissue of individuals affected by a particular subtype of focal cortical dysplasia (focal cortical dysplasia type II) that is characterized by brain abnormalities, leading to seizures and epilepsy.

Conventional genetic testing methods to identify genetic mutations in those with epilepsy often use blood or saliva from patients. However, these latest results from Dr. Lee and his team suggest that certain epilepsy-related gene mutations may only be detectable when brain tissue is analyzed.

Brain-Only Mutations in Genes that Cause Focal Cortical Dysplasia

By comparing blood and saliva samples to samples of brain tissue from a group of 40 individuals who had previously undergone brain surgery for focal cortical dysplasia type II, Dr. Lee and his team found that a significant number of these individuals (12.5%) had brain-only mutations in genes TSC1 and TSC2. Together with the previous pioneering work of his team to identify brain-only mutations in the MTOR gene in individuals with focal cortical dysplasia type II, they revealed that brain-only mutations in genes within the mTOR brain signaling pathway (including the genes TSC1, TSC2 and MTOR) are found in up to 30% of individuals with focal cortical dysplasia. The fact that these mutations were found only in the brain means that these mutations would be undetectable by conventional genetic testing methods, suggesting that investigation of brain-only mutations should be explored to a greater extent.

In addition to identifying brain-only mutations leading to focal cortical dysplasia, Dr. Lee and his team also addressed the current lack of adequate animal models to better study the disorder. The team was able to successfully recreate the brain-only mutations in genes TSC1 and TSC2 in developing mice, providing a much-needed animal model for further examination of the ways in which gene mutations can lead to focal cortical dysplasia type II.

Clinical Trials for the Treatment of Focal Cortical Dysplasia

Furthermore, the team provided evidence that mTOR inhibitors, such as rapamycin or everolimus, are promising anti-epileptic drugs for the treatment of focal cortical dysplasia. In fact, everolimus is currently under phase II clinical trial for the treatment of focal cortical dysplasia.

As noted by Dr. Lee, because focal cortical dysplasia is a drug-resistant epilepsy, many children with the disorder require invasive brain surgery as treatment. However, even in cases where surgery is performed, up to 40% of these children may still have seizures. By identifying genes associated with focal cortical dysplasia as well as creating a new way of studying the genetic mechanisms behind the disorder, Dr. Lee and his team have made progress towards the creation of novel, non-surgical targets at which to aim treatments for this devastating form of drug-resistant childhood epilepsy.

[1] Lim et al. Somatic mutations in TSC1 and TSC2 cause focal cortical dysplasia. Am J Human Genet 2017; 100(3):454-472.
[2] Guerrini et al. Diagnostic methods and treatment options for focal cortical dysplasia. Epilepsia 2015; 56(11):1669-86.
[3] Gaitanis and Donahue. Focal cortical dysplasia. Ped Neurol 2013; 49:79-87.
[4] Poduri et al. Genetic testing in the epilepsies – developments and dilemmas. Nat Rev Neurol 2014; 10(5):293-299.
[5] Lim et al. Brain somatic mutations in MTOR cause focal cortical dysplasia type II leading to intractable epilepsy. Nat Med 2015; 21(4):395-400.

May CURE Update: Epidiolex, Sabril, and Epilepsy Education Events

I was recently interviewed by Business Insider about the FDA’s review of a potential new anti-epilepsy drug, Epidiolex. In Phase III clinical trials, 44% of patients with Lennox-Gastaut Syndrome (LGS) and 43% of patients with Dravet syndrome who used Epidiolex saw a 50% or greater reduction in their seizures compared to 24% and 27% of participants who took the placebo.

Epidiolex could be the first drug derived from cannabidiol (CBD) to gain FDA approval. Unlike THC, one of the other components in marijuana, cannabidiol is not an intoxicant. So, Epidiolex does not have hallucinogenic effects. The FDA is expected to make its final decision about Epidiolex in June.

In other news: CURE is announcing the expansion of its Day of Science event; CURE is urging insurance companies to maintain reasonable access to Sabril; and you can now support CURE while drinking your morning cup of coffee. Read on….

 

DAY OF SCIENCE IS EXPANDING TO SIX LOCATIONS!

CURE’s 2018 Day of Science events kick-off in June. At these free events, you can learn about cutting-edge epilepsy therapies and treatments, via:

  • Q&A sessions with panels of epilepsy physicians
  • Small-group roundtable discussions led by experts

 

You’ll also get the opportunity to engage with others in the epilepsy community.

Registration is now open for the Days of Science in:

 

Stay tuned for details about CURE’s Days of Science in the following cities:

  • Houston
  • Los Angeles
  • Miami
  • Raleigh-Durham

 

Interested in volunteering? Please contact the Day of Science team at DOS@CUREepilepsy.org or (312) 255-1801.

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

Medtronic plc, the global leader in medical technology, announced on April 30, 2018 that the U.S. Food and Drug Administration (FDA) 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 (ANT), which is part of a network involved in seizures.

According to the Epilepsy Foundation, 3.4 million individuals in the United States have epilepsy. Antiepileptic drug (AED) medication is the primary treatment to control seizures; however, up to one third of individuals with epilepsy have seizures that do not successfully respond to AEDs.

“Many patients in the United States with severe epilepsy are not able to control their seizures with currently-available drugs and are not candidates for potentially curative surgery,” said Dr. Robert Fisher, director of the Stanford Epilepsy Center, Stanford University, and lead principal investigator of the SANTE trial. “Epilepsy that is refractory to AED treatment is an unsolved problem, and DBS therapy will now serve as an important new treatment option, including for people with poorly localized or multiple regions of seizure origin.”

The FDA approval is based on both the blinded phase and the 7-year follow-up data collected in Medtronic’s clinical trial called SANTE (Stimulation of the Anterior Nucleus of the Thalamus in Epilepsy). The SANTE trial was a prospective, randomized, double-blind pivotal study to evaluate the use of DBS therapy for patients with medically refractory epilepsy with partial-onset seizures, with or without secondary generalization, that were drug-resistant to three or more antiepileptic medications. The trial collected data from 110 patients who were implanted with a Medtronic DBS system at 17 centers located in the US.

Single-Center Long-Term Results of Vagus Nerve Stimulation for Epilepsy: A 10-17 Year Follow-Up Study

PURPOSE: The paper presents a long-term follow-up study of VNS patients, analyzing seizure outcome, medication changes, and surgical problems.

METHOD: 74 adults with VNS for 10 to 17 years were evaluated yearly as: non-responder – NR (seizure frequency reduction <50%), responder – R (reduction???50% and <90%), and 90% responder – 90R (reduction???90%). Delayed R or 90R (??4?years after surgery), patients with antiepileptic medication changes and battery or complete system replacement were identified. Statistical analysis of potential outcome predictors (age, seizure duration, MRI, seizure type) was performed.

RESULTS: The rates of R and 90R related to the patients with outcome data available for the study years 1, 2, 10, and 17 were for R 38.4%, 51.4%, 63.6%, and 77.8%, and for 90R 1.4%, 5.6%, 15.1%, and 11.1%. The absolute numbers of R and 90R increased until years 2 and 6. Antiepileptic therapy was changed in 62 patients (87.9%). There were 11 delayed R and four delayed 90R, with medication changes in the majority. At least one battery replacement was performed in 51 patients (68.9%), 49 of whom R or 90R. VNS system was completely replaced in 7 patients (9.5%) and explanted in 7 NR (9.5%). No significant predictor of VNS outcome was found.

CONCLUSIONS: After an initial increase, the rate of R (seizure reduction ??50% and <90%) and 90R (seizure reduction???90%) remains stable in long-term follow-up. The changes of antiepileptic treatment in most patients potentially influence the outcome. Battery replacements or malfunctioning system exchange reflect the patient’s satisfaction and correlate with good outcomes.

Zynerba Pharmaceuticals Announces Twelve Month ZYN002 Data from STAR 2 Study in Patients with Focal Seizures at the 2018 Annual Meeting of the American Academy of Neurology (AAN)

Zynerba Pharmaceuticals, Inc., a clinical-stage specialty neuropsychiatric pharmaceutical company dedicated to developing and commercializing innovative pharmaceutically-produced transdermal cannabinoid treatments for rare and near-rare neurological and psychiatric disorders with high unmet medical needs, is reporting new longer term open label clinical data today in the Emerging Science session of the 2018 Annual Meeting of the American Academy of Neurology (AAN) in Los Angeles, CA.

In a poster presentation entitled, “Transdermal Cannabidiol (CBD) Gel for the Treatment of Focal Epilepsy in Adults” (poster P4.468), Dr. John Messenheimer presents additional data from ongoing STAR 2 (Synthetic Transdermal CAnnabidiol for the TReatment of Epilepsy) 24-month open label extension study evaluating ZYN002 cannabidiol (CBD) transdermal gel in adult patients with focal seizures. The presentation includes data through twelve months of open label exposure to ZYN002.

The key findings include that responses to ZYN002 in the STAR 2 open label extension, as measured by reductions in focal seizures from the baseline period of STAR 1, are associated with continued treatment with ZYN002. In addition, ZYN002 was shown to be well tolerated through 12 months of treatment in STAR 2.

“These data continue 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. These data continue to provide insight into the potential for ZYN002 in certain epilepsies, and we look forward to initiating a Phase 2b study in adult refractory focal seizures in the second half of 2018.”

Zogenix Announces Presentation of New Efficacy and Safety Data from its First Pivotal Phase 3 Clinical Trial of ZX008 in Dravet Syndrome

Zogenix, Inc., a pharmaceutical company developing therapies for the treatment of rare central nervous system (CNS) disorders, today announced additional data from analyses of its first Phase 3 trial (Study 1) of the company’s investigational drug, ZX008 (low-dose fenfluramine hydrochloride), for the adjunctive treatment of seizures associated with Dravet syndrome. Top-line results from Study 1 were previously reported in September 2017. The additional Study 1 results were presented in two late-breaker poster presentations at the Emerging Science session at the 2018 American Academy of Neurology (AAN) Annual Meeting being held April 21-27 in Los Angeles, California (see study data here and here).

As previously reported, Study 1 met its primary objective of demonstrating that ZX008, at a dose of 0.8 mg/kg/day, is superior to placebo as an adjunctive therapy in the treatment of Dravet syndrome in children and young adults based on change in the frequency of convulsive seizures between the 6-week baseline observation period and the 14-week treatment period (p<0.001).

“It is highly encouraging to see that the efficacy and tolerability in this subgroup of patients who had previously failed treatment with stiripentol was comparable to the full Study 1 population,” said Rima Nabbout, M.D., Ph.D., Department of Pediatric Neurology, Reference Center for Rare Epilepsies, and one of the poster’s authors. “As stiripentol is a commonly used antiepileptic drug, it is important to understand how tolerable and effective ZX008 is in this subgroup of patients.”

Updated Recommendations on the Optimal Clinical Management of Children Receiving Dietary Therapies for Epilepsy

Ketogenic dietary therapies (KDT) are established, effective nonpharmacologic treatments for intractable childhood epilepsy. For many years KDT were implemented differently throughout the world due to lack of consistent protocols. In 2009, an expert consensus guideline for the management of children on KDT was published, focusing on topics of patient selection, pre?KDT counseling and evaluation, diet choice and attributes, implementation, supplementation, follow?up, side events, and KDT discontinuation. It has been helpful in outlining a state?of?the?art protocol, standardizing KDT for multicenter clinical trials, and identifying areas of controversy and uncertainty for future research.

Now one decade later, the organizers and authors of this guideline present a revised version with additional authors, in order to include recent research, especially regarding other dietary treatments, clarifying indications for use, side effects during initiation and ongoing use, value of supplements, and methods of KDT discontinuation. Additionally, authors completed a survey of their institution’s practices, which was compared to responses from the original consensus survey, to show trends in management over the last ten years.