Every year the American Epilepsy Society (AES) meeting gets larger. This year, over 6,000 people gathered in New Orleans to discuss the latest information about epilepsy care and the development of new treatments for epilepsy.
I look for therapies for rare genetic epilepsies, so this biases some of my focus during the meeting. At the same time, many of the biggest developments have been precisely in the field of rare epilepsies, so this has been a very exciting year.
Here is the list of what I found the most interesting at the AES 2018 meeting:
1- Many new epilepsy drugs are orphan drugs
Probably the star of the AES 2018 meeting was GW Pharmaceuticals, operating in the US as Greenwich Biosciences, with Epidiolex (cannabidiol oral solution) now in the market for the treatment of epilepsy in Dravet syndrome and Lennox-Gastaut syndrome in the US. Greenwich had a very large presence at the meeting, with a prominent spot in the exhibition hall and the most crowded scientific exhibit. There was also a very popular session on the perspectives of physicians and patients about using cannabidiol for the treatment of epilepsy, which highlighted the interest of the patient and medical community on Epidiolex.
But there is more interest in the orphan epilepsy space than just Epidiolex. Next to Greenwich at the exhibition hall we could see Zogenix, with Fintepla (fenfuramine) about to file for an NDA for the treatment of epilepsy in Dravet syndrome, and BioMarin with Brineura (cerliponase alfa) for CLN2 disease, a type of Batten disease.
There were also other orphan epilepsy players that didn’t have a stand at the exhibition hall but had important presence at the AES meeting, most notably Marinus Pharmaceuticals which is currently in Phase 3 trials in CDKL5 Deficiency Disorder (CDD) with ganaxolone. Marinus had multiple poster and platform presentations, and a very well-attended scientific exhibit, showing early clinical data as well as biomarker data in CDD and PCDH19, to orphan epilepsy syndromes.
2- From symptoms to disease: epilepsy goes beyond pharmacology
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.
Until now, we have seen progresses in many genetic epilepsies, using approaches such as enzyme replacement, antisense treatment or AAV-based gene therapy. But these were still not so visible in epilepsy, with the exception of Brineura for CLN2 disease which could be considered a neurodegenerative disease with epilepsy, more than an epilepsy syndrome. This year at AES 2018, however, we could see a broad range of disease-modifying experimental therapies in preclinical development for the treatment of different forms of epilepsy that are likely to lead to clinical trials using antisense approaches or viral gene delivery within two to three years:
Stoke Therapeutics presented some early but very impressive preclinical proof-of-concept data for their antisense oligonucleotide treatment for Dravet syndrome. The antisense treatment results in an increase in the Nav1.1 protein, and the company plans to initiate clinical trials in 2020 (see poster).
RogCon Biosciences and Ionis presented data on an antisense oligonucleotide treatment, this time for SCN2A epilepsy linked to gain-of-function mutations. The antisense treatment results in a decrease in the Nav1.2 protein and they showed efficacy in a mouse model (see poster).
A team by the Royal College of Surgeons in Ireland presented a very interesting approach, where they used antagomirs (which are also antisense oligonucleotides) to reduce the activity of miR-134 in a mouse model of epilepsy, leading to strong long-lasting seizure suppression. Interestingly, this approach would not be just targeted to a specific genetic epilepsy but might represent an alternative to pharmacological treatments or brain surgery for treating refractory epilepsy resulting from multiple (including unknown) causes.
A team from the Columbia University Medical Center also presented an approach for using viral delivery of a specific micro-RNA against the gene DNM1. This gene is mutated in an epilepsy syndrome, and the mutant alleles act have dominant negative properties. The approach, piloted in a mouse model of DNM1-dependent epileptic encephalopathy, improved multiple disease phenotypes.
Another surprise at the AES meeting was the first appearance of Encoded Genomics, still in stealth mode, as the sponsor of the Dravet Syndrome Roundtable. The Encoded team explained that the company is developing a gene therapy for Dravet syndrome, although no more details have been communicated at this point.
And although still using small molecules, Praxis Precision Medicine (1,2,3) and Xenon Pharma (1,2,3,4,5,6) also presented very interesting data of their Phase 1 programs to target specific genetic epilepsies caused by mutations in sodium and potassium channels, although they also have potential beyond these orphan epilepsies.
The number of programs in development using these new technologies, as well as the involvement of private companies in these programs, is unprecedented for the epilepsy field and make 2018 as the year when the new therapeutic approaches took a first important step in the epilepsy field. Within a few years we should see multiple of these disease-targeting programs in clinical trials.
3- Multiple great treatments for Dravet syndrome
Following the diagnosis of a child with a rare genetic disease, often families are told that the industry is not interested in developing treatments for them and that there is little research or that their disease is barely understood. This is definitely not the case for patients with Dravet syndrome.
There were 65 presentations on Dravet syndrome at the AES 2018 conference, and the syndrome is the target indication for some of the most promising pharmacological approaches in development as well as soon to reach the clinic disease-targeting approaches:
Epidiolex (cannabidiol oral solution) just got approved in 2018 in the US for treating epilepsy in Dravet syndrome (European decision expected in early 2019).
Fintepla (fenfluramine), from Zogenix, has completed two successful Phase 3 trials in Dravet syndrome with very impressive efficacy, and the main question mark around this dru,g which was a potential cardiac safety concern, has so far proven to be not a problem in this patient population. Fintepla is on track to be the next drug approved for treating this syndrome.
Ovid Therapeutics and Takedaare partnering around the development of TAK-935, a novel antiepileptic drug, which is also in clinical trials for Dravet syndrome. There were a poster and a talk on the preclinical proof-of-concept for this drug in a mouse model of Dravet syndrome and the data was extremely solid, with impressive efficacy in preventing spontaneous seizures and early mortality in the mice. So as impressive as Fintepla is in this population, TAK-935 might be a fair contender with a differentiated mechanism of action. Both therapies are also in clinical trials for Lennox-Gastaut syndrome.
Stoke Therapeutics follows the Ovid and Takeda collaboration in the pursuit of Dravet syndrome as the target indication for their lead antisense program, and also showed very good early data in a mouse model of Dravet syndrome at AES 2018. Their therapy will be the first disease-modifying approach to reach the clinic for Dravet syndrome after multiple pharmacological trials.
And as we wait for more information about the program, the gene therapy for Dravet syndrome in development by Encoded Genomics might follow Stoke’s antisense therapy into the clinic, completing a very promising pipeline of treatments in development for a single orphan epilepsy.
Possibly as a reflection of this increased industry interest in Dravet syndrome, the Epilepsy Therapy Screening Program run by the NINDS mainly at the University of Utah now offers a test in a genetic mouse model of Dravet syndrome that was also presented at AES 2018.
4- Near-approval treatments for acute repetitive seizures
There are some important progresses towards the management of acute repetitive seizures (cluster seizures) that were presented at AES 2018 and are worth highlighting.
A study presented at the conference highlighted that clusters (more than one seizure within 6 hours) were present in about half of pediatric patients with active epilepsy. Seizure clusters are common in many refractory epilepsy syndromes, and they are managed by using rescue (acute) medication. Rectal diazepam is the most widely use rescue medication for seizure clusters, but there is a strong demand from the patient community to develop alternatives. There are now two programs that would provide a suitable alternative and that were presented at AES 2018: intranasal diazepam (NRL-1, by Neurelis), and intranasal midazolam (USL261, by UCB Pharma). Both programs are expected to obtain the marketing authorization soon by the FDA. Their future in the European market is less clear given that the EMA has not yet accepted acute repetitive seizures as a separate orphan indication, which is the status of these experimental therapeutics at the FDA.
I also found interesting the description of a novel mouse model of acute repetitive seizures, which will support the development of new drugs beyond the currently used benzodiazepines.
Last, a young company called Engage Therapeutics is pursuing a very innovative EpiPen-like approach to try to abort seizures using a hand-held inhaler for fast systemic delivery of alprazolam. They announced at AES 2018 that they are starting a double-blind placebo controlled study.
5- AES is also a big meeting for patient organizations
A growing number of rare epilepsy patient organizations are using the AES annual meeting to host focused meetings with their main clinicians and scientists as well as with the companies developing therapies for that disease (or interested in doing so). Some of the veterans are the Dravet Syndrome Foundation and the Lennox-Gastaut Foundation, but we are also seeing more and more of the smaller groups, some of them in the first or second year of activity, also using AES to bring into a room the different stakeholders that are going to help them develop new treatments. In these focused meetings patient representatives and industry break their distances and learn from each other, becoming very educational and productive meetings.
Patient organizations were also present at the exhibit hall, and this year I counted 19 different groups.
Last, I really liked starting to see patient advocates take the stage as part of the main conference program. For example, I enjoyed listening to Dr Tracey Dixon-Salazar from the Lennox-Gastaut Foundation share the stage with some of the main neurologists who have run the Epidiolex clinical trials. In this type of medical conference, we should always ask ourselves: “medical specialists are telling us that this new drug has a favorable risk/benefit profile, but what do the patients think about it?”.
I had closed my review of the European Congress on Epilepsy (August 2018, Vienna) saying that “I personally missed hearing more about CDKL5 deficiency disorder and other “less popular” rare epilepsies, and about some of the non-pharmacological therapeutics in development, such as antisense therapies and gene therapy approaches.”
Looking back at those comments I’m glad to have seen more presentations about less popular rare epilepsies, including the multiple presentations by marinus on CDKL5 Deficiency Disorder, as well as the many disease-targeting approaches that I listed under section 2. In that sense I feel that the AES 2018 meeting captured better the actual developments in the field of epilepsy drug development, where rare disease populations and new technologies are two areas of considerable growth and that are changing the way we will treat epilepsy.
I can’t wait to see what 2019 has to bring!
Ana Mingorance, PhD