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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.
Two years ago, 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, so we need to run genetic epilepsy panels as soon as possible in children. AES 2017 was a great meeting, but I was still hoping there would be more of a connection between treatments and genetics. That we could move beyond genetic diagnosis and towards genetic treatments.
And 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 tremendously clear during this 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, has embraced the technologies of biotech and we have officially entered a new era.
Before I review the main take-home messages from the meeting, I want to clarify two terms that I will be using:
Developmental and epileptic encephalopathies. We don’t need to struggle with calling them “genetic epilepsies” “rare epilepsies” or “orphan epilepsies” anymore, always adding the message that “they involve much more than just epilepsy”. Now the field has a name. We are talking about the developmental and epileptic encephalopathies (DEEs), where not all are genetic (hello LGS!) but they all have a strong neurodevelopmental component that is not 100% due to the epilepsy. The term was introduced by the ILAE in 2017 and it is staying.
Genetic therapies. When we talk about gene therapies, we talk about using genes as a therapy (as in the classical AAV carrying a healthy copy of a human gene). But it is clear that our therapeutic armamentarium to target genetic diseases goes beyond that. Dr Barry Ticho from Stoke referred to their oligonucleotide therapy as a “genetic therapy”, because it treats the genetic problem even though the therapeutic agent does not deliver a gene. I loved the term, so I will use it as well to incorporate all the different DNA and RNA-targeting therapeutics regardless of them using virus, ASOs or other modalities.
MY TOP 5 INSIGHTS FROM THE AMERICAN EPILEPSY SOCIETY MEETING
In one line: AES 2019 was the year of genetic therapies for the developmental and epileptic encephalopathies.
In more detail, here is the list of what I found the most interesting at the AES 2019 meeting:
1. BEYOND SYMPTOMS: GENETIC THERAPIES
In the recent years, many large efforts in understanding the genetic basis of epilepsies led to the identification of hundreds of genes causing developmental and epileptic encephalopathies as well as other epilepsies.
Stoke Therapeutics has a slide in their investors presentation with very impressive numbers. It says:
· 50 million people globally affected by epilepsy
· 50% of epilepsies have an identified genetic cause
· More than 180 disease-associated genes
· 0 genetically-targeted therapies for epilepsies
Their Dravet syndrome program is one of the most advanced therapies that will hopefully change that number zero. It is unbelievable that with hundreds of genetic causes, often leading to severe neurodevelopmental syndromes with aggressive epilepsy and high unmet need, we have so far not one single therapy that corrects the genetic defect or its direct consequences. And we don’t need to get to the extreme of correcting genes, for some of these epilepsies it should be possible to develop small molecules that will target the disease-causing protein, either with activators or with inhibitors. Cystic Fibrosis has shown us how to do this with CFTR, and there are currently several small molecule approaches in development for the epilepsies aiming to correct the protein dysfunction that results from genetic mutations.
Looking only at corporate programs (not even including academic efforts), and likely missing some projects, the following treatments are in development (thank you to Steve Petrou for summarizing many in his slides!):
Dravet syndrome caused by SCN1A mutations: SCN1A upregulation from Stoke (ASO) and Encoded Therapeutics (AAV), and early stage ion channel activators from Xenon and Lundbeck (small molecules)
SCN2A-associated conditions: SCN2A downregulation from RogCon/Ionis (ASO), ion channel inhibitor from Xenon and Praxis (small molecule)
SCN8A developmental epileptic encephalopathy: ion channel inhibitor from Xenon (small molecule)
KCNQ2 epileptic encephalopathy: ion channel modulator from Xenon and Knopp (small molecules)
KCNT1 epileptic encephalopathy: KCNT1 downregulation from Ionis (ASO)
CDKL5 deficiency disorder: enzyme replacement therapy from Amicus (biologic) and gene therapy from Amicus and Ultragenyx (AAV).
Angelman syndrome: activation of paternal UBE3A from Ionis, Roche and Ultragenyx (ASO), and gene therapy from PTC and Pfizer (AAV)
The list is not complete, these are just some of the programs I know about or that were presented at AES. We also saw at AES some early data on the feasibility of using the Stoke platform to upregulate SynGAP1, so it is clear that the current technologies will be able to target many more of the developmental and epileptic encephalopathies, and the significant corporate activity in the space is a very good sign. And there are also many academic programs developing genetic therapies that might lead to clinical programs in the next few years.
This is just the beginning.
2. BEYOND SEIZURES
One aspect I particularly liked was to hear more and more neurologists make a difference between the symptom (seizures) and the condition (epilepsy).
Until recently it was common use “epilepsy” as meaning just seizures, and to hear “epilepsy comorbidities” to refer to the non-seizure epilepsy-associated aspects of the disease such as depression, cognitive delay or motor problems. Calling them comorbid hinted a secondary, less important, role in the disease.
In the last two years I hear clinicians speak more about epilepsy as inclusive of both seizures and the non-seizure aspects. By expanding the definition of epilepsy to go beyond seizures, we open the door for the development of new therapies that also go beyond seizure treatment. There is more and more research around those other aspects of the disease, which are very common in the developmental and epileptic encephalopathies, and the term anti-epileptic medications, referring to the classical drugs, is being replaced by anti-seizure medications. This is not just a linguistic shift, this is a broadening of the scope of a medical and research specialty, to the benefit of patients.
3. AND NOW WHAT? THE CHALLENGE OF CLINICAL TRIALS BEYOND SEIZURES
The good news is that we now understand that epilepsy conditions go well-beyond seizures and start having the therapies that could address the different disease aspects.
The bad news is that no one really knows how to design those “beyond seizures” trials, or what regulators will want to see from those therapies.
This is right now a space of enormous activity. We saw presentations at AES 2019 from companies and academic groups on what to measure in clinical trials for some of these disorders, and whenever I sit down with a patient organization to learn about clinical trials in the space this is a the top of everybody’s list: how to design trials to show efficacy beyond seizure reduction, or to show disease-modification (changes in the course of the disease). We don’t have the answers yet, this is work in progress, but we are all figuring this out together and I was happy to see the challenge of designing these trials also being discussed at AES.
4. OPENING THE COMMUNITY
Everyone who has come to the AES meetings knows that there is a very active patient community. This is precisely because of the developmental and epileptic encephalopathies, which are rare diseases (affecting less than 200,000 people in America), and the rare disease space has a very strong patient advocacy component. As a result, there is a growing number of satellite patient-scientist meetings during the AES congress and you can see patients (often parents) walking around the exhibition hall meeting companies, participating in the discussions and even presenting science.
All of this is great, but I want to put forward two ideas to make this better, since the patient groups are an essential part of the epilepsy community:
1. We need to make it easier for patient groups to attend AES. I have gone to many conferences representing a patient group and it is just too expensive to attend when using personal or charity funding. So we see things like only registering some attendees and swapping badges at the entry, or even not registering at all and just scheduling a bunch of meetings with companies and clinicians at the lobby of the nearest hotel. We all know this. And we should not ignore it. I propose sponsoring patient groups attendance to the major medical conferences in their field, with free registration (at a minimum) and possibly travel support sponsored by companies but managed by the conference organization. I don’t need to see floor stickers on the nearest hotel from (and paid by) a pharma company; I want to see those necessary members of the community being properly invited (and supported) to be in the room instead.
2. We need to make it easier to schedule the patient-run symposiums or round tables at the meeting. Right now these are not official part of the AES meeting so the different groups try to make it convenient to attendees by scheduling their meetings early in the day, or the day before the AES conference starts, and hosting them nearby the conference center. Often they clash (there not that many early mornings!) so many professionals who work on multiple syndromes have to choose which one to attend. I propose protecting some time before the conference for hosting these patient-led meetings. We have traditionally had the Dravet Syndrome Foundation Research Roundtable the day before AES in the evening. The main AES program starts the following day in the afternoon, and many people interested in Dravet knows that they should get to the hosting city one day before so they start with the Dravet Roundtable. That works great. I could see a program where we have a first day that is devoted to patient-organized symposiums, followed by the 4-5 days of main conference agenda. We can’t keep ignoring that the patient organizations are not only an important part of the attendees, but also contribute to part of the agenda. This is already happening. We must get them into the actual agenda as much as possible.
I would love to know what you think about these.
5. GENETIC TESTING IS URGENT
Genetic testing of people with epilepsy is not a “nice to have” anymore. With the discovery of hundreds of genes, and now with the development of genetic therapies, we need to know who those patients are (in addition to the many other values of knowing the cause of your disease). BioMarin, Stoke and Xenon sponsor a free (sponsored) genetic program at Invitae that will soon be open to all children in the US and Canada 8 years and younger. Currently it is for age 5 and younger. This is an excellent model and perhaps the most effective way of making sure that children with epilepsy get early genetic testing. I thank and congratulate the for companies for offering this program.
As a next step, I would like to see this expanded beyond north America (likely through other providers) and also into broader ages. I hope the data obtained by Invitae so far will help document the return on investment for these sponsored programs, and encourage their expansion.
LOOKING INTO 2020
I am excited to see the genetic therapies trials in 2020. From ion channel modulators that might help children with devastating syndromes to the arrival of the first genetic treatment for Dravet syndrome to clinical trials.
Also, the NINDS will host a very special epilepsy meeting called Curing the Epilepsies 2020: Setting Research Priorities in April 2020. This meeting follows one in 2013, and will help establish the NINDS Benchmarks for Epilepsy Research (see here the 2014 ones). The Benchmarks help shape the research priorities from NINDS on epilepsy for the next 7 years so these meetings are extremely important. I am trilled to be a member of the joint AES-NINDS team putting together the next edition of the benchmarks, and encourage you all to send your ideas before February 20 2020 though this link. This only happens every 7 years so don’t miss the chance to shape those priorities!
And I also look forward to more progresses in more developmental and epileptic encephalopathies next year. For example, I know there is a lot more going on in CDKL5 Deficiency Disorder than what we saw at AES, and I hope there will more presented next year.
Above all, 2020 will be the year of clinical trials with genetic therapies in development and epileptic encephalopathies. And I can’t wait!
Ana Mingorance, PhD