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.”

Hand holding Valtoco Nasal Spray

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.”

Antiepileptic Drug Effects on Aubjective and Objective Cognition

RATIONALE: Cognitive impairment is one of the most common complaints for persons with epilepsy (PWE). These impairments are not only associated with seizures, but are also regularly reported as adverse effects of antiepileptic drugs (AEDs). Previous studies have examined cognitive effects of both AED monotherapy and polytherapy, yet there is limited research on these differences with respect to both subjective and objective cognition. The current study uses data from previous research conducted by the Centers for Disease Control and Prevention (CDC)-sponsored Managing Epilepsy Well (MEW) Network collaborative. We used three distinct archival datasets from the following: (1) the HOBSCOTCH efficacy trial at Dartmouth-Hitchcock Medical Center (HOB-1), (2) the multisite replication trial (HOB-2), and (3) epilepsy self-management research conducted at the NYU School of Medicine.

METHODS: This retrospective analysis combined baseline data from three datasets to determine how the number of AEDs and the type of AEDs were associated with subjective (patient-reported) and objective (examiner-assessed) cognition. Subjective cognition was captured using the cognitive subscale of the Quality of Life in Epilepsy Inventory (QOLIE-31) in all three datasets (n = 224), while objective cognition was measured using the Repeated Battery for the Assessment of Neuropsychological Status (RBANS) in the HOB-1 dataset (n = 65) and the Brief Test of Adult Cognition by Telephone (BTACT) in the HOB-2 dataset (n = 91). Multivariable linear regression was utilized for our initial assessments, followed by propensity score matching to provide stronger control of covariates. Matching was based on significantly different covariates, such as education, depression, and history of prior epilepsy surgery. Nonparametric statistical tests were utilized to compare these matched subjects.

RESULTS: Subjective cognitive impairment was significantly worse among individuals on monotherapy (1 AED) compared with those on polytherapy (2+ AEDs) (adjusted p = 0.041). These findings were consistent with the propensity score matched comparison of monotherapy and polytherapy, which indicated that polytherapy was associated with worse overall subjective cognition (adjusted p = 0.01), in addition to impairments on the RBANS (Total score p = 0.05) and specific subdomains of the BTACT (Episodic Verbal Memory p < 0.01, Working Memory p < 0.01, Processing Speed p < 0.01). Interestingly, older generation AEDs were associated with better language performance than newer generation and combined generation AED therapy (RBANS Language p = 0.03). These language-specific findings remained significant after controlling for the effects of topiramate and zonisamide (p = 0.04).

CONCLUSIONS: A greater number of antiepileptic drugs (AEDs) is significantly and negatively associated with subjective and objective cognition in people with epilepsy, and is in line with previous research. Antiepileptic drug type did not, in itself, appear to be associated with subjective cognition. These findings suggest that ineffective AEDs should be replaced, rather than introducing additional AEDs to a treatment regimen. Further, while subjective and objective cognition assessments were both sensitive at detecting differences based on AED status, the neuropsychological objective subdomains offer additional and specific insights into how cognition is impaired with AEDs.

Study Suggests that FDA-Approved Drug Riluzole can be Pepurposed to Treat Epilepsies Caused by Kv1 Channel Disorders

Objective: Ion channels belonging to subfamily A of voltagegated potassium channels (Kv1) are highly expressed on axons, where they play a key role in determining resting membrane potential, in shaping action potentials, and in modulating action potential frequency during repetitive neuronal firing. This team aimed to study the genesis of seizures caused by mutations affecting Kv1 channels and searched for potential therapeutic targets.

Methods: This research team used a novel in silico model, the Laminar Cortex Model (LCM), to examine changes in neuronal excitability and network dynamics associated with loss-of-function mutations in Kv1 channels. The LCM simulates the activities of a network of tens of thousands of interconnected neurons and incorporates the kinetics of 11 types of ion channel and three classes of neurotransmitter receptor. Changes in two types of potassium currents conducted by Kv1 channels were examined: slowly inactivating D-type currents and rapidly inactivating A-type currents. Effects on neuronal firing rate, action potential shape, and neuronal oscillation state were evaluated. A systematic parameter scan was performed to identify parameter changes that can reverse the effects of the changes.

Results: Reduced axonal D-type currents led to lower firing threshold and widened action potentials, both lowering the seizure threshold. Two potential therapeutic targets for treating seizures caused by loss-of-function changes in Kv1 channels were identified: persistent sodium channels and NMDA receptors. Blocking persistent sodium channels restored the firing threshold and reduced action potential width. NMDA receptor antagonists reduced excitatory postsynaptic currents from excessive glutamate release related to widened action potentials.

Significance: Riluzole reduces persistent sodium currents and excitatory postsynaptic currents from NMDA receptor activation. The researchers state that these results suggest that this FDA-approved drug can be repurposed to treat epilepsies caused by mutations affecting axonal Kv1 channels.

Systematic Review Highlights That Clinicians Should Be Aware of Possible Skin-related Drug Reactions to Levetiracetam

PURPOSE: Recently, there have been an increased number of reports on levetiracetam (LEV) induced cutaneous adverse drug reactions (CADRs). This research team aimed to identify and critically evaluate all the descriptive studies on LEV induced-CADRs and to describe the possible clinical manifestations, management, and treatment outcomes of the condition.

METHODOLOGY: PubMed and grey literature databases were searched from inception to June 2019 without any restriction. The team also performed a bibliographic search for additional studies. Only descriptive studies on LEV-induced CADRs were included for our review. Study selection, data abstraction and quality assessment were performed by two contributors independently and disagreements were settled through consensus or through discussion with a third reviewer.

RESULTS: Data from 24 out of 88 studies, which included 25 patients (12 female and 13 male) aged from 40 weeks to 73 years, were reviewed. Patients received between 500 mg/day to 3000 mg/day of LEV. Drug reaction with eosinophilia and systemic symptoms syndrome, Steven-Johnson syndrome, toxic epidermal necrolysis, acute generalised exanthematous pustulosis, generalised hyperpigmentation and leucocytoclastic vasculitis were observed among the included patients. Immediate cessation of LEV, providing supportive care and use of topical antihistamines and anti-inflammatory drugs appeared to be the mainstay of management, and all patients were found to have recovered.

CONCLUSION: Clinicians should be aware of the possible cutaneous adverse drug reactions induced by levetiracetam to avoid the development of a potentially fatal condition. Immediate withdrawal of the drug and supporting care seem to be effective in the management of the cutaneous adverse drug reactions.

Epilepsy Research Findings: January 2020

This past month of research advances include the finding that “silencing” certain populations of neurons may stop seizures and the uncovering of a possible cause of memory impairments in individuals with epilepsy. In addition, a study found that one in every four children in the US with epilepsy has anxiety and/or depression, emphasizing the importance of investing resources into epilepsy and mental health.

Other exciting news for the epilepsy community includes the approval of a new nasally administered rescue medication called VALTOCO and the expanded availability of the no-cost epilepsy gene panel testing program Behind the Seizure® to a wider age range of children who have had an unprovoked seizure.

Summaries of these research discoveries and news highlights are below.

Research Discoveries & News

  • Seizure Control: Seizures can be “switched off” in an animal model of epilepsy by silencing one particular set of neurons located in the brainstem, specifically in an area called the substantia nigra, according to research from the Georgetown University Medical Center. Zeroing in on specific neurons suggests that treatment for epilepsy can be improved, researchers say. Learn More
  • Epilepsy and Memory: A new Cedars-Sinai study reveals how memory and abnormal brain activity are linked in patients with epilepsy. The data show that abnormal electrical pulses from specific brain cells are associated with a temporary kind of memory disruption called transient cognitive impairment. Learn More
  • Epilepsy and Depression: A study utilizing data from the 2009-2010 National Survey of Children with Special Health Care Needs found that one in four US children with epilepsy has depression and/or anxiety. The study authors concluded that physicians should consider the various factors that are related to depression and anxiety in children with epilepsy so that at-risk children can be screened and managed appropriately. Learn More
  • Treatment Approval: Neurelis, Inc. announced that the FDA has approved VALTOCO® (diazepam nasal spray) as an acute treatment of intermittent, stereotypic episodes of frequent seizure activity (seizure clusters, acute repetitive seizures) that are distinct from a patient’s usual seizure pattern in people with epilepsy 6 years of age and older. Learn More
  • Genetic Testing: The no-cost epilepsy gene panel testing program Behind the Seizure®, which aims to provide faster diagnosis for young children with epilepsy, is being extended to any child under the age of eight who has an unprovoked seizure. Learn More

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