2022 American Epilepsy Society Meeting: A Dravet-focused Recap

The American Epilepsy Society 2022 Annual Meeting took place in Nashville, Tennessee on December 2-6. This meeting is packed with academic scientists, expert clinicians and health care providers, pharmaceutical and biotechnology companies, and advocates all gathering to share updates in the field of epilepsy and hold thought discussions regarding where we have come and what should be accomplished next. There is always too much to see, too many people to network with, and never enough time. However, that is a great problem to have when there is still so much to be done to improve the lives of individuals living with epilepsy. Despite being a rare disorder, Dravet syndrome is a common theme of discussion across this meeting. It would be impossible to cover every mention, but below I have once again tried to pull some of the highlights I thought would be most interesting to the community or that made a particular impact on me. 

The Meeting before the Meeting

This year, I had the privilege to attend the TARGETing Epilepsy Meeting at St. Jude Research Hospital in Memphis, Tennessee just prior to heading to Nashville for the AES annual meeting. St. Jude Research Hospital, long known for their success in research and treatment for childhood cancer, is now working to add a significant focus on pediatric neurological diseases with their Pediatric Translational Neuroscience Initiative (PTNI). The TARGETing Epilepsy Meeting held at St. Jude Research Hospital in Memphis, Tennessee on November 29 and 30, 2022 brought together expert researchers, clinicians, industry members, government representatives, and patient advocates to discuss cutting-edge research and outstanding hurdles to improving care and reaching treatment strategies that can better address genetic epilepsies. 

Researchers presented exciting talks and research advancements such as Greg Cooper who spoke about advancements in genetic testing, called long-read sequencing, that can better identify disease-causing mutations in patients that previously lacked a genetic diagnosis from traditional sequencing methods. Lori Isom presented on work from her laboratory to better understand how the antisense-based therapies being developed by Stoke Therapeutics impact electrical activity in the brain of a Dravet mouse model. Wenxi Yu, a postdoctoral fellow funded by DSF, presented on his exciting work to show how using a genetic-based approach to impact another sodium channel gene, SCN8A, can also compensate for the loss of function of SCN1A in a mouse model of Dravet syndrome. Additional presentations can from academic and industry researchers who are developing novel gene-based therapies for an array of genetic epilepsies, really emphasizing the hope of the future for so many living with these diseases. Ingrid Scheffer spoke about her groups efforts towards a global Developmental and Epileptic Encephalopathy (DEE) Natural History Study. She highlighted the great number of genes that contribute to a vast array of childhood-onset epilepsies, as well as the complex syndromes that can arise from mutations in the same gene. One such example is actually SCN1A, where loss-of-function mutations can often lead to a diagnosis of Dravet syndrome, but rarer gain-of-function mutations in SCN1A cause an earlier seizure onset (usually prior to 3 months of age) DEE with unique symptoms including non-seizure movement disorders. Natural History Studies such as this one can help us learn more about the onset and progression of DEEs which can inform research, serve to reduce placebo arms in clinical trials, and provide information on best treatment approaches. There was also a vibrant discussion around how we can better utilize the existing patient data within electronic medical records to better supplement more formal natural history studies and capitalize on existing information using artificial intelligence (AI) and machine learning. The meeting really facilitated connection and discussion of these research advancements with an eye on capacity for translating the research into meaningful future outcomes for patients.

It was really impactful to think about the promise of St. Jude focusing on neurological diseases, particularly epilepsy. With all St. Jude Research Hospital has done to improve the outlook for childhood cancer, it is hopeful to think of the impact they can have for rare neurological diseases like Dravet syndrome.  

The DSF Research Roundtable

DSF held the 13th annual Research Roundtable on Thursday, December 1 in Nashville just prior to the start of the AES meeting. DSF announced the 2022 grant awardees and then hosted a vibrant scientific program moderated by the co-chairs of the DSF Scientific Advisory Board, Jack Parent, MD and Lori Isom, PhD. You can read more about the 2022 grant awardees in this blog and see an overview of the Research Roundtable here.

Novel Research Models of Dravet Syndrome

Animal and cell models of Dravet syndrome have allowed us to better understand the underlying cause of disease as well as to discover and test potential treatments. There are currently several well-established systems to model aspects of Dravet syndrome including patient-derived or genetically-modified cell lines, flies, fish, and mice. Each model has unique strengths; for example, the ability to screen large libraries of drugs in a genetic zebrafish model that closely replicates the anti-seizure medication responses seen in human patients. Mouse models are widely used because of their very similar genetic code and the extensively developed genetic tools researchers have to manipulate mouse genetics and assess the impacts of those changes. 

The link between Dravet syndrome and SUDEP has led researchers to more closely examine the role of SCN1A in the heart. While some measures of cardiac dysfunction have been reported in mouse and cell models, researchers at the University of Michigan set out to develop a transgenic rabbit model with an SCN1A deletion (SCN1A +/-) that could more closely replicate aspects of human heart function than the currently available model systems. Their initial experiments indicate that under the right genetic background (rabbit ‘strain’) the SCN1A+/- rabbits experience spontaneous seizures, suffer high rates of premature mortality, and have altered cardiac function suggesting they are an ideal model for these studies.a

While there are several well characterized and widely utilized mouse models of Dravet syndrome, there are still some unique genetic aspects that can be modeled in different ways to allow scientists to ask unique research questions and develop novel treatment approaches. Researchers in Tel Aviv partnered with Dravet Syndrome Foundation Spain to develop a mouse model of Dravet syndrome with a nonsense mutation in SCN1A. Nonsense mutations introduce a signal in the genetic code that tells the cell to STOP reading the gene too early, resulting in a shortened product that is generally not functional. Some scientists are working on ways to overcome the “STOP” signal so the cell continues to read the entire code for the gene. A mouse model that carries a nonsense mutation in SCN1A may be useful to researchers interested in testing this type of approach in a living animal to determine if it might be applicable eventually to human therapies.b

Another new mouse model was presented from a group out of the University of Washington that used a novel genetic approach to allow the SCN1A mutation to be more easily corrected across various developmental stages. The researchers showed that when the SCN1A mutation was corrected very early, before the mice were born, they did not develop seizure susceptibility or die prematurely. Additionally, they showed that if they corrected the gene much later in adult mice that there was still positive impact on resistance to temperature-induced seizures. They plan to continue related experiments in this model to provide insight into windows of genetic intervention and impact on symptoms in Dravet syndrome to help guide future treatment approaches.c

a. Development of a Transgenic Rabbit Model of Dravet Syndrome Roberto Ramos Mondragon, PhD – University of Michigan; Chunling Chen, MD – Research Lab Specialist Lead, Pharmacology, University of Michigan; Julie Ziobro, MD – Assistant Professor of Pediatrics, MM Pediatrics-Neurology, University of Michigan; Yan Chen, BSc Chemistry – Research Lab Specialist Senior, MM Pharmacology Department, University of Michigan; Shuyun Wang, MD – Research Laboratory Specialist Senior, MM Pharmacology Department, University of Michigan; Luis Lopez Santiago, PhD – Associate Research Scientist, Pharmacology, University of Michigan; Jack Parent, M.D. – Co-Division Chief, Epilepsy, Neurology, University of Michigan; Lori Isom, PhD – Professor and Chair of Pharmacology, Pharmacology, University of Michigan; American Epilepsy Society 2022 Annual Meeting, December 3; Poster Number:1.062
b. SCN1AR613X/WT: A Nonsense Open-access Mouse Model for Dravet Syndrome Vittoria Spinosa, PhD – Dravet Syndrome Foundation Spain; Anat Mavashov, – – Faculty of Medicine, Tel Aviv University; Yael Almog, Mrs – Faculty of Medicine, Tel Aviv University,; Marina Brusel, PhD – Faculty of Medicine, Tel Aviv University,; Moran Rubinstein, PhD – Faculty of Medicine, Tel Aviv University,; José Ángel Aibar, Mr – Dravet Syndrome Foundation Spain; American Epilepsy Society 2022 Annual Meeting, December 3; Poster Number:1.129
c. Adult Restoration of scn1a Is Protective Against Thermally Evoked Seizures in a Novel Mouse Model of Dravet Syndrome Christine Cheah, PhD – University of Washington; Megan Beckman, BS – Pharmacology – University of Washington; William Catterall, PhD – Pharmacology – University of Washington; John Oakley, MD, PhD – Neurology – University of Washington; American Epilepsy Society 2022 Annual Meeting, December 3=5; Poster Number:3.072

 

Medications in Development

The treatment pipeline for Dravet syndrome is robust following the 2018 and 2020 approvals of stiripentol (Diacomit), cannabidiol (Epidiolex), and fenfluramine (Fintepla). You can see the full pipeline of products in later phases of development here, but below I highlight a few that had abstracts at the AES meeting this year. 

Soticlestat is currently being tested by Takeda as an antiseizure medication in Phase 3 trials in Dravet syndrome and Lennox-Gastaut syndrome. The company had several poster presentations providing details from the Phase I safety trials about the metabolism of the medication which shows the medication is rapidly cleared from the body in a time-frame that supports its safety and further investigation. Work from mouse models further exemplified that the novel mechanism of action of soticlestat, which acts differently from any current anti-seizure medications through modulation of cholesterol metabolism, might make it a key treatment option for several forms of epilepsy.a, b

Cenobamate is a newer medication that acts uniquely to impact persistent sodium currents and the GABA pathway. It is currently FDA-approved for focal epilepsy, but there is growing evidence that it may be effective in genetic and generalized epilepsies. Because the mechanism of action impacting sodium channels is different than the traditional sodium channel blockers that are contraindicated in Dravet syndrome, it appears cenobamate could potentially be a treatment option for Dravet syndrome. Several studies presented at AES were investigating cenobamate in various genetic DEEs with variable success. A study from the Mayo Clinic reported 1 adult with Dravet syndrome (age 25) had a 100% reduction in generalized tonic clonic seizures during a 17-month follow-up period after adding cenobamate to their current anti-seizure medications.c

Neuropeptide Y is being tested as an intranasal treatment in a mouse model of SCN1A epilepsy. Although this is a slightly less-severe model than typical mouse models of Dravet syndrome, the treatment is still yielding positive results related to seizure protection.d It will be of interest to see how this neuropeptide might impact seizure susceptibility and SUDEP in more severe SCN1A models.

Epygenix Therapeutics presented a poster on the safety profile from their Phase I trial of EPX-100 (clemizole HCL). They are currently enrolling patient with Dravet syndrome to participate in their Phase 2 trial of EPX-100  (ARGUS) which will focus primarily on safety but will also measure efficacy. EPX-100 was developed from zebrafish drug screens that were initially partially funded by a DSF grant making this transition to the human clinic a particularly exciting milestone.e

a. Absolute Bioavailability and Mass Balance of the CH24H Inhibitor Soticlestat in Healthy Volunteers Mahnaz Asgharnejad, PharmD – Takeda Development Center Americas, Inc, Cambridge, MA, USA; Wei Yin, PhD – Takeda Development Center Americas, Inc, Cambridge, MA, USA; T. Eric Ballard, PhD – Takeda Development Center Americas, Inc, Cambridge, MA, USA; Xiaochun Zhu, PhD – Takeda Development Center Americas, Inc, Cambridge, MA, USA; Samuel Hsiao, PhD – Takeda Development Center Americas, Inc, Cambridge, MA, USA; Annette Stevenson, MS – Takeda Development Center Americas, Inc, Cambridge, MA, USA; Tom Hui, MD – Takeda Development Center Americas, Inc, Cambridge, MA, USA; Allen Hunt, MD – Celerion, Lincoln, NE, USA; Steve Han, MD, PhD – Takeda Development Center Americas, Inc, Cambridge, MA, USA; American Epilepsy Society 2022 Annual Meeting, December 5; Poster Number:3.295
b. The Atypical Anticonvulsive Mechanism of Soticlestat Characterized in Animal Models of Epilepsy Toshiya Nishi, DVM – Neuroscience Drug Discovery Unit, Takeda Pharmaceutical Company Limited, Fujisawa, Japan; Cameron Metcalf, PhD – Department of Pharmacology and Toxicology, College of Pharmacy, University of Utah, Salt Lake City, UT, USA; Steve White, PhD – Department of Pharmacy, School of Pharmacy, University of Washington, Seattle, WA, USA; American Epilepsy Society 2022 Annual Meeting, December 5; Poster Number: 3.281
c. Cenobamate in Genetic Generalized Epilepsy and Combined Generalized and Focal Epilepsy Shruti Agashe, M.D, M.S. – Mayo Clinic; David Burkholder, M.D. – Mayo Clinic; Gregory Cascino, M.D. – Mayo Clinic; Jeffrey Britton, M.D. – Mayo Clinic; Katherine Nickels, M.D. – Mayo Clinic; Katherine Noe, M.D. PhD. – Mayo Clinic; Anthony Ritaccio, M.D. – Mayo Clinic; Elaine Wirrell, M.D. – Mayo Clinic; American Epilepsy Society 2022 Annual Meeting, December 3; Poster Number: 1.224
d. Nanoparticle-encapsulated Neuropeptide Y Reduces Seizure Susceptibility in Mice Samantha Reed, BS – Emory University; Jennifer Wong, PhD – Emory University; Akanksha Kale, BS – Mercer University; Sharon Vijayanand, BS – Mercer University; Martin D’Souza, PhD – Mercer University; Kevin Murnane, PhD – Louisiana State University; Andrew Escayg, PhD – Emory University; American Epilepsy Society 2022 Annual Meeting, December 5; Poster Number:3.277
e. EPX-100 as an Adjunctive Therapy in Dravet Syndrome: Phase 1 and Phase 2 Randomized, Double-blind, Placebo-controlled Trials Lekha Rao, MD – UCLA Mattel Children’s Hospital; Lorianne Masuoka, MD – Epigenyx; Mary Shatzoff, MSc – Epigenyx; Hahn-Jun Lee, MSc, PhD – Epigenyx; Scott Baraban, PhD – University of California San Francisco and Epigenyx; American Epilepsy Society 2022 Annual Meeting, December 4; Poster Number: 2.244

Genetic-based Therapies

Genetic-based therapies are truly exploding across the field of epilepsy from early academic research avenues up to therapies being tested in human clinical trials. Genetic therapies for Dravet syndrome are leading the way and companies that are helping to translate the basic science into human therapies had several presentations at the meeting this year.

Stoke Therapeutics presented several posters with data from their Natural History Study of patients with Dravet syndrome as well as from their Phase 1/2a studies of the anti-sense oligonucleotide (ASO) STK-001 that are currently ongoing in the United States and United Kingdom. STK-001 is an RNA-based therapy that works to increase expression of the SCN1A sodium channel, Nav1.1,  from the healthy copy of the gene. The current trials for STK-001 are focused on safety and pharmacokinetics, closely monitoring for any adverse effects while determining the optimal dose level and frequency of administration. Because these types of medications are so new and require more invasive administration, via lumbar puncture, the trials have slowly moved forward adding additional patients and stepping up the dose levels and administration frequency. While this approach prioritizes a safe trial for patients, the time it takes to get information on efficacy can be longer. The good news is that so far, the trials are progressing without any major safety flags, and, even though the trials are determining that higher doses (45mg) might be more optimal, seizures reductions have been seen across all dose levels and age groups in the studies (MONARCH, ADMIRAL, SWALLOWTAIL). Notably, patients in the open-label extension trial (SWALLOWTAIL) for STK-001 that are currently receiving doses of 30mg are showing improvements in the BRIEF-P assessment, which measures executive function, although the number of patients is still small which limits the strength of the interpretation at this time. However, patients not receiving STK-001 that were followed in the BUTTERFLY observational natural history study have not shown these same improvements over time.  Visit this link to see a listing of all the posters presented from Stoke Therapeutics at AES 2022.

Encoded Therapeutics is developing an AAV-based approach that delivers an engineered transcription factor to increase gene expression of SCN1A to overcome the haploinsufficiency present in patients with Dravet syndrome. While the company prepares to begin clinical trials to test their approach, called ETX101, they have been sponsoring an observation natural history study of patients with Dravet syndrome (ENVISION). Just as in the BUTTERFLY study sponsored by Stoke Therapeutics, the ENVISION trial is seeking to better characterize the natural progression of Dravet syndrome and determine which clinical tools and scales can best measure the impacts of disease on patients. This study will help inform the assessments used in the interventional trials as well as to act as a comparison to the treatment arms to better show how an investigational treatment is impacting some of the longer-term outcomes and progression of symptoms in Dravet syndrome. a-b

CAMP4TX is developing a different kind of ASO approach that works by targeting a natural antisense transcript that would normally suppress SCN1A expression. Last year they presented on this, showing preclinical efficacy in cells and a mouse model of Dravet syndrome. This year, as they work toward investigational new drug filing, they presented their data in a non-human primate which demonstrated that after intrathecal administration (similar to a lumbar puncture) there was a good distribution of their ASO, called CAMP-SCN-001, throughout the CNS, and that it impacted SCN1A expression through increases in mRNA and protein levels.c

a. Behavior, Social-emotional, and Sleep Difficulties in Young Children with SCN1A+ Dravet Syndrome Participating in the ENVISION Study, an International, Prospective Natural History. Ingrid Scheffer, AO, FAA, FAHMS – University of Melbourne, Austin Health and Royal Children’s Hospital; M. Scott Perry, MD – Cook Children’s Medical Center; Joseph Sullivan, MD – University of California at San Francisco; Salvador Rico, MD, PhD; et al – Encoded Therapeutics; American Epilepsy Society 2022 Annual Meeting, December 4; Poster Number: 2.316
b. The ENVISION Study, an International, Prospective Natural History Study in Young Children with SCN1A+ Dravet Syndrome, 18 Month Follow-up M. Scott Perry, MD – Cook Children’s Medical Center; Ingrid Scheffer, AO, FAA, FAHMS – University of Melbourne, Austin Health; Joseph Sullivan, MD – University of California at San Francisco; Susana Boronat, MD, PhD – Hospital de la Santa Creu i Sant Pau; Salvador Rico, MD, PhD; et al – Encoded Therapeutics; American Epilepsy Society 2022 Annual Meeting, December 3; Poster Number: 1.087
c. SCN1A Upregulation by an Antisense Oligonucleotide Targeting SCN1ANAT for Treatment of Dravet Syndrome Nikolaos Giagtzoglou, PhD – Camp4TX; American Epilepsy Society 2022 Annual Meeting, December 5; Poster Number: 3.056

 

Genetics of SCN1A

Recently there has been an increased awareness and identification of patients with Gain-Of-Function (GOF) mutations in SCN1A that lead to syndromes with unique symptoms presentations that are distinct from Dravet syndrome which is caused most often by Loss-Of-Function (LOF) mutations in SCN1A. Some of the key clinical signs that may suggest the potential for a GOF SCN1A mutation include seizure onset prior to 3 months of age (sometimes as early 3 days of life), movement disorders, and/or joint contractures. Importantly, patients with GOF SCN1Amutations may actually respond well to sodium channel blockers, which would be contraindicated in Dravet syndrome because of the LOF SCN1A mutations.a,b

a. The Gain of Function SCN1A Disorder Spectrum: Novel Epilepsy Phenotypes and Therapeutic Implications Andreas Brunklaus, MD – University of Glasgow; Tobias Brünger, PhD – Cologne Center for Genomics, University of Cologne, Cologne, Germany; Tony Feng, Medical Student – Institute of Health and Wellbeing, University of Glasgow, UK; et al; American Epilepsy Society 2022 Annual Meeting, December 3; Poster Number:1.367
b. SCN1A Philadelphia Variant – a Recurrent Gain-of-function Variant Causing an Early-onset Epileptic Encephalopathy Distinct from Dravet Syndrome Jerome Clatot, PhD – CHOP; Sridhar Parthasarathy, Data Scientist – The Children Hospital of Philadelphia; Stacey Cohen, Licensed Genetic Counselor – The Children’s Hospital of Philadelphia; Jillian McKee, PL-6 Fellow – CHOP; Shavonne Massey, MD – CHOP; Ala Somarowthu, PhD – CHOP; Ethan Goldberg, MD. PhD. – CHOP; Ingo Helbig, MD – CHOP; American Epilepsy Society 2022 Annual Meeting; December 3; Poster Number:1.03

SUDEP (Sudden Unexpected Death in Epilepsy)

I was able to attend the Partner’s Against Mortality in Epilepsy (PAME) Meeting on Thursday, December 1, just prior to the main AES 2022 meeting. Given the high rates of mortality in Dravet syndrome that are primarily associated with SUDEP (Sudden Unexpected Death in Epilepsy), the PAME meeting is particularly important. This was the 10thAnniversary of this meeting, and there was much reflection on the knowledge and awareness that has grown over the last 10 years, as well as acknowledgement of how far we still need to go. Particularly poignant was the testimony of Iris Killinger, Dr. iur, who lost her son Oskar to SUDEP without ever having been counseled by a neurologist of the potential risk of SUDEP or preventative measures they should have been taking. She has since established the Oskar Killinger Foundation in her home country of Germany where she continues to fight for awareness and the imperative for clinicians to discuss this important topic with families. Researchers reflected on what the field believes is the most common phenomenon leading to SUDEP: a seizure that leads to impaired respiration during the postictal period followed by cardiac disruption. They discussed that research has begun to uncover some changes in the brain, specifically granual cell layer bilamination, that might be a commonality in SUDEP risk, although the data is still limited and the mechanisms are not immediately apparent. Afternoon talks brought focus on measurements of respiration and cardiac function as well as discussion of tools that may be able to measure parameters that could help predict or prevent SUDEP.

SUDEP and Dravet syndrome was also a focus of many presentations at the main AES meeting, with a poster from Ingrid Scheffer’s group in Australia reporting that SUDEP appears to be more prevalent in Dravet syndrome than other DEEsa, which re-emphasizes the importance of awareness and research. A study that many families in the DSF network helped to contribute to presented data from their work better characterizing patients with Dravet syndrome that have succumbed to SUDEP and looking for commonalities that may help predict risk factors.b

a. Do Rates of Status Epilepticus and SUDEP Vary Between Different Genetic Developmental and Epileptic Encephalopathies? Sophie Russ-Hall, BSc (Hons) – Department of Medicine, University of Melbourne, Austin Health; Alice Donnan, BSc, MD – Department of Medicine, University of Melbourne, Austin Health; Amy Schneider, BA, BSc, MGenCouns – Department of Medicine, University of Melbourne, Austin Health; Leonid Churilov, BSc, PhD – Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne; Florey Institute of Neurosciences and Mental Health; Ingrid Scheffer, MBBS, PhD, FRACP – Department of Medicine, University of Melbourne, Austin Health; Florey Institute of Neurosciences and Mental Health; Department of Paediatrics, University of Melbourne, Royal Children’s Hospital; American Epilepsy Society 2022 Annual Meeting; December 4; Poster Number:2.147
b. Clinical Markers Associated with Sudden Unexpected Death in Epilepsy in Dravet Syndrome Melissa Baltuano, MD – University of Oklahoma Health Sciences Center, OU Children’s Hospital; Veronica Hood, MS, PhD – Scientific Director, Dravet Syndrome Foundation; Abigail Van Nuland, MS – Research Scientist, Epilepsy Center, Ann and Robert H. Lurie Children’s Hospital of Chicago; Mary Anne Meskis, – – Executive Director, Dravet Syndrome Foundation; Linda Laux, MD – Associate Professor of Pediatrics (Neurology and Epilepsy), Pediatrics, Division of Neurology, Epilepsy Center, Ann and Robert H. Lurie Children’s Hospital of Chicago, Northwestern University Feinberg School of Medicine; American Epilepsy Society 2022 Annual Meeting; December 4; Poster Number:2.444

Reflecting on the Meeting

After 8 days immersed in the research surrounding epilepsy, while physically tired, I felt internally re-energized with the excitement of what the future holds. It is still hard for me to believe that the next generation of treatments, where we can actually correct diseases at their genetic cause, is becoming a reality. There are still so many challenges, and likely none of the current generation of genetic therapies are going to be completely curative, but I can see hope for better lives for so many living with significant disease burdens. Treatments across the board are more innovative, and stakeholders are working together to make it all happen. I saw so many rare epilepsy parents and advocates being called on to present their stories and the impacts they are having on research right alongside world-renowned clinicians and researchers. Pharmaceutical and biotechnology companies are partnering with expert researchers to test their ideas in preclinical models and also partnering with patient advocacy groups to ensure their eventual treatments and trial designs are meeting the needs of the patient communities. When I reflect on how far the field has come since the founding of DSF, and how much stronger the stakeholder community is today than it was in 2009, I feel full of hope and anticipation for what is still yet to come. 

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