Epilepsy Research Findings: December 2019

This month, the FDA approved XCOPRI, a new medication to treat partial-onset seizures in adults. This type of seizure is often difficult to control, so we are thrilled to see this treatment advancement.

Additional promising research news includes the advancement of a method of predicting seizure risk. Also, for individuals affected by Lennox-Gastaut syndrome, a new Amazon Alexa skill offers engaging, interactive play options.

Summaries of these research discoveries and news highlights are below.

Research Discoveries & News

  • New Treatment: The FDA approved SK Lifescience’s XCOPRI (cenobamate tablets) to treat partial-onset seizures in adults. Learn More
  • Seizure Prediction: The new seizure risk assessment tool from Rice University, EpiSAT, received its first validation. The automated machine-learning algorithm correctly identified changes in seizure risk — improvement, worsening, or no change — in more than 87% of cases by analyzing seizure diaries. This prediction rate is as good or better than specialized epilepsy clinicians predicting seizure risk using patient histories. Learn More
  • New Technology: Eisai Inc. launched Ella the Jellyfish, the first Amazon Alexa skill designed for those affected by Lennox-Gastaut syndrome. This skill features capabilities such as interactive play, listening, and creative activities. Learn More
  • Status Epilepticus: New findings from a team, which included CURE Scientific Advisory Members Dr. Jaideep Kapur and Dr. Dan Lowenstein, reveal that levetiracetam (Keppra), fosphenytoin (Cerebyx), and valproate (Depakote) are equally safe and effective in treating patients with status epilepticus. Learn More
  • Post-Traumatic Epilepsy: Researchers from the University of California, Irvine (UCI) developed a cell therapy to improve memory and prevent seizures in mice following traumatic brain injury. In the study, the UCI team transplanted a cell type that can generate inhibitory brain activity into mouse brains. This process formed new connections with injured brain cells and prevented the mice from developing seizures. Learn More
  • Febrile Seizures: A study examined the cognitive functioning in children ages 4-5 who experienced febrile seizures. The research found that children with early onset of febrile seizures (especially those with recurrent febrile seizures) may be at heightened risk for poorer verbal and processing speed function, and possibly at risk for other cognitive dysfunctions. The findings suggest that these children would likely benefit from neuropediatric and neuropsychological follow-up, regardless of if they are still having febrile seizures. Learn More

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Remote Programming: A Convenient and Cost-Effective Measure of Vagus Nerve Stimulation for Children with Epilepsy

This study aimed to evaluate the efficacy, adverse events and expense burden of outpatient versus remote programming for vagus nerve stimulation (VNS) in children with epilepsy.

A total of 46 children with drug-resistant epilepsy, who underwent VNS at the Pediatric Epilepsy Center, Peking University First Hospital between March 2017 and June 2018, were enrolled into the study. Participants were assigned (non-randomized) into an outpatient programming group or remote programming group (where VNS parameters were adjusted through the internet) by parental choice. The responder rate, expenditure for VNS programming and adverse events were compared between the two groups. The median age at VNS implantation was 5.17 years (3.83-6.71), with the median epileptic course being 3.79 years (2.65-4.90). Twenty-four patients were assigned to the outpatient programming group and 22 were assigned to the remote programming group. Baseline data were comparable between the two groups, with the exception of the remote group having a longer distance between their place of residence and the hospital. The median time from VNS implantation to last follow-up was 1.33 years (1.25-1.75) and 1.46 years (1.17-1.58) in the outpatient and remote groups, respectively. In the outpatient programming group, 15 patients (62.5 %,) were VNS responders and four patients (16.6 %) became seizure-free. In the remote programming group, 16 patients (72.7 %) were VNS responders and four (17.4 %) became seizure-free. Cough and hoarseness were common adverse events in both the outpatient and remote groups (33.3 % vs. 18.2 %). There were no significant differences between the two groups in terms of adverse events.

The median cost of each follow-up visit per patient in the outpatient group was 192.4 US dollars ($120.0-$376.5), of which travelling expenses were the major component, followed by accommodation fees, outpatient service fees and indirect costs. Whereas, patients in the remote programming group only needed to pay for the remote programming expense, which totaled 75.8 US dollars per person each time. The efficacy and adverse events were both comparable between the outpatient and remote programming patients. Remote programming was found to be a more cost-effective treatment, especially for patients living further away from centers specializing in epilepsy.

Study Results Support Safety and Efficacy of Fenfluramine as a Patient Option for Patients with Dravet Syndrome Receiving Stiripentol-Inclusive Regimens

Researchers investigated the safety and efficacy of fenfluramine for treating patients with Dravet syndrome who have frequent seizures despite taking a stiripentol-inclusive antiepileptic drug regimen. They conducted a double-blind, placebo-controlled, parallel-group randomized clinical trial at multiple centers randomizing patients with 6 or more convulsive seizures during the 6-week baseline period to receive fenfluramine, 0.4 mg/kg/d (maximum, 17 mg/d), or a placebo. Outcomes revealed a 54.0% greater reduction in mean monthly convulsive seizure frequency in correlation to receiving oral fenfluramine (0.4 mg/kg/d; maximum 17 mg/d) vs placebo among patients with Dravet syndrome who were taking stiripentol-containing antiepileptic drug regimens.

Among patients who were taking fenfluramine (vs placebo), a significantly greater proportion experienced a clinically meaningful (over 50%) or profound (over 75%) reduction in monthly convulsive seizure frequency. Adverse events most commonly encountered were decreased appetite, pyrexia, fatigue, and diarrhea; there was no patient who developed valvular heart disease or pulmonary hypertension. These findings support the safety and efficacy of adjunctive fenfluramine as a new treatment option for these patients.

Marinus Announces Ganaxolone Orphan Epilepsy Program Updates Including Planned Clinical Program in Tuberous Sclerosis Complex

Marinus Pharmaceuticals, Inc. announced clinical and regulatory updates for its orphan seizure programs in tuberous sclerosis complex (TSC), CDKL5 deficiency disorder (CDD) and PCDH19-related epilepsy (PCDH19-RE).

“The decision to expand our epilepsy program in TSC was strategically informed by the discovery of a new potential epilepsy biomarker, Allo-S, in our Phase 2 study in PCDH19-related epilepsy,” said Scott Braunstein, M.D., Chief Executive Officer of Marinus. “This led us to additional analyses that identified TSC as another rare genetic disorder that may be similarly impacted by Allo-S levels. We look forward to initiating a Phase 2 trial in the first half of 2020 to provide a potential targeted treatment option for these patients with limited approved therapies.”

Marinus intends to initiate a Phase 2, open label study to evaluate the safety and tolerability of adjunctive ganaxolone treatment in patients with seizures associated with TSC. Patient stratification from the Company’s PCDH19-related epilepsy Phase 2 trial identified a subpopulation of patients with improved ganaxolone responses, those with low levels of allopregnanolone-sulfate (Allo-S). Based on these data, the Company performed a biomarker analysis to identify other rare genetic epilepsies that may benefit from the GABAA-receptor modulatory effects of ganaxolone and today announced TSC as the next planned orphan epilepsy program to study the effect of ganaxolone on seizures as well as the expanded utility of a potential biomarker.

The planned Phase 2 study will be conducted at approximately 4-6 sites in the United States and enroll approximately 20-40 patients ages 2 to 65.  Patients will undergo a 4-week baseline period followed by a 12-week treatment period.  The primary endpoint for the study is percent change in 28-day primary seizure frequency through the end of the 12-week treatment period relative to the 4-week baseline period.

SK Life Science, Inc. Announces FDA Acceptance of IND Application for Anti-Epileptic Drug Candidate SKL24741

SK Life Science, Inc., announced that the FDA has accepted its investigational new drug (IND) application for SKL24741, for the treatment of epilepsy. SK life science will launch a Phase 1 clinical trial for SKL24741 in 2020.

While the exact mechanism of action is not yet fully understood, the antiepileptic effects of SKL24741 may result from its ability to reduce excitatory nerve activity by inhibiting voltage-gated sodium channels, which helps slow or stop misfiring of the brain’s electrical system that causes seizures. A range of in vitro studies have suggested that SKL24741 has higher affinity for the inactivated phase of these sodium channels, potentially allowing selective targeting of the pathological conditions of epilepsy. Preclinical in vivo studies have demonstrated efficacy in a variety of animal seizure models.

A blond woman cradles her infant in her arms, trying to soothe them.

Doing without Valproate (Depakote) in Women of Childbearing Potential with Idiopathic Generalized Epilepsy: Implications on Seizure Outcome

Objective: Valproate (VPA) use in women with idiopathic generalized epilepsy (IGE) who are of reproductive age has been a matter of concern and debate, which eventually led to the recent restrictions by regulatory agencies. The aim of our study was to investigate the relationship between VPA avoidance/switch and seizure outcome in women of childbearing potential.

Methods: The team retrospectively reviewed data from female patients with IGE, 13-50 years of age, followed since 1980. The researchers evaluated the prescription habits, and the rate of VPA switch for other antiepileptic drugs (AEDs) and its prognostic implications. Seizure remission (SR) was defined as the absence of any seizure type more than 18 months before the last medical observation. The main aim of the study was to assess (a) possible changes in seizure outcome related to VPA switch for other AEDs, especially in patients planning a pregnancy; and (b) possible differences in SR based on the presence/absence of VPA at last observation.

Results: One hundred ninety-eight patients were included in the study. Overall SR at last medical observation was 62.7%. SR significantly differed between subjects taking and those not taking VPA (P < .001) at last visit. Multiple regression models showed that taking VPA at last medical observation was strongly associated with SR in both the general population (P < .001) and the juvenile myoclonic epilepsy (JME) group (P < .001). Thirty-six (70.6%) of 51 patients who switched from VPA during follow-up experienced a clinical worsening. Switching back to VPA was more frequently associated with SR at last observation (P < .001). In those patients who substituted VPA in view of a pregnancy, SR and drug burden (monotherapy vs polytherapy) differed significantly before and after the switch.

Significance: The study suggests that valproate avoidance/switch might be associated with unsatisfactory seizure control in women with idiopathic generalized epilepsy who are of childbearing potential. These findings further highlight the complexity of the therapeutic management of female patients of reproductive age.

Three Anti-Seizure Drugs Equally Effective for Severe Form of Epilepsy

There are three treatment options commonly used by doctors in the emergency room to treat patients with refractory status epilepticus, severe seizures that continue even after benzodiazepine medications, which are effective in controlling seizures in more than two-thirds of patients. New findings published in the New England Journal of Medicine reveal that the three drugs, levetiracetam, fosphenytoin, and valproate, are equally safe and effective in treating patients with this condition. The study was supported by the National Institute of Neurological Disorders and Stroke (NINDS), part of the National Institutes of Health.

“Doctors can be confident that the particular treatment they choose for their patients with status epilepticus is safe and effective and may help them avoid the need to intubate the patient as well as stays in the intensive care unit,” said Robin Conwit, M.D., NINDS program director and an author of the study. “This was a truly collaborative, multidisciplinary study that involved pediatricians, emergency medicine doctors, neurologists, pharmacologists, and biostatisticians all contributing their expertise.”

In the Established Status Epilepticus Treatment Trial (ESETT), led by Robert Silbergleit, MD, professor at the University of Michigan, Ann Arbor; Jordan Elm, PhD, professor at Medical University of South Carolina; James Chamberlain, MD, professor at George Washington University; and Jaideep Kapur, MB, BS, PhD., professor at the University of Virginia, more than 380 children and adults were randomized to receive levetiracetam, fosphenytoin, or valproate when they came to the emergency room experiencing a seizure. The researchers were trying to determine which of the anticonvulsant drugs was most effective in stopping seizures and improving a patient’s level of responsiveness within 60 minutes of administering treatment.

The results showed that the three drugs stopped seizures and improved responsiveness in approximately half of the study participants. Specifically, these benefits were seen in 47% of subjects in the levetiracetam group, in 45% of participants in the fosphenytoin group and in 46% of subjects in the valproate group. These differences were not statistically significant.

There were no differences in serious side effects among the drugs.

FDA Approves New Treatment for Adults with Partial-Onset Seizures

The U.S. Food and Drug Administration approved 11/21/2019 XCOPRI (cenobamate tablets) to treat partial-onset seizures in adults.

“XCOPRI is a new option to treat adults with partial-onset seizures, which is an often difficult-to-control condition that can have a significant impact on patient quality of life,” said Billy Dunn, M.D., director of the Office of Neuroscience in the FDA’s Center for Drug Evaluation and Research. “Patients can have different responses to the various seizure medicines that are available. This approval provides an additional needed treatment option for people with this condition.”

A seizure is a usually short episode of abnormal electrical activity in the brain. Seizures can cause uncontrolled movements, abnormal thinking or behavior, and abnormal sensations. Movements can be violent, and changes in consciousness can occur. Seizures occur when clusters of nerve cells (neurons) in the brain undergo uncontrolled activation. A partial-onset seizure begins in a limited area of the brain.

Parent Reported Health Related Quality of Life (HRQoL) and Behavior in Young People with Epilepsy Before and Two Years After Epilepsy Surgery

PURPOSE: The aim of this study was to compare parent-reported Health Related Quality of Life (HRQoL) and behavior of young people before (baseline) and two years after pediatric epilepsy surgery (follow-up).

METHODS: The parents of 107 children who underwent epilepsy surgery completed surveys focusing on different aspects of child HRQoL and behavior at baseline and follow-up. Parents of children with multiple disabilities (n = 27) completed five additional questions focusing on child HRQoL. Changes in scores between baseline and follow-up were compared using Wilcoxon signed-rank tests. Factors associated with changes in scores were analyzed using linear regression.

RESULTS: HRQoL and behavior were significantly improved at follow-up (p < 0.001). HRQoL was also significantly improved for children with multiple disabilities (p = 0.003). Factors independently associated with improvement in HRQoL on multivariable analysis were lower baseline scores (p < 0.001), seizure-free status (p < 0.001) and improvement in behavior (p = 0.022). Factors independently associated with improvement in behavior were higher baseline difficulties (p < 0.001), reduction in antiepileptic drug (AED) usage, (p < 0.001), seizure-free status (p = 0.04), younger age (p = 0.03), and improvements in HRQoL (p = 0.028).

CONCLUSION: Parent rated HRQoL and behavior had improved two years after epilepsy surgery. Seizure freedom was associated with both improvements in HRQoL and behavior. Additionally, a reduction in AED usage contributed to reduced behavioral difficulties. All children undergoing epilepsy surgery should undergo assessment of HRQoL and behavior at baseline and follow-up.

UCB Announces availability of NAYZILAM® (midazolam) Nasal Spray CIV for Seizure Clusters in the US

UCB announced today that NAYZILAM® (midazolam) nasal spray CIV will be available in retail pharmacies on December 2, 2019, for the acute treatment of intermittent, stereotypic episodes of frequent seizure activity (i.e., seizure clusters, acute repetitive seizures) that are distinct from a patient’s usual seizure pattern in patients with epilepsy 12 years of age and older.1

NAYZILAM is the first and only rescue nasal treatment approved to treat seizure clusters in the U.S. NAYZILAM is a ready-to-use solution that can be used when and where a seizure cluster occurs and can be administered by a non-healthcare professional to a patient during or after a seizure within a cluster.1 As with all benzodiazepines, including NAYZILAM, concomitant use of benzodiazepines and opioids may result in profound sedation, respiratory depression, coma, and death.1

“Delivering another of the six potential new product launches, a UCB mission over the next five years, NAYZILAM builds on UCB’s commitment to addressing the unmet needs of people living with epilepsy,” said Mike Davis, Head of Neurology in the U.S., UCB.  “For the first time, people 12 years and older now have a nasally administered rescue therapy shown to help manage seizure clusters. NAYZILAM can be administered anywhere seizure clusters strike, allowing families to take back valuable moments that would otherwise be lost.”

It is estimated that more than 150,000 people in the U.S. with uncontrolled epilepsy also experience seizure clusters.2-4 Rescue treatment of seizure clusters is critical because when left untreated, seizure clusters can increase the risk of physical injury, neurological damage, and status epilepticus.5-8 Despite the impact of seizure clusters, many diagnosed patients may go untreated because currently available treatment options are not preferred.9-12 Currently, only one in five people living with seizure clusters report using a rescue treatment.5 Many patients seek care in the emergency department.5

“Seizure clusters are a medical emergency that can have very serious consequences for those living with them,” said Dr. Laura Lubbers, Chief Scientific Officer, Citizens United for Research in Epilepsy (CURE). “An effective seizure cluster rescue treatment, like NAYZILAM, that is convenient and easily administered, along with a seizure cluster action plan, can change the lives of people living with seizure clusters and their families.”

The approval of NAYZILAM was based on a placebo-controlled trial, with a primary efficacy endpoint of treatment success, defined by 2 components: 1) seizure termination within 10 minutes and 2) no seizure recurrence within 6 hours.1 NAYZILAM helped the majority of patients stop a seizure cluster fast and helped patients return to baseline function in approximately 90 minutes.1,13 The most common adverse reactions (greater than or equal to 5% in any NAYZILAM treatment group) were somnolence, headache, nasal discomfort, throat irritation, and rhinorrhea.1   Midazolam is associated with a high incidence of partial or complete impairment of recall for the next several hours.1

UCB is committed to finding solutions for patients with unmet needs, including people living with seizure clusters. NAYZILAM builds on UCB’s long-standing leadership in epilepsy and commitment to enabling patients to live their best lives.
It is anticipated that NAYZILAM prescriptions will cost commercial patients $40 per box.13 Each box contains two doses.1 With the NAYZILAM Savings Card, eligible patients could pay $20 per box.13

For additional medical information about NAYZILAM, patient assistance, or any other information please visit NAYZILAM.com or call ucbCARES® at 1-844-599-2273. Full affordability information can be found at UCBUSA.news/Affordability.