Every year the American Epilepsy Society (AES) meeting gets larger. This year, over 5,500 people got together in DC to discuss the latest information about epilepsy care and the development of new treatments for epilepsy.
I’m a scientist looking for a cure for a rare disease called Dravet syndrome. I first attended this conference as a pharma scientist working on new epilepsy therapeutics, later as the head of research of a Dravet syndrome patient organization, and currently as an independent consultant specialized on rare epilepsy syndromes. Because of my background, I look at this conference from the perspective of a drug hunter, a patient advocate and an industry analyst, and I must say that from all of these perspectives the 2017 edition of the AES meeting was an exceptionally interesting one.
Here is the list of what I found the most interesting at the AES meeting:
1- There is a change in epilepsy drug development towards orphan drugs.
I wrote earlier this year about Everolimus and how orphan drugs are reviving the field of epilepsy. This was very visible at the AES meeting as well. Two of the likely next approvals in epilepsy, based on their positive Phase 3 trial results, are targeting rare forms of epilepsy. These two drugs, cannabidiol (Epidiolex, GW Pharma/Greenwich Biosciences) and fenfluramine (ZX008, Zogenix), were the focus of much excitement and interest during the conference. At the same time, I couldn’t help but miss some of the largest companies that used to have much floor space at the exhibition hall in former AES meetings, like Pfizer and GSK. The pharmaceutical giants are leaving, and smaller companies with orphan drugs are filling in their space. Some loyals like UCB, Eisai and Sunovion are still staying, but times are certainly changing in epilepsy drug development.
2- Pharmacoresistant epilepsy is not forever.
We are all used to hearing that despite having many anti-epileptic medications in the market, about 30% of people with epilepsy continue to have uncontrolled seizures. This includes the large majority of the genetic epilepsy syndromes, although it goes well beyond these rare diseases. Breaking into that 30% is the Holy Grail of epilepsy drug development, and the small company Zogenix managed to pull an Indiana Jones move this year with their drug ZX008. In their recent Phase 3 clinical trial in Dravet syndrome, 25% of the patients randomized to the highest dose of fenfluramine (ZX008) had zero or 1 seizure during the 3 months of treatment. That would be 4 or less convulsive seizures in a year, down from a baseline of approximately 40 convulsive seizures per month, or about 500 per year. The median percent of seizure reduction at that dose was an impressive 72.4% versus 17.4% with placebo. The sessions organized by Zogenix during the AES meeting were among the best attended ones, and their results have given us hope in the orphan epilepsy community to dream with seizure freedom, a goal previously though to be unrealistic. Pharmacoresistant epilepsy, now we know, is not forever.
3- There are too many genetic epilepsy syndromes to not use gene panels as soon as possible.
Diagnosing correctly a child that has refractory epilepsy or epilepsy combined with neurodevelopmental problems is not easy, because there are many syndromes that look very similar or overlap substantially when it comes to clinical criteria. It is just too complicated to try to diagnose any of these diseases based uniquely in their clinical characteristics, so epilepsy specialists should consider epilepsy gene panels as a necessary and urgent test for all cases of childhood epilepsy as soon as they first see these patients. Walking around the patient advocacy area at the AES exhibition hall and trying to understand the characteristics of each syndrome was overwhelming: Dravet, Lennox-Gastaut, Tuberous Sclerosis Complex, SCN2A, PCDH19, CDKL5, STXBP1, SYNGAP1, GLUT1, KCNQ2, Batten disease. These are just the tip of the iceberg, represented at the conference by brave parents that know it is important to get their disease name in front of the specialists. And together they send a strong message to epilepsy specialists: there are just too many syndromes to not use gene panels as soon as possible.
4- The arrival of basket trials to epilepsy.
Just as it is important to be aware that epilepsy includes many individual rare syndromes, it is also important to figure out how we are going to develop therapies for all of these syndromes. A year ago at the AES meeting no one had publicly heard about the experimental drug TAK-935. It was already 2017 when Takeda and Ovid Therapeutics announced that they were partnering around this program, and that they intended to develop it for a variety of epilepsy indications. This year at AES there were multiple presentations on TAK-935 and for me the most interesting aspect is the clinical trial design: a Phase 2 basket trial combining patients with three different orphan epilepsy syndromes. In the epilepsy field we had already seen this type of basket trial in investigator-initiated studies, such as the first open-label studies with Epidiolex in the US that served as the basis for the single-syndrome placebo-controlled trials that followed, but not in a company-sponsored placebo-controlled trial. I find the basket trial approach a fantastic innovation for the epilepsy field, and I already developed these thoughts it in more detail in a previous article about genes versus syndromes.
5- Beginning to understand the dark side of epilepsy: SUDEP.
Sudden death in epilepsy (SUDEP) is a scary topic. Doctors don’t want to talk about it, in particular because we don’t understand it enough to be able to do something about it, and patients and families would also prefer to not have to hear about. Dravet syndrome has a particularly high incidence of SUDEP, so it is a field that I follow closely. Fortunately there is much research and growing awareness on SUDEP, and we could see at the AES meeting very valuable research that gets us closer to understanding how SUDEP happens. Some time ago it was thought to be of cardiac origin, but nowadays we know that SUDEP starts in the brainstem, and that it is essentially a seizure during sleep that originates or spreads to the brainstem area causing a shutdown of the neurons that control breathing, followed by respiratory arrest and cardiac arrest.
This year at AES we saw research using a mouse model of Dravet syndrome that showed that the brainstem circuits that regulate breathing are dysfunctional in this syndrome, and could trigger hypoventilation when the response should be hyperventilation to increase oxygen saturation. We also saw clinical research in patients with Dravet syndrome that showed that there is also an increased parasympathetic tone during sleep leading to very low heart rate. The extraordinary practical value of these findings is that patients could wear sensors that would produce an alert when oxygen saturation and heart rate drop below regular seizure thresholds and alert a caregiver trained in CPR techniques, which are known to be at times efficacious when practiced early in cases of SUDEP.
Overall, I felt that this year AES meeting was very positive, showing a great progression of the field that now moves towards orphan indications (with new drugs and clinical trial designs), where patient organizations gain relevance (also a characteristic of the orphan drug field), and where we start having new drugs able to break the barrier of pharmacoresistance and the understanding needed to detect, and hopefully prevent, the big problem that is SUDEP.
For those of you that also attended the AES meeting, I would love hearing about those trends or progresses that you felt were the most interesting ones!
Ana Mingorance, PhD