News Topics: Treatments

Invited Commentary: Ketamine Should Be Started Earlier in the Course of Human Status Epilepticus as a Neuroprotectant

Ketamine is currently being used as an anesthetic/antiepileptic drug in refractory status epilepticus. To validate its use, 2 clinical trials are recruiting patients. However, preclinical studies of its use in chemically induced status epilepticus in rodents have shown that it is remarkably neuroprotective, through N-methyl-d-aspartate–receptor blockade, even when given after the onset of status epilepticus. Human studies have shown that status epilepticus–induced brain damage can be caused by a glutamate analogue and that it occurs in the same brain regions as in the animal studies.

Researchers therefore propose that ketamine be started early in the course of human status epilepticus as a neuroprotectant and that it be continued until epileptic discharges are eliminated. Using it as an anesthetic/antiepileptic drug late in the course of refractory status epilepticus only ensures that it is given after widespread brain damage has occurred.

Neuroelectrics Announces Positive Results for Treatment of Medication-Resistant Epilepsy Using Starstim™

At the recent American Epilepsy Society Annual Meeting in New Orleans, Neuroelectrics Corporation presented positive results from its clinical trial treating patients with drug resistant epilepsy with Starstim™, a device that uses mild electric currents applied on the scalp to calm abnormal activity of the brain. Of the seventeen patients that completed the study, treatment with Neuroelectrics’ Starstim™ device resulted in a reduction in seizure frequency of at least 40% from baseline in 75% of the patients, measured eight weeks after treatment. Also, no device-related adverse events were reported during the study.

Neuroelectrics sponsored the FDA-approved investigational device study of its Starstim™ product (NCT02866240) at Boston Children’s Hospital, with adult patients being referred from nearby Beth Israel Deaconess Medical Center. A parallel study following the same protocol was conducted at the National Institute of Neurology and Neurosurgery in Mexico City.

All patients enrolled in the study had not responded to at least two anti-epileptic medications, and for many the next step would be brain surgery to resect the region of the brain where the seizures originate. The treatment protocol used 20 minutes of daily stimulation applied for 10 days times over two weeks, followed by an eight-week monitoring period to measure seizure frequency.

Cannabidiol Reduces Seizures in Patients with Lennox-Gastaut Syndrome: Interim Analysis of an Open-Label Extension Study

Objective: Patients with Lennox-Gastaut syndrome (LGS) who completed 1 of 2 randomized, double-blind, placebo-controlled trials of add-on cannabidiol (CBD) (GWPCARE3, NCT02224560 or GWPCARE4, NCT02224690) were invited to enroll in an open-label extension (OLE) study evaluating the long-term safety and efficacy of CBD (GWPCARE5, NCT02224573). This study is an interim analysis of the safety, efficacy, and patient-reported outcomes from this trial.

Methods: Patients received a pharmaceutical formulation of highly purified CBD oral solution (Epidiolex; 100 mg/mL), titrated from 2.5 to 20 mg/kg/d over a 2-week titration period, in addition to their existing medications. Doses could be reduced if not tolerated or increased up to 30 mg/kg/d if thought to be of benefit.

Results: This interim analysis was based on a November 2016 data cut. Of 368 patients who completed treatment in GWPCARE3 and GWPCARE4, 366 (99.5%) enrolled in the OLE study (GWPCARE5). Median treatment duration was 38 weeks at a mean modal dose of 23 mg/kg/d. Most patients (92.1%) experienced adverse events (AEs), primarily of mild (32.5%) or moderate (43.4%) severity. The most common AEs were diarrhea (26.8%), somnolence (23.5%), and convulsion (21.3%). 35 patients (9.6%) discontinued treatment due to AEs. Liver transaminase elevations were reported in 37 patients (10.1%), of whom 29 were receiving concomitant valproic acid; 34 cases resolved spontaneously or with dose modification of CBD or concomitant medication. Median reduction from baseline in drop seizure frequency (quantified monthly over 12-week periods) ranged from 48% to 60% through week 48. Median reduction in monthly total seizure frequency ranged from 48% to 57% across all 12-week periods through week 48. 88% of patients/caregivers reported an improvement in the patient’s overall condition per the Subject/Caregiver Global Impression of Change scale.

Significance: In this study, long-term add-on cannabidiol treatment had an acceptable safety profile in patients with LGS and led to sustained reductions in seizures.

Zogenix Submits New Drug Application to FDA and Marketing Authorization Application to European Medicines Agency for FINTEPLA® for the Treatment of Dravet Syndrome

Zogenix, Inc. announced it has completed its rolling submission of a New Drug Application (NDA) to the FDA and submitted a Marketing Authorization Application (MAA) to the European Medicines Agency (EMA) for FINTEPLA (ZX008, low-dose fenfluramine) for the treatment of seizures associated with Dravet syndrome. Dravet syndrome is an intractable and difficult-to-treat epilepsy that begins in infancy and is associated with frequent, severe, and potentially life-threatening seizures, developmental delay, and cognitive impairment.

Both applications are based on data from two pivotal Phase 3 trials in Dravet syndrome and an interim analysis from an ongoing open-label extension study, which included 232 patients treated for up to 21 months.

Lisuride Shows Promise as Dravet Syndrome Treatment, Zebrafish Study Suggests

Lisuride, an anti-parkinson medicine with demonstrated anti-seizure effects, was able to stop epileptic activity in a model of convulsant Dravet syndrome zebrafish, researchers report. The study with that finding, “Drug repurposing for Dravet syndrome in scn1Lab?/? mutant zebrafish,” was published in Epilepsia.

Recent studies have used a zebrafish model of Dravet syndrome to reveal the role of pharmacologic modulation of the serotonin (5-HT) system in treating drug-resistant seizures. Serotonin is a chemical known as a neurotransmitter (used to transmit messages between nerve cells). It plays a key role in the central nervous system (CNS) and the body’s function in general.

“With the aim to bring novel therapeutics to the market together with reducing the costs associated with traditional de novo drug development, many efforts are underway to repurpose existing drugs,” researchers wrote.

As such, investigators from the University of Leuven in Belgium, preformed a literature search on already marketed medicines that could affect the serotonin system.

They found three compounds that filled these criteria: rizatriptan (a headache medicine, brand name Maxalt), lisuride (antiparkinson medicine, brand names Dopergin, Proclacam, and Revanil) and efavirenz (an anti-HIV medicine, brand name Sustiva, among others).

They then investigated the feasibility of repurposing the above-mentioned marketed medicines as anti-epileptic drugs, particularly in difficult-to-treat epilepsy conditions like Dravet syndrome.

Fenfluramine, a Serotonin-Releasing Drug, Prevents Seizure-Induced Respiratory Arrest and is Anticonvulsant in the DBA/1 Mouse Model of SUDEP

OBJECTIVE: Prevention of sudden unexpected death in epilepsy (SUDEP) is a critical goal for epilepsy therapy. The DBA/1 mouse model of SUDEP exhibits an elevated susceptibility to seizure-induced death in response to electroconvulsive shock, hyperthermia, convulsant drug, and acoustic stimulation. The serotonin hypothesis of SUDEP is based on findings that treatments which modify serotonergic function significantly alter susceptibility to seizure-induced sudden death in several epilepsy models, including DBA/1 mice. Serotonergic abnormalities have also recently been observed in human SUDEP. Fenfluramine is a drug that enhances serotonin release in the brain. Recent studies have found that the addition of fenfluramine improved seizure control in patients with Dravet syndrome, which has a high incidence of SUDEP. Therefore, we investigated the effects of fenfluramine on seizures and seizure-induced respiratory arrest (S-IRA) in DBA/1 mice.

METHODS: The dose and time course of the effects of fenfluramine (i.p.) on audiogenic seizures (Sz) induced by an electric bell in DBA/1 mice were determined. Videos of Sz-induced behaviors were recorded for analysis. Statistical significance (P < 0.05) was evaluated using the chi-square test.

RESULTS: Sixteen hours after administration of 15 mg/kg of fenfluramine, a high incidence of selective block of S-IRA susceptibility (P < 0.001) occurred in DBA/1 mice without blocking any convulsive behavior. Thirty minutes after 20-40 mg/kg of fenfluramine, significant reductions of seizure incidence and severity, as well as S-IRA susceptibility occurred, which were long-lasting (less than or equal to 48 hours). The median effective dose (ED50 ) of fenfluramine for significantly reducing Sz at 30 minutes was 21 mg/kg.

SIGNIFICANCE: This study presents the first evidence for the effectiveness of fenfluramine in reducing seizure incidence, severity, and seizure-induced respiratory arrest susceptibility in a mammalian SUDEP model. The ability of fenfluramine to block seizure-induced respiratory arrest selectively suggests the potential usefulness of fenfluramine in prophylaxis of SUDEP. These results further confirm and extend the serotonin hypothesis of SUDEP.

Omega-3 Supplementation Associated With Fewer And Shorter Seizures In Epileptics

A triple-blind trial reported in Clinical and Translational Medicine found a benefit for supplementation with the omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) among men and women with intractable seizures.

The trial included 50 patients with treatment-resistant epilepsy who received a placebo or 180 milligrams (mg) EPA plus 120 mg DHA twice daily for 16 weeks. Seizure frequency and duration, and blood levels of the inflammatory factors tumor necrosis factor-alpha (TNF-a) and interleukin-6 (IL-6) were assessed at the beginning and end of the trial.

FDA to Review Cenobamate for the Treatment of Partial-Onset Seizures

The FDA has accepted for filing the New Drug Application (NDA) for cenobamate (SK Life Science), an investigational antiepileptic drug being developed for the treatment of partial-onset seizures in adults.

The NDA submission includes results from a clinical trial program which included over 1900 patients. Adjunctive treatment with cenobamate was found to significantly decrease seizure frequency in 2 well-controlled studies, however cases of drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome were reported in early clinical development among the first patients exposed to the drug. In December 2018, results from a large Phase 3 safety study showed that among the 1037 patients exposed to cenobamate, no cases of DRESS were identified; reducing the starting dose and slowing titration rate appeared to reduce the risk.

Pregabalin Effective in Reducing Seizure Frequency in Children with Focal Onset Seizures

In this double-blind, randomized, placebo-controlled, international study, researchers assessed the effectiveness and safety of pregabalin as adjunctive treatment for children (aged 4-16 years) with partial-onset seizures, termed focal onset seizures for this investigation. The criteria for selection included focal onset seizures and a stable regimen of 1 to 3 antiepileptic drugs. Pregabalin 2.5 mg/kg/d, 10 mg/kg/d or placebo were used in the study, with doses increased to 3.5 or 14 mg/kg/d for subjects weighing <30 kg. According to findings, pregabalin 10 mg/kg/d was effective in reducing the seizure frequency in children with focal onset seizures vs placebo, and both doses of pregabalin were generally safe and well tolerated. Common adverse events included somnolence, increased weight and increased appetite.

Ohio State Leading World’s First Study Using Focused Ultrasound to Treat Epilepsy

In a first-in-world clinical trial, researchers at The Ohio State University College of Medicine are studying how well focused ultrasound surgery works in adults with a specific type of epilepsy whose seizures are not controlled by medication.

Up to 10 adults with the “medically refractory lobe focal onset” type of epilepsy will be enrolled in this study. The technique uses magnetic resonance-guided focused ultrasound through an intact skull to reach tissue deep in the brain without incisions or radiation. With this technology, 1,024 ultrasound beams pass through the scalp, skull and brain tissue without causing any harm and converge at a focal point to ablate specific brain tissue involved in epilepsy.

“We’re pursuing this clinical trial because we know there’s a large unmet clinical need. More than 20 million people worldwide live with uncontrollable seizures because no available treatment works for them,” said neurosurgeon Dr. Vibhor Krishna, who is leading the study at The Ohio State University Wexner Medical Center and Ohio State’s Neurological Institute. “Our goals are to test the safety of this procedure and study changes in seizure frequency in these patients.”