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.
This year the meeting was virtual, which made the exhibit hall and the poster sessions less exciting but also made the presentations more accessible, including a 90-day on-demand period after the meeting to catch up with all of the parallel tracks.
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, which come under many names like Developmental and Epileptic Encephalopathies (DEEs) since not all of them are genetic. There is a lot more that is presented at the AES meeting and that I will not cover. These are my own 5 insights from the American Epilepsy Society 2020 meeting.
1. DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHIES AT THE CENTER OF THE AGENDA
The main difference between DEEs and general epilepsy is not their frequency. DEEs are largely genetic, and have many more impacts than just seizures, so as the DEEs take more space in the agenda at AES, the conversation also turns from seizures to non-seizure comborbidities, and from symptomatic management to genetic treatments.
This year the discussion around DEEs was again very prominent in the conference agenda, making it hard to miss by attending clinicians. For example, we opened the congress with a Presidential Symposium focused on DEES. There was also a very interesting Investigator Workshop dedicated to pediatric trials, particularly relevant for these patient populations, and another Investigator Workshop that I moderated dedicated to genetic treatments in DEEs. And we had different industry-sponsored symptosia around rare childhood epilepsies including DEEs as well.
Going through my notes on how the discussion around DEEs has evolved from one year to the next at AES we can track that increasing prominence:
In 2017, there was already growing attention for the “orphan epilepsies” and everybody was excited about cannabidiol and fenfluramine. It was starting to become clear that there are just too many genetic syndromes to try to diagnose them one by one, and that we need to run genetic epilepsy panels as soon as possible in children and reevaluate adults. AES 2017 was a great meeting, but I was still hoping that we could move beyond genetic diagnosis and towards genetic treatments.
Then we made a big jump in that direction at the American Epilepsy Society meeting in 2018. I wrote in that article: “There was one key progress visible at the AES 2018 meeting that defines a before and after moment in the field of epilepsy, and this is the arrival of non-pharmacological therapies for treating epilepsy.”
That “before and after” was even more clear during last year’s conference. During AES 2019, the sessions on genetic therapies and antisense oligonucleotide (ASO) therapies for rare epilepsies were filled to full (standing) capacity and the organizers had to close the doors. The epilepsy field, which has been until recently dominated by pharmacology, had embraced the technologies of biotech and we have officially entered a new era. I wrote that “AES 2019 was the year of genetic therapies for the developmental and epileptic encephalopathies”.
AES 2020 provided a continuation to these discussions, with greater visibility for the DEEs, their particular challenges and the treatments in development that target their biological cause. This prominence is turning the conversation from one of interest mainly for a subgroup of people (like me!) into a central topic in epilepsy community.
And this is very important, because as these conversations are featured more often at the congress and also in the major sessions, they reach a broader audience of practicing neurologists and epileptologists who might not often get exposed to the genetic epilepsies. My hope is that this will translate into more awareness, with more patients being evaluated for potential genetic syndromes and with that more diagnosis. And with more diagnosis we get more targeted therapies researched and taken into the clinic, so it is critical to get that first ball rolling: the one of broader awareness among clinicians.
2. BIG PROGRESS IN DRAVET SYNDROME
The poster child for how the epilepsy field is moving from treating mainly symptoms to chasing cures (genes), is Dravet syndrome. And that is because Dravet syndrome holds one foot in the classical clinical epilepsy syndromes (it is not a genetic diagnosis), and one foot into the mono-genetic disorder space, with a large majority of patients having SCN1A haploinsufficiency. So it was the ideal “transitional disorder”.
Because of that, we can see in Dravet syndrome an impressive progress in barely a decade from having no clinical trials, to having initial trials with symptomatic treatments, to having multiple symptomatic treatment approvals, to now having genetic therapies in development. I expect many other syndromes to follow, probably with faster timelines to genetic therapies.
2020 was a very good year for Dravet syndrome and that was seen in the AES 2020 meeting. This is a very-short summary of the progresses in Dravet syndrome therapy development presented at AES 2020:
The European approval of Fintepla (fenfluramine) for Dravet syndrome makes it the 3rd drug specifically approved for treatment seizures in Dravet syndrome, together with Diacomit (stiripentol) and Epidiolex/Epidyolex (cannabidiol). We could see data at the conference on fenfluramine’s long term efficacy in adult patients with Dravet syndrome as well as long-term safety data.
Takeda and Ovid Therapeutics presented data on a Phase 2 study with the drug Soticlestat, an indirect modulator of NMDA activity, with about 34% seizure reduction in the placebo-controlled study, similar to cannabidiol. The companies have announced their intent to pursue a Phase 3 program for Soticlestat in Dravet syndrome in the near future.
In preparation for clinical trials that can measure non-seizure outcomes in Dravet syndrome, Stoke is running an observational study called BUTTERFLY, and they presented at AES their first results indicating the feasibility of a small collection of clinical scales to measure these outcomes. This might not sound very exciting, but it is a milestone study that will help us transition from running clinical trials in Dravet syndrome as epilepsy trials, to running them as neurodevelopmental disorder trials – and those are the ones we need for genetic therapies.
Staying with Stoke, the company is developing an ASO to increase functional SCN1A mRNA and protein expression and dosed their first patient some months ago, making it the first patient with Dravet syndrome to ever receive a therapy designed to rescue their genetic problem, another major milestone study for the field. At AES, Stoke presented their Phase 1b/2a trial design (MONARCH study), that focuses on PK, safety and tolerability but will also produce some early efficacy signal. The company expects to have some early data from this study in 2021.
A bit earlier in the pipeline, Encoded Therapeutics is using an AAV approach for Dravet syndrome where they drive the expression of a transcriptional activator for SCN1A only in interneurons. The purpose is to increase SCN1A and therefore Nav1.1 only in interneurons, which are the main neuronal population that needs it. Last year they presented their preclinical proof-of-concept in mice and this year they showed they had taken a large step towards the clinic presenting the biodistribution and safety of their gene therapy in non-human primates. The company has announced that their one-time treatment for Dravet could start clinical trials in 2021.
There are additional gene therapies for Dravet syndrome in development, and as part of the Investigator Workshop that I organized, Dr Ricobaraza from CIMA presented an adenovirus-based experimental therapy that they are developing to supplement SCN1A expression in the brain. This therapy showed broad rescue of disease phenotypes in SCN1A mutant mice and uses a different approach to the gene therapy from Encoded by supplementing SCN1A expression instead of boosting endogenous expression.
And Xenon Pharma, a Canadian biotech company, presented early proof-of-principle in mice for a small molecule Nav1.1 activator. The discovery of this class of compounds was one of my favorite poster presentations from 2019 and this year Xenon was able to come with additional data, including in mice with SCN1A haploinsufficiency. Following an ASO and a viral-delivered gene therapy, a small molecule able to increase Nav1.1 activity can be a game changes and reminds me of risdipram, the small molecule from Roche for the treatment of SMN.
If your main interest is in this syndrome, I recommend you to also read the AES summary from the Dravet Syndrome Foundation.
3. AND NOT JUST DRAVET SYNDROME
The industry interest in orphan indications within the epilepsy space doesn’t stop at Dravet syndrome. The adoption of genetic panels for diagnosis of pediatric neurological conditions has led to the identification of many other syndromes that present with epilepsy, and many more patients with each of these conditions. This has helped us describe them as new disorders and start clinical trials looking for effective medications.
A disorder that is following the steps of Dravet syndrome is CDKL5 Deficiency Disorder (CDD).
At AES 2020 we saw the results of the first pivotal trial in CDD, a 101-patient Phase 3 trial with ganaxolone (by Marinus Pharmaceuticals). This clinical trial, called the Marigold study, demonstrated efficacy of ganaxolone in reducing seizures in this population and might lead to the first approval for CDD. The company plans to apply for marketing authorization in 2021. Something that caught my eye looking at the trial data is that at baseline, CDD patients have 50-60 major motor seizures per month, stressing both the severity of the disorder and the urgent need for effective medications.
Dr Devinsky from NYU presented the results of an ongoing open-label Phase 2 study with fenfluramine in CDD, with 6 patients with CDD showing a 90% reduction in tonic-clonic seizures. This makes fenfluramine a very promising potential treatment for CDD, and I hope to see it evaluated in larger placebo-controlled studies for this disorder.
Dr Devinsky also presented a review of all clinical trials so far in CDD, including clinical trial data with cannabidiol, ataluren and soticlestat. This is important because many therapeutic programs in development for CDD were not presented at the AES 2020 meeting, and if we hadn’t seen this review we would think that there are fewer developments in CDD.
This is one of my main observations from the meeting, which I explore further in the next point. We had several presentations on the different DEEs, often as a group, but a lot of the therapeutic developments were missing from the conference. In particular we were missing virtually all of the genetic treatments in early development.
We saw trial data in Lennox-Gastaut Syndrome with Soticlestat (Phase 2) and fenfluramine (Phase 3), and early clinical data on the pharmacokinetics of NBI-921352/XEN901, a Nav1.6 inhibitor, that is being developed for SCN8A developmental and epileptic encephalopathy and that I look forward to seeing it reach patients in future trials.
But there is so much more that was missing from the conference! I would have liked to know how the ASOs and small molecules for SCN2A-associated disorders are doing, how the KCNQ2 modulators from Xenon and Knopp are doing, if there are progresses with the ASO for KCNT1 epileptic encephalopathy, and if there are any new therapeutic developments to target SynGAP1 or STXBP1 or PCDH19 or many others. And that all leads me to my next point….
4. SOME OF THE BEST UPDATES OF THE YEAR WERE MISSING FROM AES
I know that many of my readers are parents of children with rare epilepsy syndromes, so I want to stress this message: there is a lot that was not presented at AES 2020. If there was nothing (or little) presented about your child’s disease it DOES NOT mean that there is no reach being done on treatments for their disease.
So while the AES congress is the best meeting of the year for epilepsy, it does not get deep enough in all of the different areas, in particular when it comes to academic efforts or some genetic approaches. This is not the Society’s fault. A small part of the program is chosen by AES but the large bulk of it is determined bottom-up: clinicians and scientists (and some times patient groups) submit proposals for sessions, such as investigator workshops, or for individual presentations, and these are then selected based on quality and interest in the area – and clearly AES has seen a major interest for DEEs and genetic treatments. But if people don’t submit some project for presentation at AES, it will be missing. And a lot is missing.
Where can you find those project updates? Quite a bit of it will be presented at antisense oligonucleotide meetings or gene therapy meetings while they are still in early development. For example, this year there were two different gene therapies for CDD that were presented at the American Society for Gene and Cell Therapy meeting, and you would have never known this had happened if you only attended AES 2020. Much of the academic work doesn’t get presented at “clinician” conferences either, and they are more likely to be presented at neuroscience meetings for example.
And hands down the best place where you will find all this information is at the scientific meetings organized by the patient community. These are the best meetings to get a complete view of all of what is coming up for each disorder. At the CDKL5 Forum organized by the Loulou Foundation we review every year the state of all research efforts and see presentations by the teams driving this science. Other examples are the Dravet Syndrome Foundation Biennial Conference, the SynGap Research Fund Roundtable, the Foundation for Angelman Syndrome Therapeutics (FAST) Global Summit and many others.
And this latest one is important to highlight, because the treatment development announcement that I consider the most groundbreaking one of 2020 is the early data in Angelman syndrome from GeneTx and Ultragenyx. Their treatment, GTX-102, is an ASO that allows for the unsilencing of the second copy of UBE3A in patients with Angelman syndrome. Preliminary data from the first 5 patients with Angelman syndrome treated with the ASO showed very large improvement in all of them with reports of efficacy that we simply didn’t know were possible in just 4 months (or at all) in a neurodevelopmental disease. Improvements like previously non-verbal patients acquiring spoken language, learning to respond to their name or learning to self-feed with a fork. All of this in 4 months! There are some safety concerns with this therapy that the companies hope to be able to manage, but what is most important to me is what we have just seen as biologically possible.
I hope all families of patients with DEEs have heard about these data. And this was a finding that will probably never make it to AES because it was not about seizures, but it is the holy grail that we look for in DEEs, which is why I stress the need to make sure we attend the meetings organized by the research foundations and patient organizations, so that we know the true state of scientific development in the space.
Coming back to AES, I am very happy with the general conversation featuring so prominently the DEEs, but not with how much (how little?) we get to hear about therapeutic programs in development for each of the DEEs. In addition to following the developments in those disorders through the separate disease-focused meetings, I encourage us all to submit proposals about these disorders to be presented at AES 2021, and perhaps we can try to include more presentations that review the pipeline for the syndromes like the one from Dr Devinsky for CDD. That will help us get a more complete overview of treatments in development at AES.
5. DIFFERENT TRIALS, DIFFERENT CHALLENGES
A very interesting conversation at AES is that the traditional clinical trial design in epilepsy will not be enough for all the new syndromes or for all the new treatments.
We talked about the challenge with “ultra-rare” diseases, where you might have few diagnosed with that disease, or perhaps a treatment (like a mutation-targeted ASO) that could only work in a handful of patients at most. In these cases, it is too hard to satisfy the usual regulatory requirements for running a trial, so some patients and some companies are pushing for n-of-1 “trials”. And I use quotation marks around the word trials in this case, because as Dr Adam Numis from UCSF puts so well into words: “is this research or is this clinical care?”. And if we are essentially using those trials for clinical care, we need to be cognizant that they don’t represent proper research so they might end up not being reproducible (like quinidine and KCNT1).
We also talked about non-seizure outcome measures and endpoints for clinical trials, which we all want to see in the DEEs. Some observational studies are starting to identify some possible outcome measures, but then we hit the next challenge: how long do trials need to be to see an improvement in some of these outcomes? And would it be ethical to have patients wait in a placebo group all that time? I really enjoyed Dr Madison Berl’s presentation about some non-seizure outcomes that could potentially show a change earlier, and her recommendation to use raw scores in these clinical scales (not the total scores) to focus on items that are more specific for that patient population and likely to respond sooner.
About this, a related discussion that I would like to hear more about next year is how we will interpret all of those non-seizure outcomes and where to trace the line for something being clinically meaningful. In the patient community they speak about “inchstones”, the little accomplishments that might not usually count as a developmental milestone but that really make a big different to patients and their families. My hope is that genetic treatments will be so impressive that it will be obvious that they improve patient outcomes, like in the SMA trials, but until we have those treatments we need to identify the best way to capture these inchstones as well.
LOOKING INTO 2021
I think we are all happy to get done with 2020… for many reasons. 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 Stoke early results in Dravet syndrome with STK001 (their ASO for SCN1A) and the initiation of clinical trials with ETX101 (gene therapy) from Encoded Therapeutics.
I look forward to ganaxolone filing for approval for CDD.
I look forward to more phase 3 studies in more DEEs, including Soticlestat and fenfluramine and potentially others.
I look forward to more ASOs and gene therapies approaching clinic. I want to see more proof-of-concept in mice, biodistribution studies, and IND-enabling programs. Step-by-step getting us close to trials.
I also keep an eye on those small molecules that also target the disease and that could be transformational for some channelopathies.
I look forward to many research foundation and patient organization-led conferences in 2021, virtual or not, where we can get a view of all efforts ongoing on these disorders and establish collaborations and networks.
And I look forward to more beautiful surprises, like the ASO results in Angelman, that remind us that we still don’t know what biology can do if we come up with the right therapy.
Ana Mingorance, PhD