Accelerating the Development of Therapies for Anti-Epileptogenesis and Disease Modification

The “Accelerating the Development of Therapies for Anti-Epileptogenesis and Disease Modification” workshop, on August 6-7, 2018, brought together experts in the field of epilepsy to examine the current state of the science of the disease and provided an opportunity for participants to discuss gaps in research and knowledge and suggest strategies for overcoming some of those obstacles.

Walter Koroshetz, M.D., director of NINDS, provided opening remarks at the workshop, emphasizing that epilepsy is a circuit disorder and noting that our understanding of brain circuitry has drastically improved over the last five years. He described the focus of the workshop as looking carefully into the clues that science has given us to prevent epilepsy, develop better treatment options, and improve quality of life for people affected by this disease.

In the months leading up to the workshop, working groups focusing on clinical research, biomarkers,  preclinical research and industry/regulatory issues, held meetings to discuss the latest findings in those areas. Their conclusions were presented at the workshop, and those talks were followed by breakout sessions, in which participants discussed gaps and opportunities for further research. The breakout groups developed sets of priorities, which will be presented to the community in the form of a white paper.

The Clinical Research Working Group described current research in the areas of post-traumatic epileptogenesis, in which epilepsy is triggered by head injury, and trials examining epilepsy development in children with tuberous sclerosis complex. The Working Group also discussed considerations to keep in mind while designing clinical studies looking at disease modification in epilepsy.

The Regulatory and Industry Working Group noted that in drug development, the primary focus is on anti-convulsant therapies, and not as much emphasis on treatments that may prevent epilepsy or on disease-modifying strategies that may help alleviate a range of symptoms associated with the disease. The group also presented a review of the revised FDA Early Alzheimer’s Disease Guidance, which was released in February 2018, noting that the new document highlights earlier stages of the disease and emphasizes the use of biomarkers in clinical studies. During this set of presentations, patient-centered clinical endpoints were considered, including focusing on symptoms other than seizures and opportunities for taking a personalized approach to disease-modifying studies. It was also noted that in planning clinical studies, all stakeholders, including patients and their advocates, should be involved in the discussions.

The Preclinical Research Working Group focused their presentations on the use of animal models in epilepsy research and new strategies for conducting this research, including using consortia and team science approaches. Potential therapeutic strategies for genetic as well as acquired epilepsy were reviewed, including use of gene therapy, blocking specific proteins session, and using anti-inflammatory drugs to slow down disease progression.  This session also highlighted the observation that many preclinical studies focus on epilepsy prevention, even though most individuals with epilepsy will not go to a doctor until after the disease has been established. Potential benefits of disease modifying treatments were discussed, including improvement in quality of life and decreases in the amount of required medication.

Presentations in the next session from the Biomarker Working Group focused on the definition of biomarkers as specific features or molecules associated with a disease that can be measured, to show disease progression or improvement following treatment. A variety of potential biomarkers were described including blood-based proteins associated with neuroinflammation and autoantibodies, blood microRNAs, and biomarkers obtained from cerebrospinal fluid. Non-invasive methods, including MRI scans and electroencephalograms (EEG) that measure brain electrical activity, can be helpful in diagnosing epilepsy. It was also noted that it may not be possible to assign a single biomarker for all of the different forms of epilepsy and that researchers should consider a range of potential biomarkers for the disease.

The final session considered the Alzheimer's Disease Neuroimaging Initiative (ADNI) as a potential model for epilepsy research. ADNI is a multisite, longitudinal clinical study that was established to identify biomarkers for recognizing AD in its earliest stages and tracking disease progression. One of the main features of this public-private partnership has been data sharing on a large scale, which has resulted in more than 1000 publications. Following the success of ADNI, the Human Epilepsy Project aims to follow individuals for six years, collecting blood samples, brain scans, and cognitive testing data.    

Following the state-of-the-research presentations, meeting participants attended break-out sessions focusing on clinical/regulatory issues, preclinical science, and biomarkers/translational research. During the sessions, participants discussed gaps and challenges to progress, identified opportunities for research, and developed a list of recommendations to help move the field forward.   

One of the key recommendations from the clinical/regulatory break-out group was to reexamine the way that epilepsy clinical trials are conducted, including refining trial design and developing new methodology. More research is needed to help guide the length of follow-up in clinical studies, when interventions should be given, and the best outcomes to measure. Another recommendation was to develop relevant animal models of epilepsy that more closely mirror the human disease.

The primary recommendation from the Biomarkers breakout group was the development of an epilepsy-specific database and repository of biomarkers. A lot of the current research in epilepsy biomarker development focuses on ways to improve diagnosis of the disease, but this group recommends that researchers also look for biomarkers that identify disease risk and help track prognosis. The group also recommended that the community reach consensus on a roadmap for moving potential biomarkers from exploratory research into validation, for eventual use in the clinic.   

The preclinical breakout group recommended that NIH host a workshop for the research community to come to agreement on the point at which a preclinical finding is ready to advance to a clinical trial. Related to this was a recommendation to develop ways to validate discoveries in animals to make them relevant to people. This group also suggested using the circuit-related tools that have been developed through the NIH BRAIN Initiative and adapting them for preclinical studies of epilepsy.

The preclinical and biomarker breakout groups also emphasized the need for infrastructure to support data sharing and analysis, as well as to house data servers and tissue repositories. 

The workshop concluded with a panel discussion about funding opportunities in epilepsy research at NIH, the Department of Defense (DoD), and the European Commission (EC). Workshop attendees learned about various NIH-sponsored initiatives for translational research, including opportunities for small businesses, support for development of medical devices, and the Epilepsy Therapy Screening Program, which aims to identify new drugs for the disease. The DoD primarily focuses on epilepsy that develops after traumatic brain injury and current research opportunities target prevention, identification of risk factors, and ways in which epilepsy medication affects outcomes of head injury. The EC supports a number of epilepsy-related initiatives, including collaborations on a global scale and public-private partnerships to help advance the research.