Earlier this December, DSF Staff and Board Members attended the 2024 American Epilepsy Society Meeting to learn about the exciting advancements occurring in epilepsy research, make connections and cement current collaborations, advocate for and seek out new research opportunities, and raise awareness of Dravet syndrome and the work of DSF and the patient-community to support research and clinical care. Amazingly, searching the abstracts presented at the meeting for the term ‘Dravet’ yielded over 90 results. For context, fifteen years ago when DSF was established, there were only ten. And beyond these abstracts that summarize the content of posters, Dravet syndrome also took center stage throughout the conference, including the prestigious Presidential Symposium as well as various other symposiums and sessions focused on the future of treatments for epilepsy. As in year’s past, I will recap some of the highlights from this year’s meeting for the field of Dravet syndrome, including a flurry of updates from DSF-funded researchers.
Disease Modification is on the Horizon for Dravet Syndrome
One of the extreme highlights of AES this year was the possibility of disease modification for Dravet syndrome beginning to look like a reality. Stoke therapeutics provided updates on their ongoing studies of the antisense oligonucleotide zorevunersen (previously STK-001). Zorevunersen targets the cause of Dravet syndrome by upregulating expression from the SCN1A gene to increase levels of the sodium channel Nav1.1. From the recently completed Phase 1/2a and open-label extension studies they have reported impressive reductions in seizures that appear to sustain over time as well as early readouts of positive impacts on cognition and behavior as measured by the Vineland-3 assessment (Abstract #2.364 and #2.379). A separate study confirmed that the levels of improvement being measured in the study are within the range of score improvements that caregivers to patients with Dravet syndrome have indicated as meaningful change (Abstract #3.383).
Further driving home what these types of improvements might look like in a real-world scenario, on Sunday night during the meeting videos of a patient with Dravet syndrome before and 8-months after treatment with zorevunersen were shown. The 12-year old patient was shown buttoning a shirt, kicking a ball, doing simple motor tests and answering some verbal questions from a clinician with some quite striking improvements in the videos following treatment. These videos were also shown again the following morning in a public webcast (which can be found at this page). It felt like a pivotal moment, not only for Dravet syndrome, but for much of the genetic and developmental epilepsy community, as the potential for disease modification was exemplified, and in an adolescent. And while it is certainly a time of hope and appropriate to take a moment to celebrate this incredible advancement that will hopefully change the course of many lives, it is also very important to step back to recognize that more work must still be done to ensure safety and certainty in the effectiveness of this novel therapeutic approach. The before and after videos are moving, but it’s important to remember this is just one patient, and there may be variability in the response between patients. While the combined data looks promising, and the data sets are growing, there are still relatively small numbers of patients that have received this therapy.
The next step will be for Stoke to initiate their Phase 3 studies. We anticipate a targeted dosing approach informed from the previous Phase and a study design that will provide strong evidence of safety and efficacy for zorevunersen. Currently Stoke is working with regulatory authorities in the United States and globally to initiate the Phase 3 study with a consistent trial design to optimize the data collected from participants in the study. Recently, the FDA awarded zorevunersen Breakthrough Therapy Designation, which provides access to all Fast Track designation features, including intensive guidance on an efficient drug development program and an organizational commitment involving senior FDA managers.
Coming Up the Pipeline
Xenon pharmaceuticals presented data that selectively activating Nav1.1 channels with a small molecule compound (XPC-A) in a mouse model of Dravet syndrome can restore the function of interneurons, reduce susceptibility to seizures, and improve motor deficits. (Abstract #3.395)
Bloom Sciences reported on their Phase 1 study of BL-001, a live biotherapeutic being developed for the treatment of epilepsy. BL-001 was well tolerated and measures of metabolomics in these healthy controls following dosing support the mechanistic hypothesis for BL-001 based on the metabolic shifts observed following use of the ketogenic diet. (Abstract 2.373)
Longboard presented interim results from their open-label extension study of bexicaserin (previously LP352), continuing to a show a favorable safety profile and maintenance of seizure reductions. They are currently beginning Phase 3 studies for bexicaserin in Dravet syndrome as well as other DEEs. (Minh Le et al Abstract #1.509)
Bright Minds Biosciences reported from their Phase 1 studies of their novel 5-HT2C agonist (BMB-101) in healthy volunteers. BMB-101 had a favorable safety profile and biomarker data supported the purported mechanism of action. They have planned a Phase II study for BMB-101 in developemental and epileptic encephalopathies as well as in absence epilepsy. (Vasilkevich et al Abstract# 1.532).
Rethinking Sodium Channel Blockers
While traditionally sodium channel blockers are contraindicated in Dravet syndrome, a new class of sodium channel-targeted anti-seizure medications may actually be a therapeutic option. Some sodium channels, like Nav1.1 (encoded by the SCN1A gene that is impacted in Dravet syndrome), open and close quite quickly. However, other sodium channels, like Nav1.6 (encoded by the SCN8A gene), close more slowly and have a more persistent current. These differences in channel dynamics have allowed for a new class of therapeutics to specifically target the persistent sodium currents, without further suppressing the Nav1.1 transient currents that are important for inhibitory neurons. Ultimately, as Dr. Raman Sankar pointed out during a session on novel therapeutics, our understanding of the biology of sodium channels from the immense work on channelopathies has actually led to the discovery of this novel class of antiseizure medications that may be beneficial for targeted genetic epilepsies but also as a generalized antiseizure medication approach that avoids suppression of the brain’s existing inhibitory networks and focuses on the overexcitation.
One such therapeutic, cenobamate (Xcopri) continues to gain traction as an option for patients with Dravet syndrome, although the numbers of patients reported thus far remain small. Erol et al (Abstract 3.419) reported that three out of four patients saw significant improvements in seizure control after addition of cenobamate to their antiseizure medication regimen, adding some additional insights to the small number of patients already reported in the published literature.
Praxis Precision Medicines met with DSF to discuss their molecule relutrigine (previously PRAX-562), which has shown initial efficacy in SCN2A and SCN8A DEEs. Relutrigine works by modulating specifically sodium channel hyperexcitability, without suppression of inhibitory networks, similar to the concepts described above. And just last week, relutragine was granted Rare Pediatric Disease Designation for Dravet syndrome by the FDA, which helps to expedite the review process for new drug or biologic applications. Praxis is currently working towards expansions of their studies for relutrigine to include additional DEEs like Dravet syndrome.
Neuromodulation
Neuromodulation techniques continue to be a hot topic in sessions and posters. There were several reports focused on VNS, but given the paucity of information on other neuromodulation techniques I wanted to highlight another, even though the report was a limited case report of a single patient with Dravet syndrome who saw success with RNS (responsive neurostimulation) implantation. RNS is approved for adults with focal epilepsy, but some evidence is beginning to suggest that it could also be effective in generalized epilepsies, like Dravet syndrome. This report from a 7-year old female with Dravet syndrome detailed that prior to implantation she was experiencing >100 seizures each day (myoclonic, atonic, hemiclonic, and generalized tonic-clonic seizures) with frequent status epilepticus despite utilization of top-line antiseizure treatments. The patient saw improvements, most robustly in atonic and myoclonic seizures, with another overall estimated seizure reduction of 50-75% post-RNS implantation. While these are results from only a single patient, they represent some of the first evidence that RNS could be a treatment option for Dravet syndrome. (Philiben et al Abstract #1.169)
Modeling Dravet Syndrome
A poster from Alexion Pharmaceuticals (Kelley and Stricos Abstract #1.233) exemplified the ability to use patient-derived iPSCs to culture GABAergic neurons as a model for therapeutic development. Using high-density microelectrode arrays they could record electrical activity from individual neurons over time and monitor the response to therapeutics. A group from the Florey Institute (Mattei et al Abstract #1.073) similarly utilized patient-derived iPSCs to form 3-dimensional cell cultures called spheroids to model aspects of brain development in Dravet syndrome. Treatment of the spheroids with fenfluramine could rescue dysfunction in neuronal firing, suggesting the potential utility of this model system to investigate therapeutic efficacy of compounds.
During the presidential session, Scott Baraban, PhD recounted the history of the development of zebrafish as a model for epilepsy spearheaded by his laboratory, focusing heavily on the development of a Dravet zebrafish model that allowed for high-throughput screens of drug libraries to look for compounds that might be highly effective at reducing seizures in Dravet syndrome. Indeed, there were ‘hits’ from these screens, and amazingly these have led to literal ‘aquarium to bedside’ translations. In 2017, a small cohort of patients with Dravet syndrome were able to enter a study for lorcaserin, a drug at the time used for weight loss, but that was found to be effective for seizure control in this population. Additionally, a drug called clemizole, which was previously marketed as an antihistamine, was discovered as effective in the zebrafish model and is now currently in Phase 2 clinical studies for Dravet syndrome. In totality, not only does this represent an exciting drug discovery that will hopefully improve the lives of patients, but also underlines the importance and utility of zebrafish as a model system that may lead to further future therapeutic discoveries for Dravet syndrome and other genetic epilepsies.
Also during the presidential symposium, Ethan Goldberg, MD, PhD explained how some of the advancements in microscopy and imaging are allowing new insights into epileptogenesis in mouse models of Dravet syndrome and other similar epilepsies. Techniques like 2-photon calcium imaging are enabling researchers to monitor electrical activity in the brain of alive, behaving mice which allows discovery and characterization of dysfunction in specific brain circuits. These techniques combined with the powerful genetic mouse models could lead to new understanding of the mechanisms that lead to seizures.
A new animal model of Dravet syndrome is also being developed that may provide insights into SUDEP that were not possible in other existing models. Rabbits provide a unique opportunity to examine cardiac function that more closely mirrors human cardiac electrophysiology, and their larger size allows for deployment of unique technology for monitoring and intervention. Dr. Lori Isom’s group at the University of Michigan has created a rabbit model carrying a mutation in SCN1A that mimics the haploinsufficiency seen in patients with Dravet syndrome. The rabbits have spontaneous and temperature-sensitive seizures as well as a high rate of mortality. Initial work has uncovered that these Dravet-rabbits have altered respiratory and cardiac activity. They hope that further investigation may provide new insights into the mechanisms of SUDEP.
DSF-Funded Researchers were Active at AES
Sophie Hill, PhD presented a poster from a collaboration between the laboratories of Ethan Goldberg and Brian Theyel showing the first evidence that ectopic action potentials are significantly impaired in inhibitory interneurons in a mouse model of Dravet syndrome. These impairments may contribute to the overall impaired action potential propagation in these cells in Dravet syndrome. (Abstract #1.038)
Ashwini Sri Hari, PhD, Cameron Metcalf, PhD and their colleagues at the University of Utah investigated gene expression changes in the hindbrain and lungs of a mouse model of Dravet syndrome looking for potential insights into SUDEP. They found alterations in pathways related to metabolism, cellular protein processing, and inflammation. (Abstract #1.016)
David Auerbach, PhD (Abstract #3.570 ; Ryan, Scheffer, & Auerbach) has been investigating whether there are cardiac electrical abnormalities in patients with developmental epilepsies that are associated with high rates of SUDEP. They report an increased prevalence of QTc prolongation in patients with Dravet syndrome and Lennox-Gastaut syndrome than rates that would be expected in the general population, providing clues to inform future inquiries into SUDEP mechanisms.
Researchers from Children’s Hospital of Philadelphia led by Ingo Helbig, MD working on the Dravet Genome Study reported a preliminary look at reconstruction of longitudinal clinical data from 80 patients with SCN1A-related disorders. They were able to map seizure types and frequency, medication use, and other clinical features across time, as well as make comparisons in medication responses between patients with loss- and gain-of-function SCN1A mutations (Mercurio et al Abstract #3.120).
William Nobis’ laboratory (Abstract #3.068) detailed progress in assessing the efficacy of exposure to the odorant 2-phenylethanol (2-PE; also known as rose hip oil) to prevent premature mortality in a mouse model of Dravet syndrome. They found exposure to 2-PE for 15 days led to a trend of increased survival. Exposure in another induced seizure model reduced seizure severity. They plan to expand their sample size, assess if respiratory parameters are impacted, and investigate mechanistically how brain networks may be impacted by odorant exposure.
Meiling Zhao, PhD and the laboratory of Joanna Mattis, MD, PhD reported on novel insights into how the neurons involved in noradrenaline signaling are impacted following heat-induced seizures in Dravet syndrome. They found this population of neurons to be temporarily inhibited during temperature-induced seizures as well as changes in the levels of norepinephrine in the hippocampus surrounding seizure onset. (Abstract #3.026)
Mackenzie Howard, PhD and his laboratory has been investigating the role of the cerebellum in an SCN1B model of developmental and epileptic encephalopathy. They report impairment of learning when Scn1b is disrupted specifically in the purkinje cells in the cerebellum of mice. They also demonstrated deficiencies in electrical signaling in this cell population from these mice. Importantly, this represents validation of a new research model for Dravet syndrome that may provide insight into the mechanisms of non-seizure symptoms in patients.(Guillen et al Abstract #1.023)
I hope today’s blogs provided some exciting updates on the research and advancements that are occurring for the field of Dravet syndrome as showcased at AES. We will continue to watch and share as updates come in the new year!
