AES 2022: genetic epilepsies reach escape velocity

PART 1 – ESCAPE VELOCITY

 

I often write a summary of the main lessons from the American Epilepsy Society meeting, but this year there was so so much about the rare epilepsy syndromes that I was not able to follow the main conference, there was barely enough time to follow all what was happening around the syndromes (which you also see referred to as Developmental and Epileptic Encephalopathies, or DEEs).

So I will focus my summary this year on the development of therapies for the rare epilepsy syndromes.

The conference started really strong, with the SYNGAP1 Conference the day before the main AES conference, where we learnt from Dr Jacquie French that for the first time, in 2022 we had more trials in rare epilepsies than in adult epilepsy. Even if people with rare diseases represent only about 20% of the total number of people with epilepsy, now they have the lion’s share of the trials. This is huge news!

And during the main AES meeting it was clear that indeed, much of the attention is currently on the rare epilepsies, with much of the agenda dedicated to genetic diagnostic, understanding how the adults with rare epilepsies look (so we can find them and develop treatments!), and much much research on the development of treatments. That’s why I believe that this year, with the milestone of having as many trials in syndromes as in regular epilepsy, we have crossed a line and likely reached escape velocity. Because it is not only about the two or three “famous” syndromes anymore, or about anti-seizure drugs being tested for the syndromes. We have crossed a different line.

At the other side of this line are treatments that target the cause of the monogenetic epilepsies. And those treatments look very different than classical anti-seizure drugs, and those trials also look different. 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.

 

PART 2 – TREATMENTS TO CORRECT THE CAUSE OF 8 SYNDROMES

Here are some of my highlights for eight of these monogenetic syndromes as an update to families. There are more diseases, don’t be discouraged if yours is not covered in this summary, I couldn’t do all of them.


SCN1A

Dravet syndrome is the (mostly) monogenetic syndrome that has received the most attention so far, and as a result the one with the most approved therapeutics. We saw many updates at AES about the approved drugs, and presentations about ongoing clinical trials with soticlestat (Phase 3) and EPX-100 (Phase 2). But I will focus on the treatments for the cause of the disease.

One of the most anticipated news of this congress were the early results from Stoke using an antisense oligonucleotide (ASO) called STK-001 to increase the good copy of the gene SCN1A. That’s because Dravet syndrome is a haploinsufficiency, which means that one copy of the gene is bad but one is good and can be exploited to produce enough protein from that one copy. That’s what Stoke is doing. After completing lower doses as part of the safety protocol for this type of therapy, Stoke has recently started administering higher doses to patients with Dravet syndrome and seen seizure frequency reduction and also improvements in non-seizure aspects of the disease. There is more information about this on their website. This is still the first small group of patients receiving enough dose to measure efficacy, and the results look very positive to me.

Another company using a similar antisense (ASO) approach, but directed to the SCN1A gene (not the RNA like Stoke), is CAMP4, that presented at AES how they are getting their antisense treatment ready for clinical trials (this is the antisense that OPKO was developing).

At the SYNGAP1 pre-meeting we saw a fantastic presentation from Tevard Bio about their approach to attack Dravet syndrome using different approaches all directed to the SCN1A RNA. And while Tevard still needs more time to get to clinical trials, Encoded Therapeutics is very close to starting trials with their gene therapy using a virus to increase SCN1A expression from the good gene copy, and presented at AES their work on finding good clinical scales to measure non-seizure symptoms of Dravet syndrome (the AES links are broken, so you will have to take my word for it). Encoded is preparing to start trials in very young children with Dravet syndrome (not yet started), and their gene therapy has the potential to change the developmental trajectory of these kids. The challenge is to get the right scales to capture that efficacy, so both them and Stoke have observational studies ongoing to validate those scales.

And Dravet syndrome also has at least two companies developing activators for the Nav1.1 channel, Lundbeck and Xenon. These are drugs, what scientists call small molecules, and not genetic therapies. From these two, Xenon has the most advanced program (another broken AES link that I cannot use), and I could see the Dravet syndrome space developing similar to SMA and have first an ASO approved, then a gene therapy, and finally a small molecule, all restoring sufficient levels of the sodium channel currents.   

Shout-out to Veronica Hood, Scientific Director of the Dravet Syndrome Foundation who gave a fantastic talk about the impact of the patient groups in Dravet syndrome with major roles as conveners, educators, funders of early research and resource curators.

 

SCN2A

SCN2A is another sodium channel very important for neuronal functioning, so important that mutations that cause too much activity produce one of these developmental and epileptic encephalopathies (I will call it SCN2A Gain-of-Function) and mutations that cause one copy to not function also produce a syndrome with epilepsy and cognitive and behavioral manifestations (I will call it SCN2A Loss-of-Function). That means scientists need to find ways to turn off the channel or the gene for the first group, and find ways to boost expression of the good copy for the second group.

The company Praxis is doing just that, and working at both approaches with different types of treatment modalities. The most advanced program is called PRAX-562 and is a drug (a small molecule) designed to inhibit only two channels: Nav1.2 (that is the one produced by SCN2A) and Nav1.6 (produced by SCN8A). This drug looks really promising for people who carry mutations in either one of these channels that causes the channel to work too much, so it is for the Gain-of-Function mutations. And Praxis is about to start clinical trials for these two syndromes after completing Phase 1 in healthy volunteers.   

What’s interesting is that Praxis also has a second program for people with SCN2A Gain-of-Function, and that is an ASO called PRAX-222 developed in collaboration with Ionis, and it is also getting ready to start clinical trials. So 2023 is going to be a very good year for SCN2A Gain-of-Function. And Praxis is also working on an ASO to do the opposite: increase SCN2A expression. This is a treatment for the SCN2A Loss-of-Function patents and it is still at earlier stages of development.

I will mention Praxis more times in this summary because they are working on more syndromes, and I want to highlight that this company has parents of kids with rare DEEs working with them as part of the team, and this is a very good sign. When we have scientists working within patient organizations, and patient advocates working within biotech/pharma companies, we can start breaking down many of the communication and cultural barriers between both worlds and developing better medicines.

 

SCN8A

SCN8A is the gene that encodes for another very important sodium channel, called Nav1.6. This is a channel that makes excitatory neurons fire, so the most common mutations are the Gain-of-Function type, that make those neurons way too active. What we need is clear: reduce the channel expression, or inhibit the channel activity.

This patient community has done a really good work at trial readiness, and we saw at least three therapeutic programs at AES (I might be missing some):

I look forward to the conference on SCN2A and SCN8A next spring because it looks like we will have many news about clinical trials for these syndromes!

 

KCNQ2

And from sodium channels we move now to potassium channels. This gene is very famous in epilepsy, because if you have a very young baby, under one month of age, that starts having seizures, the most likely cause is mutations in this gene. What these kids need is openers for this potassium channel, activators.  

And there are two companies developing activators, one is Xenon, who are taking an older drug (ezogabine) that was taken off the market back into the market this time for KCNQ2 epilepsy. The drug is currently in Phase 3 studies, which means that if the trial is successful it will lead to an approval for KCNQ2. The second one is also an activator, from Knopp/Biohaven, that is currently in Phase 1 studies and will then move on to trials in patients with KCNQ2 epilepsy.

As with SCN8A, we have gone from not having trials to having even competing trials with drugs designed to correct the channel problem, either too much (Nav1.6) or too little (the potassium channel Kv7) activity. And I mainly look forward to seeing the potential benefit of these drugs past the very early years, once children with KCNQ2 mutations often stop having epilepsy but still have the developmental impacts that are due to the channel malfunction.

 

SYNGAP1

There is so so much going on for SYNGAP1 that I cannot summarize it all here. The pre-AES SYNGAP1 conference was fantastic, with many families in the room (and also all of the famous clinicians and many companies). There are iPSC models and mice and rats, I really liked the rat model and how it can be used to study drug response for seizures, sleep and cognition. They also have an idea of the SYNGAP1 isoform that is needed for gene therapies, and the “reversibility experiment” of putting SYNGAP1 back into adult mice has been done and it looks very positive. There is also a lot of work ongoing around patient data, like Ciitizen to see natural history, and an outcome measure for communication called ORCA being adapted to SYNGAP1 with funding from FDA. It’s all looking ready for therapies to be run through trials! There are two very strong SYNGAP1 foundations working to get trial ready and it shows.

And talking about therapies, there are several ASOs in development for SYNGAP1 and other modalities of gene therapies. What happens in this disease is the classical haploinsufficiency: one good copy of the gene, and one bad copy of the gene. That’s why the focus of these therapies is in promoting more expression from the good copy so that synapses can go back to working well again.

Praxis is working on an ASO to increase SYNGAP1. It is called PRAX-090 and in recent presentations Praxis says they hope to nominate a candidate in 2023. A “candidate” is when the company considers that their experimental drug or antisense is “good enough”, and at that point they stop tweaking it and start generating the animal safety data that is needed for trials, so it usually takes 1 to 1,5 years from the time of candidate nomination to starting trials.

Stoke Therapeutics, the company developing the ASO for Dravet syndrome (SCN1A) also has a program for SYNGAP1 using the very same approach, and they have partnered it with Acadia. And another company called CAMP4, that is also working on upregulating SCN1A for Dravet syndrome, presented at AES their early work towards also developing an ASO approach for SYNGAP1. And there are some additional academic and industry (Ionis) efforts to develop ASO treatments, so it is likely that SYNGAP1 families will get multiple options of clinical trials to increase protein levels, which should be a treatment for all the different symptoms of the disorder.

But antisense oligonucleotides are not the only approach to rescue SYNGAP1 expression. At the pre-AES conference we saw how Tevard is applying some of their gene therapies to increase expression from the SYNGAP1 RNA, and how scientists at Penn are using a CRISPR-like approach (called dCas9) to increase expression from the good gene copy. These are all very early stage efforts that are likely to reach clinical trials after the ASO treatments.

So you see, a lot going on, and not everything is presented at AES! And shout-out to Marta Dahiya, a clinician and SYNGAP1 mum who gave a very interesting talk during the main AES conference about digital natural history studies using platforms like the one from Invitae/Ciitizen.   

 

STXBP1

Like the one before, STXBP1 is also a synaptic protein that when mutated causes haploinsufficiency: one good copy of the gene, and one bad copy of the gene. And the main therapeutic strategy to target the cause of the disease is therefore to promote more expression, often by exploiting the good copy, so that synapses can go back to working well again.

At AES there were several presentations around documenting the natural history of the disease, and also on validating scales to be able to run trials that count more than just seizures. The patient organization is working on a very large natural history study designed to validate outcome measures, and has recently announced natural history efforts by the companies Capsida and Encoded Therapeutics. These are gene therapy companies, the ones that use a virus to deliver the therapy to the brain, so we can imagine that gene therapies for STXBP1 are being developed even if they haven’t yet been announced.  

There is also a known collaboration between the company Ionis and the Prosser lab to develop and ASO to restore STXBP1 expression, and at AES we also saw a presentation from the company Q-State about an antisense program to restore STXBP1 expression, which is still at early stages.   

So it looks to me like STXBP1 disorder, like SYNGAP1 and others, have multiple companies working unannounced on therapies to correct expression of their faulty gene and that by next year AES there will likely be many more projects that have been officially announced. I very much look forward to that!

 

PCDH19

This is an interesting gene, because it encodes for a protein that makes cells touch each other to connect. It is in the X chromosome, so in females half of the neurons express the good X chromosome and the other half the one with the mutated PCDH19. That means that they have two type of neurons, with only half expressing the cell touch protein, and that is a problem because for neurons to touch each other they need to have the same code: either they both have PCDH19 or they don’t. What doesn’t work is only some having it. That is why in males, that express their only X chromosome in all neurons, mutations in PCDH19 don’t cause disease, because all neurons express the same code: no PCDH19.  

There are at least two ASOs in development to make all neurons have the same cell touch code by eliminating expression of PCDH19 in all neurons in girls/women with PCDH19-Clustering Epilepsy. The first one is from Praxis, and is called PRAX-080 and as for SYNGAP1 the company has recently communicated that they hope to nominate a candidate in 2023 (the fully optimized ASO that then gets prepared to go to clinical trials). And the company Ionis is collaborating with the Parent lab to also develop an ASO that will achieve the same result: make female neurons like make neurons by knocking down PCDH19.

I like that for PCDH19 we have had clinical trials with small molecules (ganaxolone Phase 2) so we know for sure that seizures are countable and how a phase 2 trial could look. That helps de-risk the field for future trials, when companies will likely still count seizures as the main symptom for drug approval in addition to including scales to measure improvements in behavior and other domains – just as currently for Dravet syndrome.

 

CDKL5

CDKL5 Deficiency Disorder (CDD) is another DEE where the gene is in the X chromosome, but in this case the protein is a kinase and the problem is not that neurons don’t connect with different neurons, but that half of the neurons are missing the very important function of the protein CDKL5. The therapeutic goal is to put that protein back, with the added challenge that because only one CDKL5 copy is expressed in each neuron (only the good one or only the bad one) we cannot use many of the strategies used for haploinsufficiencies.  

I dedicated a recent update to CDD from the CDKL5 Forum 2022, so please see that link to read how the first gene therapy trials to bring a new copy of CDKL5 to the brain of people with CDD might start as early as next year. And 2022 was a good year for CDD, we had the first drug approved for the disease: ganaxolone (approved by FDA, pending EU approval). So this year we had a new player in the big AES exhibit, with the large stand for Marinus highlighting their data for ganaxolone in CDD and helping educate the medical community about this rare epilepsy that now has a treatment.

As for PCDH19 epilepsy, CDD has very clear epilepsy that has been used already in clinical trials as the main measure for efficacy and that will help de-risk the upcoming clinical trials with therapies directed to correcting the cause, which should improve seizures as well as non-seizure symptoms (which are so much harder to measure). And like for other syndromes, what was talked at AES was just the top of the iceberg, and there are many more treatments in development for the cause of the disease that were not presented at the main medical conference.  Check out the Forum update for that.

 

3 – IN CLOSING

If you are a rare disease parent you might have only read the section about your loved one’s disease gene. So I encourage you to do two things:

One, please remember that companies often don’t talk about their projects until they are close to trials, and not all present at AES, so what you read above is only a snippet of what’s going on in reality (iceberg!).

Two, whether you are a parent or a scientist, step back and look at all the syndromes and the global picture that emerges: I have only talked about the treatments in development to address the cause of the syndrome, not the symptom. Long gone are the times when there were no trials in the syndromes so we didn’t have good clinical evidence about anti-convulsant drug efficacy in them. And we are even closing chapter two, the one of cannabidiol and the other anti-convulsant drugs being tested and approved for syndromes, although their activity is not specific to the syndromes. What you are seeing here is different. You are seeing multitude of programs to block or open channels, to increase expression of good gene copies or reduce expression of bad ones, and several are already in clinical trials in patients. We are closing chapter two, and reading from chapter three… the one with treatments for the cause of the disease reaching clinical trials. And the speed at which this is happening, and how broadspread it is across different syndromes, is unstoppable. We have reached escape velocity.

 

 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.