Beyond Dravet and LGS: Elizabeth Thiele, MD, PhD, on New Data for Epidiolex in DEEs

At the 2025 American Epilepsy Society (AES) Annual Meeting, held December 5-9 in Atlana Georgia, new data were presented exploring the use of Epidiolex (Jazz Pharmaceuticals), a purified cannabidiol oral solution, across a broader range of developmental and epileptic encephalopathies. Although Epidiolex is FDA approved for Dravet syndrome (DS), Lennox Gastaut syndrome (LGS), and tuberous sclerosis complex (TSC), its history began with an expanded access program that enrolled patients with many different etiologies of epilepsy.

The analysis, presented by Elizabeth Thiele, MD, PhD, included 135 patients with developmental epileptic encephalopathies (DEEs), including Aicardi syndrome (12.6%), CDKL5 mutations (14.8%), epilepsy with myoclonic-atonic seizures (8.1%), Dup15q syndrome (8.1%), early infantile epileptic encephalopathy (4.4%), febrile infection–related epilepsy syndrome (9.6%), myoclonic absence epilepsy (3.7%), SCN2A mutations (3.7%), Sturge-Weber syndrome (3.7%), and other genetic epilepsies (31.1%). All told, CBD treatment was associated with a median reduction of 58.1% and 51.8% in convulsive and total seizures, respectively, after 12 weeks compared with an external placebo control arm (ECA). Notably, these results were maintained through week 48, with reductions of 63.5% and 60.0%.

Thiele, a long-standing leader in pediatric epilepsy care, sat down with NeurologyLive® during the meeting to discuss the main findings and clinical implications of the analysis. She describes why genetic epilepsies such as CDKL5, SCN2A related disorders, and other rare syndromes require continued therapeutic focus, and how Epidiolex has demonstrated sustained efficacy and tolerability in many of these populations through expanded access and long term follow up. Thiele, director of the Pediatric Epilepsy Program at Massachusetts General Hospital, also reflected on the increased knowledge base of CBD since its approval, as well as ways to create more innovative clinical trials for patients with severe and refractory epilepsies.

NeurologyLive: For our clinical audience, can you provide an overview of this study and some of the main takeaways you had from the analysis?

Elizabeth Thiele, MD, PhD: As you know, the program development with CBD started with the expanded access program, which is fairly unique in anti seizure medication development. That program enrolled patients with epilepsy from many different etiologies. It eventually led to the sponsored trials and the randomized controlled trials in Dravet syndrome, Lennox Gastaut syndrome, and tuberous sclerosis complex. But clearly the expanded access program enrolled patients with many other causes of seizures. What this analysis shows is that, in addition to the three disorders that have FDA approval, we now have evidence that CBD can be effective in treating many of the different DEEs and other causes of epilepsy. I think that is really important, because many of those patients still have a significant unmet need for medications that are effective and well tolerated. Showing that CBD can be effective for many of those patients, with maintained efficacy over time and good safety and tolerability, is an important finding.

Can you discuss why it is important to study and support DEE populations beyond Dravet and LGS, such as those with CDKL5 deficiency disorder, SCN2A mutations, and Sturge-Weber syndrome?

Epidiolex is FDA approved for Dravet syndrome, LGS, and tuberous sclerosis complex, but there are numerous other causes of epilepsy, particularly genetic causes. We are now up to over one thousand genes associated with epilepsy, and many of them lead to DEEs. This includes CDKL5, SCN2A, and many others. There is a significant unmet need in these populations. Many patients have a very high incidence of refractory epilepsy, high seizure burden, and the developmental epileptic component of the disorder. These patients are in great need of more options. The data from this analysis show that Epidiolex can be an effective and well tolerated therapy for many of these individuals. As you mentioned, they do not have a lot of therapies to choose from, so having confidence that CBD can be helpful is meaningful.

You have been involved with Epidiolex for many years. What have we learned since the approvals in 2018 and 2020, and how has clinical comfort with CBD evolved?

My journey with CBD and Epidiolex started in 2012 with the first patient who went from the United States to the United Kingdom to receive CBD, and that patient had a clear response. That led to the expanded access program, then the sponsored trials, and then the FDA approvals. It has been quite a journey. At the beginning, many people were very opposed to the idea of a product derived from cannabis or medical marijuana being used to treat epilepsy. There were many people who were not open minded about the possibility that it could be effective, even though we have thousands of years of experience suggesting cannabis can treat seizures.

What we have learned is exciting. Since the approvals in 2018 we are now almost eight years out. I have patients who began in the expanded access program in 2014 and are still on Epidiolex with continued efficacy and tolerability. It is not a silver bullet, which we could have anticipated, but for many people it can be very effective and well tolerated, with sustained efficacy over years. That is important, because many of our medications lose efficacy over time. Seeing such sustained benefit with CBD has been one of the major lessons.

As someone who has run many phase 3 trials and helped develop several drugs, how can the field continue pushing the needle forward and designing more creative clinical trials, especially given the renewed activity in epilepsy drug development?

What has been exciting over the past five to ten years is the change in how we think about treating epilepsy. When I started, we treated focal seizures and generalized seizures. With advances in genetics and a deeper understanding of genetic epilepsies, along with contributions from patient advocacy groups, our concept of treatment development has shifted toward disease modifying and syndrome specific therapies.

The approval of CBD for Dravet syndrome was the first seizure medication approved specifically for one of the DEEs. That meant a lot to the Dravet community and to the broader DEE and epilepsy communities. There is a lot of excitement now. Companies are thinking about new mechanisms and new approaches to treating seizures, not just sodium channel drugs and our traditional pathways.

There is also movement toward different trial designs, not just the traditional randomized controlled trial. There is interest in platform trials and basket trials for DEEs. The question is, how can we get effective, well tolerated medications to as many people as possible, especially those with rare disorders. I am biased as a pediatric epileptologist, but if a medication is effective in DEEs, unless it is highly mechanism specific, it is likely to help others with refractory epilepsy as well.

Transcript edited for clarity. Click here for more AES 2025 coverage.