Epilepsy Research Findings: March 2020

This month’s research highlights feature promising work by former CURE Grantees and CURE partners.

Former CURE Grantee Dr. Kristina Simeone’s recent research has uncovered a potential predictive biomarker for Sudden Unexpected Death in Epilepsy (SUDEP). Dr. Simeone’s work was supported by the Benninghoven family in memory of Cameron Benninghoven.

We also feature research by another former CURE Grantee, Dr. Angelique Bordey, who along with her research team published exciting findings showing that targeting a particular protein in the brain can reduce or prevent seizures in mouse models of difficult-to-treat epilepsy.

We are also highlighting research by Dr. Daniel Correa and his work through the EpiBioS4Rx Public Engagement Core, a project in which CURE participates. Dr. Correa’s research indicates that greater efforts should be made to ensure online epilepsy health education materials are more easily understandable to the general population to increase epilepsy literacy.

These findings, as well as others, can be found below:

Research Discoveries & News

SUDEP: Research featuring the work of former CURE Grantee Dr. Kristina Simeone found a potential time-based biomarker of impending SUDEP. Dr. Simeone found cardiac and respiratory dysfunction that changed over time in mice at risk for SUDEP and may serve as a biomarker to indicate who is at risk for SUDEP. She also found that this dysfunction could be lessened by blocking a particular type of receptor in the brain, the orexin receptor. Learn More
This research was supported by the Benninghoven family in memory of Cameron Benninghoven.
Uncontrolled Epilepsy Treatment: Former CURE Grantee Dr. Angelique Bordey and her research team utilized an experimental drug to reduce seizures in mouse models of tuberous sclerosis complex (a rare genetic epilepsy) and a subset of focal cortical dysplasia type II (a brain malformation causing epilepsy). The team found that seizures can be prevented or reduced by targeting a protein called actin-cross linking protein filament A which is often elevated in the brains of humans with these epilepsies. Learn More
Online Epilepsy Education: Researcher Dr. Daniel Correa found that the majority of online health education materials related to traumatic brain injury (TBI), epilepsy, and post-traumatic epilepsy (PTE) do not meet the sixth-grade reading level recommendation from most health organizations. This study was published as part of the CURE-supported EpiBioS4Rx Public Engagement Core, an NINDS initiative focused on ensuring successful future clinical trials to prevent the development of PTE following TBI. This study suggests that improving the readability of health education materials may increase epilepsy-related health literacy, leading to more effective recruitment efforts for future clinical trials, as well as better patient-centered results. Learn More
New Treatment: Valtoco (diazepam), a nasal spray intended to treat seizure emergencies in patients 6 years of age and older, is now commercially available in the US. Learn More
Clinical Trial: Engage Therapeutics announced that its Phase 2b StATES study of Staccato® alprazolam, an orally inhaled therapy designed to terminate an active epileptic seizure, met its primary endpoint. This endpoint was a proportion of responders achieving cessation of seizure activity within two minutes of treatment administration and no recurrence within two hours. Learn More
Post-Traumatic Epilepsy: Research suggests that rats treated with certain drugs within a few days of a traumatic brain injury have a dramatically reduced risk of developing epilepsy later in life. Researchers found that suppressing an immune system receptor called Toll-like receptor 4 shortly after brain injury reduces seizure susceptibility and neuronal excitability in an important part of the brain called the hippocampus. Learn More
SCN8A Encephalopathy: A therapy that enables researchers to control gene expression in the brain, called antisense oligonucleotides (ASOs), has been utilized to stop seizures in a mouse model of SCN8A encephalopathy, a rare childhood epilepsy. By using ASOs, researchers delayed seizure activity and increased the lifespan of these mice. Learn More

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FDA Approves MRI Labeling for Neurostimulation System Designed to Prevent Seizures

The Food and Drug Administration (FDA) has approved MRI labeling for the RNS® System (NeuroPace), a closed-loop brain-responsive neurostimulation system indicated as adjunctive therapy to reduce the frequency of seizures in adults with partial onset seizures who have undergone diagnostic testing that localized no more than 2 epileptogenic foci, are refractory to 2 or more antiepileptic medications, and currently have frequent and disabling seizures (motor partial seizures, complex partial seizures and / or secondarily generalized seizures).

With this approval, an MRI scan may be safely performed on patients with the RNS-320 neurostimulator model under the specific conditions of safe use detailed in the MRI Guidelines for the RNS System, providing an additional option for patients with focal onset seizures with brain anomalies that require frequent monitoring (ie, patients with tuberous sclerosis, brain tumors, and multiple sclerosis).

“MRI conditional labeling opens up valuable medical imaging possibilities for our patients treated with the model RNS-320 neurostimulator, who can now receive full-body 1.5T magnetic resonance imaging scans under appropriate conditions,” said Michael Favet, President and CEO of NeuroPace. “I’m pleased that we have removed a potential barrier to treatment and increased the number of patients who can benefit from this life-changing therapy.”

Engage Therapeutics Announces Phase 2b StATES Study of Staccato® Alprazolam for Seizure Cessation Meets Primary Endpoint

Engage Therapeutics, Inc., a clinical-stage biopharmaceutical company focused on developing an orally inhaled therapy designed to terminate an active epileptic seizure, today announced that its Phase 2b StATES study of Staccato® alprazolam met its primary endpoint which was proportion of responders achieving cessation of seizure activity within two minutes of treatment administration and no recurrence within two hours.

“With statistically significant and clinically meaningful Phase 2 results in this randomized, placebo-controlled trial, Staccato alprazolam has demonstrated the ability to rapidly terminate seizures in patients with epilepsy in two minutes or less and prevent recurrence of seizure within two hours,” said Jaqueline French, MD, the study’s principal investigator and professor of neurology and co-director of epilepsy research and epilepsy clinical trials at NYU Langone Health’s Comprehensive Epilepsy Center, and founder/director of the Epilepsy Study Consortium. “We are now one step closer to bringing to patients an EpiPen®-like rescue treatment that works fast enough to terminate an active seizure episode. We look forward to initiating a Phase 3 study in the outpatient setting later this year.”

Drug Shows Promise in Reducing Seizures in Those with Severe Epilepsy

Featuring the work of former CURE Grantee, Dr. Angelique Bordey

People who suffer severe and recurring seizures have few good treatment options, but an experimental drug can reduce seizures in mouse models of two underlying disorders that can cause chronic epilepsy, Yale researchers report in the journal Science Translational Medicine.

Severe forms of epilepsy caused by brain lesions or malformations are usually treated with surgeries and anti-seizure medication. However, the prognosis for many of these patients remains poor, said Angelique Bordey, professor of neurosurgery and of cellular and molecular physiology.

“This is a completely new treatment with unexpected benefits,” Bordey said.

In a study led by first author Longbo Zhang, the Bordey lab reports the elevated expression of actin-cross linking protein filamin A (FLNA) in the brain tissue of many patients with two genetic disorders linked to intractable seizures: tuberous sclerosis complex (TSC) and a subset of focal cortical dysplasia type II. Both disorders are associated with disruption of a regulator of cell growth and cortical malformations with enlarged, dysmorphic cells that are responsible for seizures. Using a drug targeting FLNA to treat mice models of the disorders, Bordey’s lab found that cell enlargement and seizures could be prevented or reduced.

Bordey said her lab plans to explore whether the drug will be effective in treating people with epilepsy and perhaps other symptoms of TSC, such as behavioral problems, including social and intellectual deficits.

The work was primarily funded by the National Institute of Neurological Disorders and Stroke.

FDA Extends Review of Fintepla for Dravet Syndrome; Response Expected in June

The FDA extended by three months the review period for Zogenix’s New Drug Application (NDA) for Fintepla (ZX008), an investigational anti-seizure therapy for patients with Dravet syndrome.

The agency now expects to provide a decision by June 25 on whether to approve Fintepla for the treatment of seizures associated with Dravet.

The extension will allow the FDA more time to review additional data Zogenix submitted in response to a request from the agency. “The FDA determined that the submission of this information constituted a major amendment to the NDA,” Zogenix said.

The company resubmitted the data in November 2019. The FDA gave the application priority review status, meaning it could take action within six months, instead of the standard 10 months.

Study Finds Chances of Successful Long-Term Seizure Control Declines with Each Reoperation

Long-term seizure control is achievable in patients with failed prior epilepsy surgery, but the likelihood of success decreases with each reoperative attempt, regardless of other clinical factors. So finds the first single-center study of longitudinal outcomes and outcome predictors following epilepsy reoperations in a large cohort of patients with medically refractory focal epilepsy.

The study, published by Cleveland Clinic Epilepsy Center staff in Epilepsia, proposes a novel concept of “surgical refractoriness” as a possible contributor to the diminishing returns from repeated epilepsy surgeries.

“Our findings, particularly the notion of surgical refractoriness of the epileptogenic zone, underscore the need for prudent selection of candidates for reoperative epilepsy surgery,” says the study’s corresponding author, Lara Jehi, MD, Research Director in Cleveland Clinic’s Epilepsy Center. “As our tools for seizure localization improve, there is an understandable urge to consider further surgery after a previous surgical failure, to address any residual epileptogenic tissue. However, our results build on other recent data suggesting that inherent and potentially genetic patient characteristics may raise the risk of operative failure regardless of the quality of localization and resection.”

Neurelis Announces Commercial Availability Valtoco (Diazepam Nasal Spray) Seizure Cluster Rescue

Neurelis Press Release

Neurelis, Inc., announced today the commercial availability of VALTOCO^® (diazepam nasal spray) 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 adult and pediatric patients 6 years of age and older.

Neurelis President and CEO Craig Chambliss said the company has been working diligently to deliver VALTOCO to the epilepsy community following the U.S. Food and Drug Administration (FDA) approval of VALTOCO on January 10, 2020, where it recognized VALTOCO’s intranasal route of administration as clinically superior to the previously approved standard of care treatment. “We understand the high unmet need for VALTOCO and we are very pleased to be able to make this available for patients with seizure clusters less than two months after our FDA approval,” Chambliss said. “Our commitment to the epilepsy community drives every team member at Neurelis as we accomplish this goal.”

In the United States, there are over 3.4 million people with epilepsy, with approximately 200,000 new patients diagnosed each year. Despite the availability of chronic, daily oral medications to control epilepsy, a significant number of these patients continue to experience seizures. Of these uncontrolled patients, as many as 170,000 are at risk for episodes of frequent seizure activity, also known as seizure clusters or acute repetitive seizures, representing a significant unmet need in the epilepsy community.

Chuck DeWildt, Chief Commercial Officer at Neurelis, announced Maxor Specialty Pharmacy has been selected as the national pharmacy provider and has already begun filling patient prescriptions. “VALTOCO is the first commercial product for Neurelis and we are now rapidly building our commercial organization,” DeWildt said. “Working with Maxor allows us to expedite the availability of VALTOCO for patients, healthcare providers and care partners who need it in advance of VALTOCO availability in retail pharmacies in the near future.” He added that Maxor will be able to serve all patients regardless of the type of insurance (commercial, private insurance, Medicaid or Medicare).

Michael Einodshofer, Chief Pharmacy Officer of Maxor, commented, “We look forward to our relationship with Neurelis and helping epilepsy patients across the country quickly gain access to this important new treatment.”

In an effort to support patients, Neurelis is offering a VALTOCO copay assistance program through which eligible patients could pay as little as $20 for the prescription. Neurelis has also set up a patient assistance program in which eligible patients who do not have insurance may qualify for additional assistance.

Jacqueline A. French, MD, professor in the Department of Neurology at NYU Langone Health’s Comprehensive Epilepsy Center and Chief Medical & Innovation Officer for the Epilepsy Foundation, said, “Having a seizure cluster rescue treatment that is generally safe, reliable and ready-to-use is great news for our epilepsy community. Seizure rescue treatments such as this, combined with an up-to-date seizure rescue treatment plan, can help improve the quality of life for those experiencing seizure clusters.”

New Therapy Stops Seizures in Mouse Model of Rare Childhood Epilepsy

SCN8A encephalopathy could be improved with a treatment already approved for other uses.

Seizure disorders in babies are frightening and heartbreaking. A new basic science breakthrough offers hope for a potential treatment for rare developmental and epileptic encephalopathies resulting from a single genetic mutation. The gene in question, called SCN8A, controls a sodium channel that allows neurons to transmit an electric signal. When this gene is mutated, these channels can become hyperactive, resulting in recurrent seizures. The average age of onset of SCN8A-related encephalopathy is just four months old.

“Approximately half of patients are severely impaired and cannot walk or talk,” says Miriam Meisler, Ph.D. Meisler is the Myron Levine Distinguished University Professor of Human Genetics and a Professor of Neurology at U-M Medical School. She and her team have studied this disease and its genetic mechanisms for many years, painstakingly developing mouse models that would allow for testing new therapies.

Within the past few years, a new therapy called antisense oligonucleotide (ASOs) has entered the scene, enabling researchers to control gene expression. ASOs are short DNA or RNA molecules designed to block messenger RNA molecules and their encoded proteins. This allows them to control the amount of RNA expressed by mutated genes, dampening their effects on the body.

The team realized the potential of ASOs for this seizure disorder. Their first achievement was developing a mouse model that accurately and predictably mimicked the disease in people. They generated a mouse with the same SCN8A mutation found in several patients but with the mutation turned off long enough to test the therapy.

Developing mice with an “on switch”, they were able to administer the ASO, and then turn on the mutation. “The effect was dramatic and unambiguous,” says Meisler. “We had a four-fold increase in lifespan, with added effects of repeated treatments.” There was no evidence of low-level seizure activity in the treated mice.

FDA Accepts NDA for Aquestive’s Libervant for Seizures

The FDA accepted Aquestive Therapeutics’ New Drug Application (NDA) for Libervant (diazepam) Buccal Film for seizure clusters. It has a target action date of September 27, 2020.

Libervant is a formulation of diazepam on a soluble film that is administered on the inside of the cheek. It is intended for fast treatment of acute uncontrolled seizures in refractory patients with epilepsy on stable anti-epileptic drugs (AEDs). If approved, it will be the first oral diazepam-based therapy approved for seizure clusters. The FDA granted it Orphan Drug designation in November 2016.

“The FDA filing acceptance for Libervant is an important milestone in our mission to provide epilepsy patients with a broader array of treatment options, that represent major contributions to patient care,” said Keith J. Kendall, Aquestive’s chief executive officer.

Investigators Found No Notable Difference in Seizure Control Between Patients Whose Blood Levels of Antiepileptic Drugs Were Monitored and Those Whose Levels Were Not Monitored

Article featuring commentary from CURE Grantee Dr. Pavel Klein

Doing routine monitoring of drug levels of the newer antiepileptic drugs (AEDs) may not lead to better seizure control or treatment tolerance for patients with epilepsy, according to a randomized trial from Switzerland.

The trial compared a group of patients whose doctors knew the results of their patient’s systematic therapeutic drug monitoring with a group of patients whose blood test results were not revealed to the treating physician. The investigators found no notable difference between the two groups when it came to seizure control and adverse events over the length of the study, which was published in the January issue of Annals of Neurology.

“The main finding is that despite the variable bioavailability of the newer- generation AEDs, the systematic monitoring of their plasma levels does not bring a tangible benefit for patients,” said Jan Novy, MD, PhD, the study supervisor, neurologist, and senior lecturer at the University of Lausanne.

However, therapeutic drug monitoring of the newer AEDs is advisable in certain situations, such as when the patient is pregnant or there is a suspicion the patient is not taking the medication as prescribed, Dr. Novy told Neurology Today in an interview.

Pavel Klein, MD, FAAN, founder and director of the Mid-Atlantic Epilepsy Center In Bethesda, MD, said the new study echoes an epilepsy treatment mantra he learned in residency that “you treat the patient, not blood levels.”

“The study confirms the general clinical practice impression that usefulness of getting drug levels on the newer AEDs is limited when you compare a patient against the general population, especially given the broad therapeutic ranges of the newer AEDs, which are so broad as to be virtually meaningless.”

Research Discoveries & News

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