Drug Development for Rare Paediatric Epilepsies: Current State and Future Directions

Rare diseases provide a challenge in the evaluation of new therapies. However, orphan drug development is of increasing interest because of the legislation enabling facilitated support by regulatory agencies through scientific advice, and the protection of the molecules with orphan designation.

In the landscape of the rare epilepsies, very few syndromes, namely Dravet syndrome, Lennox-Gastaut syndrome and West syndrome, have been subject to orphan drug development. Despite orphan designations for rare epilepsies having dramatically increased in the past 10 years, the number of approved drugs remains limited and restricted to a handful of epilepsy syndromes.

In this paper, researchers describe the current state of orphan drug development for rare epilepsies. They identified a large number of compounds currently under investigation, but mostly in the same rare epilepsy syndromes as in the past. A rationale for further development in rare epilepsies could be based on the match between the drug mechanisms of action and the knowledge of the causative gene mutation or by evidence from animal models. In case of the absence of strong pathophysiological hypotheses, exploratory/basket clinical studies could be helpful to identify a subpopulation that may benefit from the new drug.

The team provides some suggestions for future improvements in orphan drug development such as promoting pediatric drug investigations, better evaluation of the incidence and the prevalence, together with the natural history data, and the development of new primary outcomes.

Results of a Randomized Study of the Safety and Efficacy of Cenobamate in Adults with Uncontrolled Focal Seizures Published in The Lancet Neurology

SK Life Science announced The Lancet Neurology has published results from a multicenter, double-blind, randomized, placebo-controlled, dose-response study of the safety and efficacy of cenobamate, an investigational anti-epileptic drug (AED), in adults with uncontrolled focal (partial-onset) seizures. The results of the study demonstrated that adjunctive treatment with cenobamate produced significant reductions in seizures compared to placebo.

Eligible patients taking 1-3 AEDs were randomized to once daily placebo or cenobamate 100 mg, 200 mg or 400 mg and treated for 18 weeks (6-week titration phase followed by a 12-week maintenance phase at the target dose). Key study findings included statistically significant greater median percent reductions in focal seizure frequency over the entire treatment period compared to baseline for the cenobamate 100 mg, 200 mg and 400 mg groups (36%, 55% and 55%, respectively) compared to the placebo group (24%). Additionally, a statistically significant greater percentage of patients achieved a 50% or greater reduction in focal seizures during the maintenance phase compared to baseline for the cenobamate 100 mg, 200 mg and 400 mg groups (40%, 56% and 64%, respectively) compared to the placebo group (25%). Furthermore, during the maintenance phase, 4%, 11% and 21% of patients treated with cenobamate 100 mg, 200 mg and 400 mg, respectively, reported no focal seizures compared with only 1% of placebo-treated patients.

“This is the first publication showing the results of a randomized, controlled clinical trial of cenobamate in adults with uncontrolled focal seizures,” said Gregory L. Krauss, MD, professor of neurology at Johns Hopkins University and lead author of the study. “The results demonstrated significant dose-related reductions in seizure frequency with cenobamate during the maintenance phase compared to placebo. Encouragingly, a high number of patients had zero seizures during the maintenance phase in the 200 mg and 400 mg groups.”

Evolution of Concepts in Epilepsy Surgery

At the time of the first meeting of the International League Against Epilepsy (ILAE) in 1909, surgical treatment for epilepsy had been accepted as an alternative therapy for over two decades, but was rarely practiced, considered a last resort for carefully selected patients. Localization was based on ictal semiology and identification of a structural lesion. Very few papers on epilepsy surgery were presented at ILAE meetings or published in Epilepsia during the first half of the 20th century.

A modest explosion in interest in epilepsy surgery at mid-century resulted from recognition that “invisible” epileptogenic lesions could be identified by EEG, especially for temporal lobe epilepsy. Epilepsy surgery received a second boost in popularity toward the end of the 20th century with the advent of structural and functional neuroimaging, and the number of epilepsy centers worldwide doubled between the first Palm Desert conference in 1986 and the second Palm Desert conference in 1992. Neuroimaging also helped to increase application of surgical treatment to infants and young children with severe epilepsies. Epilepsy surgery was accepted as standard of care for drug-resistant focal epilepsy and was well-represented at international ILAE congresses and in Epilepsia.

Advances continue into the 21st century with the introduction of laser ablation, and palliative neuromodulation approaches, which have greatly increased the population of patients who can benefit from surgery. Modern presurgical evaluation techniques have also made surgical treatment possible in many countries with limited resources.

Three randomized control trials now have definitively proved the safety and efficacy of epilepsy surgery, however this alternative therapy remains under-utilized even in the industrialized world, where less than 1% of potential candidates are being referred to epilepsy centers. Furthermore, those who are referred receive surgery an average of 20 years after onset of epilepsy, often too late to avoid irreversible disability. The major challenges in realizing the full potential of epilepsy surgery, therefore, are not as much in the continued improvement of the treatment itself, as they are in addressing the treatment gap that is preventing appropriate patients from being referred to full-service epilepsy centers.

Image Credit: INS UMR 1106

Simulation-based Method To Target Epilepsy Goes to Clinical Trials

A novel method to improve outcomes of surgery to treat epilepsy has now received approval for clinical testing in 13 French hospitals. The approach could provide a better therapeutic perspective against the drug-resistant form of the disease, which constitutes one-third of all cases, and is a development by Human Brain Project scientist Viktor Jirsa and an interdisciplinary team of collaborators.

To help clinicians plan surgery strategies, the scientists created personalized brain models of patients and simulate the spread of abnormal activity during epileptic seizures. The method represents the first example of a personalized brain modeling approach entering the clinic and will now be assessed over four years in a cohort of 356 patients under strict requirements.

The Human Brain Project and The Virtual Brain

Over the last five years and in large part within the framework of the Human Brain Project, Jirsa and his team worked on an approach that could bring a change. The team has adapted the open network simulator The Virtual Brain towards applications in epilepsy. This work has laid foundations for the project EPINOV, short for “Improving EPilepsy surgery management and progNOsis using Virtual brain technology”, a consortium coordinated by Fabrice Bartolomei (Hôpital de la Timone) that brings together theorists like Jirsa, clinical neuroscientists, in particular from Marseille and Lyon, and the industry partner Dassault Systèmes.

After two pilot studies showed promising results for the approach, the EPINOV-consortium has received approval from the French regulatory authority to put their approach to the test in a full-scale multi-centric trial with almost 400 prospective patients.

A dropper adding liquid to an extract in a bottle with cannibals leafs in the background.

Study Provides Insights on the Effects of Cannabidiol on Severe Form of Epilepsy, LGS

Results from a study published in the British Journal of Clinical Pharmacology may help explain why cannabidiol (CBD)—a chemical component of marijuana with no psychoactive properties—reduces the frequency of seizures in patients with a severe form of epilepsy. The effect may be explained by a drug-drug interaction between cannabidiol and the anti-seizure medication clobazam.

The form of epilepsy examined in the study is called Lennox–Gastaut syndrome. Investigators conducted clinical trial simulations for the effect of 20 mg/kg/day cannabidiol on seizure frequency in patients with this syndrome.

“The effects of cannabidiol on seizure frequency in Lennox-Gastaut patients could be explained entirely through estimated elevations of blood levels of clobazam, which might mean that cannabidiol in itself may not have any, or at best limited, antiepileptic effects,” said senior author Geert Jan Groeneveld, MD, PhD, of the Centre for Human Drug Research, in The Netherlands.

Hemispherectomy in Adults and Adolescents: Seizure and Functional Outcomes in 47 Patients

Objective: To examine longitudinal seizure and functional outcomes after hemispherectomy in adults and adolescents.

Methods: This team reviewed 47 consecutive patients older than 16 years who underwent hemispherectomy between 1996 and 2016 at our center. Clinical, electroencephalographic (EEG), imaging, neuropsychological, surgical, and functional status data were analyzed.

Results: Thirty-six patients were 18 years or older at surgery; 11 were aged between 16 and 18 years. Brain injury leading to hemispheric epilepsy occurred before 10 years of age in 41 (87%) patients. At a mean follow-up of 5.3 postoperative years (median = 2.9 years), 36 (77%) had Engel class I outcome. Longitudinal outcome analysis showed 84% seizure freedom (Engel IA) at 6 months, 76% at 2 years, and 76% at 5 years and beyond, with stable longitudinal outcomes up to 12 years from surgery. Multivariate analysis demonstrated that acute postoperative seizures and contralateral interictal spikes at 6-month follow-up EEG were associated with seizure recurrence. Patients who could walk unaided preoperatively and had no cerebral peduncle atrophy on brain magnetic resonance imaging were more likely to experience worsening of motor function postoperatively. Otherwise, postoperative ambulatory status and hand function were unchanged. Of the 19 patients who completed neuropsychological testing, 17 demonstrated stable or improved postoperative outcomes.

Significance: Hemispherectomy in adults is a safe and effective procedure, with seizure freedom rates and functional outcome similar to those observed in children.

Gene Therapy for Epilepsy Shows Promise in Animal Models

A new gene therapy concept has been developed for the treatment of temporal lobe epilepsy. The researchers demonstrated that this strategy is capable of suppressing seizures at their site of origin on demand in animal models.

The study was conducted at Charité – Universitätsmedizin Berlin, Germany and the Medical University of Innsbruck, Austria. The method is now being optimised for clinical trials.

The technique involves the selective delivery of a specific gene to nerve cells within the area of the brain where the epileptic seizures originate.

The gene is delivered via an adeno-associated virus (AAV), which then provides the cells with the information they need to synthesise dynorphins: naturally produces peptides that modulate neural activity.

Professor Christoph Schwarzer, one of the lead researchers, said: “High-frequency stimulation of the nerve cells, such as that seen at the beginning of a seizure, results in the release of stored dynorphins. Dynorphin dampens signal transduction and as a result, the epileptic seizure doesn’t spread… As the cells will only release this substance when needed, this type of gene therapy is referred to as ‘release-on-demand’.”

Using an animal model, the researchers were able to show that this gene therapy is capable of suppressing epileptic seizures for several months.

Moreover, no side effects were observed, which the researchers suggest is due to the site-specific release of dynorphin and its short duration of action.

The back of a woman's head with EEG sensors attached.

Kootenai Health in Idaho Unveils Epilepsy Monitoring Unit

The facility is designed to allow patients to safely experience seizures while medical staff make observations.

A state of the art facility designed to treat people with seizures has finally arrived at Kootenai Health. The facility, which required years of planning and preparation, will hopefully cut down on months-long waiting times for local patients.

Called an epilepsy monitoring unit, or EMU, the facility is designed to allow patients to safely experience seizures while medical staff make observations. Specifically, epileptic patients who are experiencing challenges treating their seizures will undergo monitoring in EMUs.

“It’s amazing. It’s absolutely amazing,” said Judy Hayton, Kootenai Health’s Neurodiagnostics lab manager, of the new facility. The hospital’s four EMU rooms opened last June.

Study Finds Fewer Google Searches for Epilepsy Surgery Over 15-Year Period

BACKGROUND: Epilepsy surgery is an effective treatment for drug-resistant epilepsy. Some centers have noticed changes in referral patterns.

AIM: The aim of this study was to determine if online infodemiological data related to epilepsy surgery reflect reported changes in referrals to surgical centers.

METHODS: Google Trends and Pageview analysis of temporal trends of searches conducted in Google and Wikipedia for epilepsy surgery, using key search terms such as “epilepsy surgery” and terms related to pathology, operation type, and investigative practice.

RESULTS: Over the 15-year time period studied by Google trend analysis, when the initial three-year epoch and final three-year epoch are compared, a 56.1% decline in search volume for “epilepsy surgery” was observed. Vagus nerve stimulation and laser ablation are increasingly searched items. Pageview analysis shows that temporal lobe epilepsy remains the most commonly searched subtype of epilepsy and hippocampal sclerosis was searched for more than focal cortical dysplasia.

CONCLUSION: This study suggests a lower search interest over time in epilepsy surgery, and various associated terms, with increased interest in vagus nerve stimulation and laser ablation procedures over time. There is no clear indication from these data regarding the apparent shift from mesial temporal cases to an increase in extratemporal case workload.

Zogenix Announces New Positive Data for Its Investigational Drug FINTEPLA® in Dravet Syndrome

Zogenix, Inc. announced positive new data for its investigational drug, FINTEPLA® (ZX008, fenfluramine), for the treatment of seizures associated with Dravet syndrome. The data were presented in five scientific posters, available here, at the recent Childhood Neurology Society (CNS) Congress. The posters include data showing long-term, clinically meaningful reduction in convulsive seizure frequency in young Dravet syndrome patients (under 6 years of age) in an ongoing Open-Label Extension (OLE) study, as well as data from a post-hoc analysis showing clinically meaningful and profound reduction in the frequency of high-risk tonic-clonic (grand-mal) seizures in Dravet syndrome patients treated in two previously completed Phase 3 clinical trials. Other data include the results of a Phase 1 study to assess the potential drug-drug interaction of fenfluramine and cannabidiol (CBD).

“These data continue to demonstrate the significant clinical impact Fintepla has shown in studies of Dravet syndrome patients,” said Bradley Galer, M.D., Executive Vice President and Chief Medical Officer at Zogenix. “These new results clearly show the impact this drug candidate has had on some of the most vulnerable patients, those who are younger than 6 years of age, as well as those suffering from generalized tonic-clonic seizures, a recognized risk factor for sudden unexplained death in epilepsy (SUDEP).”