NeuroVoices: Joseph Sullivan, MD, on ETX101 Gene Regulation Therapy and Early POLARIS Findings in Dravet Syndrome

Dravet syndrome (DS), a rare epilepsy, is most often caused by loss of function variants in SCN1A, leading to impaired NaV1.1 activity in GABAergic inhibitory interneurons and downstream network hyperexcitability. While current antiseizure medications and syndrome specific options can reduce seizure burden, a major unmet need remains: therapies that meaningfully shift the developmental trajectory in this developmental and epileptic encephalopathy, particularly if delivered early in life when developmental departure becomes more apparent.

At the 2025 American Epilepsy Society (AES) Annual Meeting, held December 5-9 in Atlanta, Georgia, investigators presented positive interim data from a phase 1/2 program assessing ETX-101 (Encoded Therapeutics), a one-time AAV9-based gene regulation therapy, as a treatment for DS. Led by Joseph Sullivan, MD, the phase 1/2 program, dubbed POLARIS, includes 3 open-label dose escalation studies across the U.S., U.K., and Australia. These trials, some of the first gene therapy studies in DS, are enriched toward younger children to align with natural history window where disease modification may be more impactful.

During the meeting, NeurologyLive^® sat down with Sullivan, director of the Pediatric Epilepsy Center at UCSF, to discuss some of the findings presented, along with the mechanism and rationale behind this new therapeutic. As part of a new NeuroVoices, Sullivan, a research titan in the field, walked through the global POLARIS program, as well as previewed some of the promising findings on seizure burden and neurodevelopmental measures further supporting EXT-101’s development.

NeurologyLive: Before we go into any of the nitty gritty about efficacy or safety, can you provide some insight for our clinical audience on this therapy in general, how it operates, and some of the promise behind this agent?

Joseph Sullivan, MD: We know that the main cell type implicated in the cause of Dravet syndrome is the GABAergic inhibitory interneurons. You have haploinsufficiency in those GABAergic inhibitory interneurons, which results in excessive excitation and decreased inhibition across neuronal networks.

A lot of the therapies that we are now looking at are trying to restore that haploinsufficiency. I think one key advantage of this therapy is that it has cell specificity. The target is to actually increase SCN1A production specifically in the GABAergic inhibitory interneurons. That cell specificity is really important, because that is where the disease biology is centered.

From a broader perspective, why do you think we have not seen something like this succeed earlier, especially given how much we understand about the underlying causes of Dravet syndrome?

I think the biggest issue has been that this is a central nervous system disorder, and trying to target gene expression within the central nervous system has immense challenges. Delivering therapies to the brain, getting the right cells targeted, and doing so safely has been extremely difficult.

That said, we have made a lot of progress just in the last five years. There are now multiple disease modifying therapies in the pipeline, and from what I understand about other agents that have been presented here at this meeting, there is a lot of exciting work going on. It has taken a while to get here, but I do think we are really on a precipice where things are going to start moving very quickly.

Can you give us an overview of what the POLARIS program looks like, including how the phase 1/2 studies are structured and what they are aiming to achieve?

The POLARIS program is a phase 1/2 program that includes three different studies being conducted in three different countries, including the United States, the United Kingdom, and Australia. There are different age ranges included at different sites, but overall, the lower age limit is six months, and the upper age limit is seven years.

We are really trying to enrich the study population to include children under three years of age, because based on the natural history studies, this early time period is when we see the developmental departure from typical development. That early window is potentially the best opportunity to intervene and have the greatest disease modifying impact.

From your perspective as someone who has conducted many phase 3 trials, what considerations go into a study like this, especially when working with younger patients whose seizure burden may still be evolving?

This age group definitely presents challenges. We know that seizures are frequent in Dravet syndrome, but when we are targeting very young patients, they may not yet have seizures as frequently as they will at three or four years of age.

Historically, phase 3 clinical trials have included patients who average about one seizure per week. Those patients certainly exist in younger age groups, but they are not as common. So, it required some creativity to balance getting the therapy into younger patients who are still having enough seizures to include seizure frequency as a meaningful efficacy outcome, while also keeping in mind that we are really trying to impact overall developmental trajectory.

Based on natural history studies, there seems to be an inflection point around two years of age. If we can intervene around that time, it may give us the best opportunity to show a clinically meaningful benefit in developmental outcomes.

Can you walk us through the efficacy data that were presented and what clinicians should take away from those findings?

This was a first in human study using an AAV9 based therapy, so our first priority was to be very cautious and make sure we understood the safety and tolerability profile. We started at dose level one and then gradually escalated dosing based on our observations in each cohort.

Once a dose was deemed safe and well tolerated, we moved on to the next dose level. So far, we have enrolled and dosed 19 patients, and we have safety data on all of them. The safety signal has been very reassuring. The most common treatment emergent adverse event has been transaminase elevation in four patients, all of whom were asymptomatic. Three of those resolved without any intervention, and one patient required a brief course of steroids.

In terms of seizures, at dose level one, which was the lowest dose, we did not see a substantial reduction in seizure frequency. When you look at the data more closely, that is actually consistent with what we see in natural history studies, where seizures tend to increase during this age window.

At dose level two, we started to see some preliminary signals of efficacy. It was not dramatic at the cohort level, but there were individual patients who experienced reductions of 20% and even up to 60% in seizure frequency.

At dose level three, the signal became much more compelling. In that cohort of three children, there was a 78% median reduction in seizures, and that effect was sustained out to seven months. That finding really highlights the potential durability of a one time therapy.

Patients have also received dose level four, but we do not yet have longer term efficacy data for that cohort, and we are looking forward to seeing those results as more follow up becomes available.

What should clinicians expect in terms of timelines for additional data from the POLARIS program?

More patients have been enrolled in dose levels three and four because we want to understand whether there is a differential response between doses, and we also want to give the therapy enough time to work. We are hoping that by late first quarter or early second quarter, we will have more data, including longer term follow up on the patients already presented, as well as additional data from the higher dose cohorts.

You mentioned earlier that development was another key endpoint. Can you walk us through what you observed on the developmental side?

Development was a critical outcome for us because Dravet syndrome is a developmental and epileptic encephalopathy. While seizure control is important, our ultimate goal is to alter the developmental trajectory.

We have developmental data across the first three dose levels. Looking at 16 patients and their Vineland scores, when we compare those data to what we see in natural history studies over 52 weeks, natural history patients tend to make very slow, incremental gains.

In contrast, in patients treated with ETX101, within the first 16 weeks after therapy, the cohort appeared to catch up to what we would normally expect to see after 52 weeks in natural history. In other words, developmental gains that usually take a full year were achieved within the first four months after treatment.

What was particularly remarkable was what we saw in the small cohort with 52 week follow up. The magnitude of developmental change was something we have really never seen before, especially in expressive and receptive communication. Based on caregiver surveys and clinical experience, communication is one of the most important developmental domains for these patients, because the inability to communicate has a significant downstream impact on quality of life.

We also assessed cognition using the Bayley Scales of Infant Development, specifically in children who were dosed under 24 months of age. When we compared those results to natural history, we saw a dramatic acceleration in the rate of skill acquisition. The rate of acquisition surpassed what we would expect in neurotypical development, not in the sense that these children were developing beyond typical expectations, but rather that they were catching up and narrowing the developmental gap.

For one patient with 52 week follow up, that child is now two years old and tracking neurodevelopmentally normal. These are still very small numbers, which is why we are so eager to continue following these patients over time and expand the dataset.

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

REFERENCE
1. Sullivan J, Scheffer IE, Howell KB, et al. POLARIS Phase 1/2 Program Interim Safety and Preliminary Efficacy Results of ETX101, a One-Time Gene Regulation Therapy, in Young Children with Dravet Syndrome. Presented at: 2025 AES Annual Meeting; December 5-9; Atlanta, Georgia. ABSTRACT 1.308.