The American Epilepsy Society (AES) meeting is the largest epilepsy meeting of the year, and because it takes place every month of December it also serves as an annual review on the understanding and treatment of epilepsies. I look forward every year to the first week of December for this reason.
I look for therapies for rare genetic epilepsies, and in the recent years this area has exploded to take over much of the AES meeting. Because of that, I will focus this update on the rare genetic epilepsies, or Developmental and Epileptic Encephalopathies (DEEs). There is a lot more that is presented at the AES meeting and that I will not cover. These are my top 5 insights from the American Epilepsy Society 2021 meeting.
1. Natural History Studies are tremendously important
When companies develop treatments for seizures as a symptom, it is straightforward to run trials: just count seizures. But when companies start developing treatments that treat the cause of that epilepsy, and in particular when we are talking about complex neurodevelopmental syndromes with epilepsy, then clinical trials are more complex than just counting seizures, and need more solid data on the usual symptoms and severity that those patients have so that we can know if there is efficacy. This is where Natural History Studies (a type of observational study) specifically designed to inform on clinical trial design come into play. And we are seeing a big number of these.
Several of these ongoing studies were presented at the AES meeting. The BUTTERFLY study by Stoke Therapeutics is an observational study to characterize clinical scales to measure the non-seizure aspects of Dravet syndrome, and has already shown promise with several scales that could be used in interventional clinical trials. The ENVISION study by Encoded Therapeutics, has also helped validate scales and determine the baseline characteristics on non-seizure outcomes in young children with Dravet syndrome. Both companies are developing treatments to rescue SCN1A gene expression in Dravet syndrome, so these observational studies are designed to make those treatment trials possible, and both observational studies are already producing very useful data.
We also saw example of more proactive observational studies that are already ongoing even before companies are ready for trials, like an SCN8A Natural History Study resulting from a partnership between hospitals and patient groups, and a consortium working on STXBP1 Natural History. While these studies are simpler than the company-run Dravet syndrome studies, and don’t validate scales, they help us understand the collection of symptoms and their severity in these syndromes, and guide the design of the clinical-trial enabling studies. It is also remarkable that both studies include data from more than 500 patients from each syndrome!
If you are running or supporting a rare epilepsy patient group, I recommend you also check these two additional resources to understand why these studies are so important and consider how it could work for your disorder:
1) The pre-competitive industry collaboration involving seven biopharmaceutical companies and the Loulou Foundation to run an observational study specifically designed to evaluate the feasibility and suitability of a collection of clinical outcome measures in CDKL5 deficiency: here and here.
2) The amazing Mike Granglia from SYNGAP Research Fund explains in a recent video why Natural History Studies specifically designed to inform on clinical trial design are so so important to not delay the initiation of clinical trials for these syndromes. Please watch it, the Natural History Studies part starts around minute 5:45 but the entire videos are fantastic.
2 – Gene therapies are coming for many epilepsies
There are many reasons to believe that many of the genetic epilepsies will benefit much from restoring gene expression in patients, even in older individuals. And we saw several studies in mice presented at AES where scientists returned gene expression to mice with genetic epilepsies showing very good efficacy. See for example this study in CDKL5 Deficiency Disorder, this one in SCN1A Dravet syndrome, and this one in STXBP1-related DEE.
To be able to do that in patients, scientists need to develop gene therapy approaches using antisense oligonucleotides (ASOs) or virus that can bring to the brain the missing gene, or virus that can bring to the gene CRISPR approaches or transcription factors (see review of options for Dravet syndrome here). We saw several of this presented at AES this year.
The most advanced program is the one from Stoke Therapeutics. In addition to presenting an update about their observational study, Stoke presented new information about how their ASO to increase SCN1A distributes within the brain in non-human primates, and the likely doses that are needed to produce enough sodium channel in the brain in trials. From their data, it seems that repeated administration of 30mg of STK-001 (their ASO to increase SCN1A levels) will be a good target to to achieve active brain levels in patients. They are not yet administering those levels to patients because the interventional trial is still at early stages, and it is a Phase 1/2 trial without any prior trial in healthy volunteers, therefore starting with only one administration of STK-001 to Dravet patients at very low dose and moving from there to higher doses, still with only one administration to monitor safety, and then starting with repeated dosing also from lower concentrations to higher. From this early data, Stoke reports good tolerability, and a trend towards having less seizures but all participants had received either only one administration of STK-001 or multiple administrations of 20mg, so we really have to wait for the trial to reach higher dose with repeated administration in order to see the therapeutic potential of this treatment. We might potentially see this first from their UK study, called ADMIRAL, where Stoke will evaluate multiple doses of up to 70mg [see Note for parents at the end of this text].
Behind STK-001, there are several therapies in development, all designed to increase SCN1A for Dravet syndrome, that have not yet started clinical trials. You can see a summary of all those approaches here, where I explain the biology of SCN1A deficiency and the options to increase it.
Encoded Therapeutics is developing ETX101, a gene therapy that uses an AAV virus to upregulate SCN1A in the brain. They are preparing to start clinical trials, and this year presented data on their observational study as well as on understanding caregiver perspective to better design their upcoming clinical trial. A company called CAMP4 has acquired the rights to the ASO program from OPKO to upregulate SCN1A, and talked about the preclinical data that is available for this program at AES. And there are at least three academic groups developing viral-based gene therapies for Dravet syndrome, all focused on increasing the SCN1A gene: the adenovirus program that we saw last year at AES, a new one this year, and a CRISPR-ON approach being developed in Italy.
We also saw preclinical data for a gene therapy program for SLC13a5 Deficiency, showing efficacy in young mice and also in young adults, which is very promising towards future studies. And scientists at UCL in the UK are working on bringing gene therapy to non-genetic epilepsy! Their gene therapy is designed to sense if neurons are hyperactive, turn on and produce potassium channels (which makes neurons less excitable), and as soon as neurons are not hyperactive anymore, turn off. This means that neurons would only make use of that gene therapy when they truly need it. They are still trying it in mice, so it is at early stages, but I found this research one of the most groundbreaking presented AES.
3 – Not all is gene therapy: Many exciting progresses with small molecule drugs
We had a very good year of progresses in small molecule drugs (“normal medicines”) for epilepsy, including for rare and non-rare epilepsies.
Probably the most impressive is the Phase 2 data of XEN1101 in adult patients with focal onset seizures, which is the most common seizure type. There are more than 20 drugs approved for treating focal onset seizures, and trials are done with the new drug added on top of whatever the patients are already taking, so it is very difficult to see impressive efficacy in this oversaturated space. Yet XEN1101 achieved a reduction in seizures of up to 52% at the highest dose. This is rare and exceptionally good.
There were also several updates on late-stage programs presented. We saw post-Phase 3 trial data for fenfluramine in Dravet syndrome, and for ganaxolone in CDKL5 Deficiency Disorder, both looking really good. Ganaxolone has also shown efficacy in PCDH19 epilepsy in a Phase 2 study, with 61,5% of seizure reduction. There is an ongoing trial in young children with diazepam nasal spray as a rescue medication, and Takeda presented how they plan to count seizures in Lennox-Gastaut syndrome in their Phase 3 trial with soticlestat which has a novel glutamatergic mechanism of action.
And I liked to see several innovative compounds coming up in the earlier pipeline. Eisai has a GAT1 inhibitor called E2730 as a potential alternative to tiagabine. A KCC2 activator might have potential for treating seizures in Rett syndrome. Praxis has a sodium channel blocker called PRAX-562 with preclinical efficacy for SCN8A and SCN2A Gain-of-Function epilepsies, and Xenon has sodium channel potentiators with preclinical efficacy for Dravet syndrome (SCN1A).
I might be missing some compounds, but it is clear that 2021 was a very good year for the developments of medications for epilepsy, with some really strong data in clinical trials and in the “real world”, and with new drugs that have novel mechanisms of action at early discovery stages.
4 – Understanding genetics in epilepsy
It is likely that most epilepsies have some genetic contribution. As we learn more about it, and genetic testing becomes more common, we will find many more individuals with rare genetic syndromes and start finding sub-groups of patients with “common” epilepsy that might respond better to certain treatments.
Xenon Pharma has a drug in Phase 3 for KCNQ2-related epilepsy, and they are one of the sponsors of the Invitae genetic testing program for epilepsy. So they interrogated the data from Invitae to see how many of the cases are due to KCNQ2 mutations. I knew this disease was one of the most common genetic epilepsies, but I did not expect the numbers that they got: KCNQ2 is by far the leading cause of neonatal epilepsy, and still the most common in children under 6 months of age. We urgently need early genetic testing for epilepsy to not miss these cases!
There are still new genetic causes of childhood epilepsy being found, like SLC7A3 and SYNJ1 mutations, and scientists are able to create mouse models of genetic epilepsies that require mutations in more than one gene. And a large collaboration of scientists has put together a portal called NDD-CNV to collect information on copy number variations in neurodevelopmental disorders (many with epilepsy) to assist with variant interpretation, which is very important for syndromes like Dup15q and 8p disorders.
And we saw several genotype/phenotype studies where scientists try to see if different types of mutations produce different prognosis which is a common question from parents after genetic diagnosis (see for example SCN1A and STXBP1). There is a little bit of correlation when you compare mutation type in hundreds of patients, but it doesn’t seem that we will be able to predict the development of a child just knowing the specific mutation that they have in a given gene. There was also a massive study in 11,500 patients with epilepsy that relied on phenotype keywords to see if they could be matched to genes, and it identified certain keywords that are preferentially associated with some syndromes like “hemiclonic” and Dravet syndrome, and that suggests that we could potentially use good phenotypic descriptions to prioritize genes to test in these patients. I still believe the best option is to just sequence all people with epilepsy for all epilepsy genes or the entire exome/genome, with particular urgency for young children.
5. Patient groups are building research-enabling platforms
This year we saw some very important research efforts led by patient groups, with the purpose of making it very easy for scientists and companies to work in their disorders:
The NDD-CNV portal is hosted by the Broad Institute and co-developed with the Dup15q Alliance, Project 8p, and Ring 14 US and Ring14 International. It is a natural synergy among structural variant disorders (as opposed to point mutations) and I encourage you to check out the link.
A similar effort, the GRIN Portal, is also hosted by the Broad Institute and developed in partnership with several national and international GRIN patient organizations, and provides information about the genes, the disorders that they cause when mutated and the consequences of specific variants to facilitate interpretation.
Yet another portal hosted by the Broad Institute is the SLC6A1 Portal, with analogous information about SLC6A1 and also with collaboration from patient organizations.
Shout out to Dr Dennis Lal from the Cleveland Clinic and the Broad Institute for making those three portals positive (and more, like the sodium channel portal), and being such an amazing advocate and promotor for patient-led research in genetic epilepsy.
The SYNGAP Research Fund and Ciitizen have also brought together the largest cohort of SYNGAP1-related disorder patients in a platform to collect real world evidence, which will help design clinical trials for this syndrome. And I already mentioned the SCN8A Natural History Study and STXBP1 Natural History Study which are also happening thanks to the effort and leadership of patient organizations.
I believe this type of effort is the best investment that patient groups can do, more than investing on any single research program. It requires that the patient group takes a leadership position in the field and builds the blocks that will facilitate and de-risk individual programs. And it has required a cultural change where clinicians and academic scientists are now very open to partnering with patient organizations and co-leading these efforts. 2021 was a great example of this.
LOOKING INTO 2022
As we look into the new year there are some planned milestones that I look forward to, and some things that I hope will also come true:
I look forward to efficacy data from STK-001 in Dravet syndrome, and the initiation of clinical trials with ETX101.
I look forward to ganaxolone getting approved for CDD, and fenfluramine showing positive results in the ongoing Phase 3 (if interim data is already available by then)
I look forward for more genetic therapies moving into trials. There are several preclinical programs with ASOs and viral-based gene therapies, and in the coming years we should see several of these moving into trials.
And I look forward to seeing progress with several small molecules that target disease-causing proteins, as in KCNQ2, SCN2A, SCN9A and SCN1A Dravet syndrome. Short of gene therapies these might be the best treatments for these disorders.
Ana Mingorance, PhD
Note for parents of someone with Dravet syndrome: when fenfluramine and CBD started trials in Dravet they already had data from adults with other diseases, same for soticlestat and others, so by the time they started trials in Dravet they could immediately administer the drug at the therapeutic dose daily for three months to see efficacy. That is different with STK-001 because it is a disease-specific treatment targeted to people with deficiency in SCN1A so they had to start trials directly in patients and figure out the tolerable and effective dose also in patients, going little by little and starting with low doses. The way I see it, it wouldn’t be correct to compare the current Phase 1/2 Stoke trial with a Phase 3 with other drugs. They are still building up to getting to the best doses, and so far so good.
Disclaimer: These are my own impressions from the presentations and topics that I was most interested in. I write these texts with the parents of individuals with rare epilepsies in mind, so excuse also my lack of technical accuracy in parts.