The International League Against Epilepsy (ILAE) hosts every two years an international epilepsy congress (IEC) that just took place in Dublin. The main conference in the field is still the American Epilepsy Society meeting that takes place every year in early December (check out my summary of the 2022 AES meeting) but the IEC is a close second.
This text is not meant to be an exhaustive review of all what was discussed at the IEC. These are my highlights, as a rare epilepsy scientist who has been attending this type of conference for many years. Fun fact: did you know that in 2013 this conference was also held in Dublin? That was the year I decided to leave pharma to be able to work directly with rare disease patient groups. So this conference was very special for me, being back at the IEC in Dublin exactly 10 years later.
Here are the 9 messages that grabbed my eye during the IEC2023 conference, plus a bonus message. As usual, I focus on the development of treatments for rare epilepsy syndromes or DEEs.
1. Voice of the patient in the agenda
Amber Freed from SLC6A1 Connect
The IEC organizers did a great job at having many of their sessions open with the voice of the patient. And not just in the small rooms.
Amber Freed from SLC6A1 got to open the Presidential Symposium of the conference. The day before we heard from Gabi Conecker about SCN8A, and both supermums told the audience of clinicians about how the complexity of the DEEs mean that (1) we need coordinated multidisciplinary care, and (2) doctors need to listen to families. Listen not only because it is a nice human thing to do, but also because people with DEEs can do strange things that is not clear what they are (seizures? stereotopies? movement disorder?) so doctors really need to listen to families to understand what’s happening.
These are not new messages, but it is a new stage: the BIG stage. And such change is important to normalize the message that families are central to how we take care of people with DEEs, and that for that to happen we need to regard them as peers, including sharing stage. No more sitting at the back of the room listening to clinicians.
2. Comorbidity doesn’t mean comorbidity
Dr Scott Demarest from Colorado explained this very well. He said that:
We always talk about “comorbidities” because we are epileptologists, so everything that is not epilepsy is a comorbidity. But really these are also defining features of a syndrome, not necessarily set off to the side.
Dr Antonio Gil-Nagel from Madrid also explained later in the conference that only 3% of patients with DEEs have only seizures, so almost everyone has many more things going on: intellectual disability, developmental delay, endocrine problems, motor problems, language problems (the % of non-verbal people with DEEs is high!). He said that in his practice, families often report behavioral problems as their top priority, with aggressivity and impulsivity causing much stress to families.
I’ve also heard this a lot from families (Syngapians and PHD19 girls, I’m thinking of you here)
For me it was clear at the IEC2023 that this “comorbidity doesn’t mean comorbidity” message is sinking in, not only because we heard it from everyone (parents and doctors on stage) but also because there were several sessions dedicated to some of the non-seizure aspects of DEEs. And remember that this is an epilepsy conference! not a neurodevelopmental meeting, so this is really a big step towards helping look at these diseases more globally, which is an absolute requirement towards being able to manage them more globally.
3. Changing the therapeutic goal and how we talk about DEEs
Dr Elaine Wirrell from the Mayo Clinic explained the therapeutic goal for DEEs and how it is different from managing a patient who only has epilepsy. For epilepsy it usually is to try to get to seizure freedom with no (or manageable) side effects. For DEEs, which are so tough to treat, the goal of zero seizures would mean excessive sedation. Instead, the therapeutic goal should be:
“target the most problematic seizures, avoid therapies that might worsen seizures, avoid excessive polypharmacology, and manage the comorbidities to maximize the quality of life”
But that is now, when all we have is anti-seizure drugs and some anti-anxiety or anti-depressant medications, melatonin and others to sleep… all symptomatic! (and rarely very effective). The therapeutic goal will change once we have access to real disease-modifying therapies, which I talk about in some of the next sections.
Dr Elaine Wirrell also gave another very good talk where she reminded collages that words do matter, and to please stop using the term “catastrophic epilepsy”, in particular when explaining to parents what their child has been diagnosed with.
I have a friend (and Dravet dad) called Julian who would often start his presentations with exactly that word, “catastrophic”, as the single word in a slide. And would pause there. To let it sink into the bones of everyone in the audience. Catastrophic means that nothing can be done, it erases all hope.
And Dr Wirrell was fantastic at reminding us that catastrophic is not a medical term, and that:
“words matter! We CAN make a difference for people with developmental and epileptic encephalopathies and they ARE NOT catastrophic!”
She was a fantastic speaker.
4. What is disease modification?
Another of my favorite speakers was Dr Scott Demarest from Colorado. He spoke about how disease-modification “means we have to care about things other than epilepsy” and commented on some of the efforts in development to measure those other symptoms during clinical trials. As he explained, a clinical trial with a disease-modifying therapy (like those correcting a gene problem) has to be different from epilepsy clinical trials. This is not about counting seizures for 12 weeks, this is about counting a lot of new things for a lot longer than 12 weeks. For some of the syndromes we might not even be able to use seizure frequency as the primary endpoint (not enough or hard to count), but that’s ok, we are now seeing more assessments developed for many other disease aspects.
Dr Scott Demarest on disease-modifying trials for DEEs
Dr Demarest explained that disease-modifying therapies are treatments that target the fundamental basis of a condition, and that aim to improve the entirety of the phenotype, but do not necessarily mean “cure” in the sense of erasing the disease completely. But most DEE families that I know already call “cure” a treatment that targets the gene and improves several of the symptoms, so I think we agree on the goal: tackle the biology, and give the body a chance to do its best.
And I would like to take a second to pause here, and let you all realize how this conversation is an inflexion point in the field. This is the International League Against Epilepsy talking about disease-modification (!!), talking about cures, about fixing genes, about getting those treatments through clinical trials. All center stage.
As Prof Ingrid Scheffer from Melbourne said later in the conference, “if you came from the Stoke session, you know that gene therapies are here and now”.
Let that sink in.
It is not just the Stoke clinical trial. It is the whole field. It is a whole pipeline of treatments designed to target the genetic problem of several of the DEEs (many not presented at the IEC2023). This is an inflexion point in the field. Disease-modifying therapies are here and now.
5. Talking a lot about outcome measures
The imminent arrival of therapies that can do more than reducing seizures is changing how we think of clinical trials. Now we want to measure much more, and measuring more means having the scales or assessments to measure those things. That’s called clinical outcome measures.
Outcome measures are not a synonym with a comorbidity, they are scales to measure that comorbidity. It is sometimes confusing, also if we add the word endpoint which is the “goal” of moving that scale. Here is a simple example:
Imagine that you want to gain muscle mass to be able to get better at weightlifting:
The two “comorbidities/symptoms” to measure: weight and strength
Outcome measure 1: scale that can discriminate muscle and fat
Endpoint 1: two more Kg of muscle in X months
Outcome measure 2: measuring the maximum amount of weight you can lift for one repetition
Endpoint 2: increase the weight that you can lift for one repetition by X Kg
So as you can see we start getting into the technical aspects of clinical trials, like the specific assessments that we should use, which by the way should meet the requirements for being used for drug assessment, and also deciding what the goal change should be (the endpoint).
By the way, Clinical Outcomes Research is like a whole field of science! And here we have the clinicians who treat patients with DEEs rolling up their sleeves and getting fully fluent on the technicalities to develop outcome measures and endpoints that can help us run the new clinical trials. IEC2023 looked nothing like the 2013 edition, which was all about using approved anti-seizure drugs better. I tell you, this is an inflexion point in the field. And there is much more community involvement in the field, counting both clinicians and patients, than ever before.
This also opened up interesting debates: not all assessments are equal, so conclusions should NOT be also considered equally. Some of the companies with drugs approved to treat seizures in DEEs are using surveys or scales that capture the parent’s perception of how their child is doing to say that their drug can improve behavior or cognition. A doctor from the audience said very strongly (and rightfully) that you cannot claim that a drug can improve cognition if you don’t use psychological assessments to confirm that. So by all means you should listen to parents to understand the patient experience on a particular drug, but you need to go beyond that and involve neuropsychologists if you want to make certain claims of efficacy.
In the example above about weightlifting, it is not about whether you feel stronger, or your coach thinks that you are stronger, it is about whether we can verify that increase in muscle mass and performance.
Prominent stands with drugs for Dravet syndrome and LGS
6. A big part of the agenda is about DEEs…but mostly about three of them
DEEs were part of pretty much every session at the IEC2023, and often the only subject of entire sessions.
Much of this is because we are diagnosing many more of the syndromes, and learning about them, so at some point the discussion on seizure types (focal onset and generalized) takes as much space as the discussion about different syndromes.
But part of this is because pharma companies sponsor many of the sessions, and they of course want to talk about the diseases that they have drugs for. So with Epidyolex and Fintepla and Diacomit we got to hear a lot about Dravet syndrome, Lennox-Gastaut syndrome, and TSC. You could hear about these diseases in the exhibit area and also in all the sessions that companies sponsored.
And this is great as a field! But it was painfully narrow to focus so much on those few diseases. I understand that this is because a big focus of the conference is to learn about the medicines that are available and how to use them, and we now have several medicines for those syndromes. And also these are some of the most common syndromes so clinicians end up seeing many more of these patients than those with more rare DEEs. But I still believe the agenda skewed a bit too far.
Prof Ingrid Scheffer from Melbourne gave us a number that was truly eye opening: there are 925 monogenic epilepsy genes, and 825 of those explain about half of all DEE cases (others might not be genetic or a gene has not been found yet). That’s a lot!
Compare that to the focus on three syndromes.
I know that there were several sessions on genetics and I missed those (I read Dr Dennis Lal on Twitter to know what was said: @LalDennis). But those sessions focus largely on genetics as a way to DIAGNOSE, not as a way to TREAT. I think the only exception was the talk “Single gene approaches to precision medicine” precisely by Dennis Lal.
What would I like to see at a conference? I would like to see more discussions on DEE as a class, including all of the very rare genetic ones that we keep discovering year after year. Rare genetic DEEs have two things that make them different from other DEEs, so they need more space in this type of conference or we will not be prepared to treat them:
1) They are genetic, so we can think of ways to develop disease-modifying treatments for every single one. Isn’t this great? We might not know the best drug to treat a teenager with LGS but it is very straightforward to know what a child with a genetic DEE needs – the tricky part is to make that treatment. Some will be small molecule drugs to correct an ion channel activity (if that’s the cause of their DEE, like for SCN8A) or an ASO to change the protein expression levels (like for SYNGAP) or a gene therapy to put a gene back (like for CDKL5). Yes we will still help these patients with anti-seizure drugs, but we should talk more about all of the DEEs that have known genes and the different ways we could try to correct that problem and how we can turn those ideas into realities. If we do that, we will bring much more biotech (not just old pharma) to the table, and we really need that.
2) All genes produce a spectrum of phenotypes, and this impacts clinical trials. The clinical diagnoses for DEEs describe an electroclinical profile that is relatively homogeneous, that’s why clinicians have given it a name. But the genetic diagnoses of DEEs all produce a spectrum of symptoms and prognosis. That’s why you can have both Lennox-Gastaut syndrome as your epilepsy type, and CDKL5 deficiency disorder as your genetic diagnosis for example. So clinical trials for the majority of the DEEs, which are genetic diagnoses, are going to be a lot harder, and need more complex trials, relying more on non-seizure outcome measures. They cannot be left off the stage as we focus on Dravet syndrome and LGS and a few other clinical diagnoses (the ones that are good for epilepsy trials).
All that said, I think this is also about a field having been studied for longer. I liked how Dr Rima Nabbout from Paris acknowledged that we were talking a lot about Dravet syndrome at the conference, but also WHY it has become likely the most popular epilepsy syndrome at the meeting. She said:
“Dravet syndrome is emblematic because many years ago there were families that decided that they wanted to work hand in hand with the clinicians, with the pharma industry, and with the whole world”.
And she is 100% right. 12 years ago I started working with Dravet syndrome families to figure out how to make the disease better known to industry. There was only Diacomit and only in Europe. There were no plans for more trials, no companies interested. Dravet syndrome today, is many of the monogenetic DEEs in 5-10 years.
7. Adult neurologists step up
As we get better about diagnosing DEEs, and about taking care of these patients, we have more and more adults with DEEs. This contrasts with adult neurologists receiving a lot less training on these “childhood epilepsies”. And ironically, we are now running trials in patients under 18 years of age in these populations so some drugs get approved only for 18 and younger, or approved for more ages but without data in adults.
And to quote Dr Nabbout again:
“if children are not small adults, it is important to know that adults are not big children”
As patients grow, often the main concerns about their disease change. The parents of a small child with a DEE might worry mostly about seizures, but the parents of a 25 year old with a DEE are more concerned with aggressive behaviors and their son’s declining ability to walk independently, for example. It is important to also make sure that the usual multidisciplinary (and more coordinated) care of pediatric patients is also applied to adults after they transition to adult care, but this doesn’t happen so often. The International League has created a taskforce on transition (from pediatric to adult medical care), and it is led by Dr Nabbout. This is great.
8. Hot drug #1: XEN1101
This drug is not in development for any DEE, but looks great for focal-onset and generalized seizures (currently in Phase 3 trials for both) and is a good example for the type of small molecule drug that we could develop for different types of DEE. XEN1101 opens up an ion channel called Kv7, so that more potassium can flow through. There is one DEE caused by mutations in that very same potassium channel gene, and patients need exactly a drug that can open up the ion channel Kv7 because they only have half of the number that they need (KCNQ2 haploinsufficiency).
This is one of the most exciting drugs in development for epilepsy right now, and could be very useful for patients with KCNQ2-related epilepsy once it gets approved. For many of the DEEs caused by mutations in ion channels, small molecule drugs like XEN1101 could be the way forward.
9. Hot drug #2: STK-001
The second main strategy for genetic DEEs is to use advanced therapeutics like ASOs and gene therapies to tackle the genetic problem. That is what the ASO STK-001 from Stoke Therapeutics is doing: upregulating the mRNA for SCN1A so that patients with Dravet syndrome can have more of the ion channel. Dravet syndrome is largely caused by SCN1A haploinsufficiency so this is the ideal type of treatment to try to treat the entire syndrome.
Stoke initiated the current Phase 1/2 trial about three years ago, first with only a single administration to find tolerable levels, and then with multiple administrations of increasing doses. This is the first trial of its kind for DEEs, so it has allowed us to learn many things, like how long to wait before expecting improvement, but also which types of improvements and how large. The IEC2023 was the first large conference where Stoke presented their clinical trial data, after announcing the latest results this summer. And it is safe to say that they have finally found the good doses and the treatment is looking quite good. To quote Dr Dennis Lal recap of the data presentation:
“impressively, not only many patients have >50% seizure reduction but also cognitive measures show improvement.”
And that is what makes this treatment so special, the possibility to improve symptoms beyond epilepsy, in a way that can be quantifiable in clinical trials, because it is not acting on a symptom but on the disease itself.
Or as Dr Scott Perry from Texas said:
“finally a treatment showing evidence of true disease modification for Dravet syndrome!”
And I want to remind you that Dravet syndrome today, is many of the monogenetic DEEs in 5-10 years.
There is more to treatment development for DEEs than what we saw
At the last AES meeting I wrote that:
“We have crossed the line of developing treatments for symptoms, to developing treatments for the cause of the disease. And the line of focusing on a few syndromes only (those with the most patients), to seeing treatments in development for many more. That’s escape velocity.”
The IEC2023 meeting capture the first part very well, but missed the mark on the second. It captured very well the change in mentality and priorities of the clinicians and their representing organizations, perhaps even better than at AES, but barely scratched the surface of the true therapy development pipeline for DEEs, for many DEEs, so I recommend you to read my summary of the last AES meeting in this website, and see you in Orlando for AES2023.
I hope you enjoyed this update, let me know your thoughts in the comments,
Ana Mingorance, PhD
Disclaimer: I write these texts with the parents of people with rare epilepsy syndromes in mind, so excuse also my lack of technical accuracy in parts.