AAN 2026 | Recent advances in clinical trials for DEEs: trial design and novel agents

In the last year, let’s say even the last few years, but more of those of what I’m talking about is really something that is up and running, happening right now in these months, we are increasingly seeing some kind of shift from syndrome-specific clinical trials to basket-designed trials, where, for example, patients with different developmental and epileptic encephalopathies, they are enrolled in the trials based on some shared features. And it can be either a mechanism of action or it can be on the other side a clinical phenotype. What is a common feature is that all patients should have countable motor seizures. And what is actually happening and why most relevantly is happening? So why we are trying to put together patients with different DEEs in single trials? Because individuals with DEEs, they are rare. I mean, they are rare epilepsies, making definitely traditional trials a little bit slower, and traditional trials can be underpowered, and many therapies like network-level drugs, or for example, serotonergic modulation, they may act actually on some shared pathophysiological pathways. With this, we may hypothesize that there may be faster access to therapies across different syndromes. The trans-syndromic endpoints like the motor seizures or the quality of life is an endpoint which is greater emphasized in the last timing. But also there are with this some clinical challenges, some key challenges, like the heterogeneity of response, it can increase because we’re including in same trials different populations of patients. There is the risk of diluting the syndrome-specific effects and of course depending upon the overall number of patients which are enrolled in a clinical trial there is the need for a post hoc certification which may include and which may consider genotype mechanisms and the phenotype.

Some examples that I can give you are two or three, starting with the disease-modifying Dravet therapy with zorevunersen, which is happening right now around the world as a Phase III trial, but the Phase II data have been recent published, and what comes out of the Phase II study is that there is a sustained reduction of seizure frequency and increased seizure-free days over time and so interesting signals behind seizures which includes improvement in the adaptive behavior in patients with Dravet syndrome and improving also in communication and motor function and quality of life. Other interesting trials are the one with bexicaserin in the DEE population of patients and if we look at and again this is a Phase III clinical trial which is up and running around the world right now but if we look back on the Phase II data from the PACIFIC study, bexicaserin produced around a median reduction of countable motor seizures in around 60% reduction in countable motor seizures, which was compared with around 20% with placebo and with nice interesting signals across populations of patients with Dravet syndrome, Lennox-Gastaut syndrome, and other developmental and epileptic encephalopathies. Lastly, I wanted to mention also the use of the clinical trial on relutrigine in patients carrying genetic variants in SCN2A and SCN8A genes. And the program reported positive results in both populations of patients and this is actually something that was so strongly seen that the process is a speed up of the process going through the filing to regulatory agencies.

Overall, to summarize, I mean, in the world of pediatric epilepsies and developmental and epileptic encephalopathies, there is a huge interest and there is a huge fresh energy with a number of medications and with different approaches, including both drugs, but also methodologies like antisense oligonucleotides, which are now used in clinical trials, still in clinical trials for different epilepsies. So my overall message is that definitely we’re moving in our field from rather than saying another anti-seizure medication to toward what we call mechanism-informed epilepsy care. So broad agents can be effective in some DEEs. We need to explore more. Some data are already there, but the future and what is happening actually right now, it will definitely make a signature, make an important moment for patients with developmental and epileptic encephalopathies.

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