Key Highlights from POLARIS Gene Therapy Trial Data for Dravet Syndrome

Speaker 1 (00:00): 

My name is Joseph Sullivan. I'm a Professor of Neurology at the University of California, San Francisco, where I work as a Pediatric Epileptologist. So the ENVISION study really served as the baseline natural history study so that we could move forward with an interventional trial. And this program is called POLARIS. The POLARIS program consists of 3 different clinical trials that are enrolling children between the age of 6 months and all the way up to 7 years of age. And this intervention is a potentially one time AAV9-based gene therapy that's targeting the underlying cause of Dravet syndrome being the haploinsufficiency in the NaV1.1 sodium channel protein. It's doing this by delivering an engineered transcription factor that has cell specificity for the GABAergic inhibitory interneurons. And by delivering this transcription factor, we are hopeful to upregulate the NaV1.1 production at the DNA level. 

(01:02): 

And as an AAV9-based therapy where there's been many other programs that have looked at safety and tolerability, the primary outcome measures for this POLARIS program was to ensure safety and tolerability in these young children. And so here at the 2025 American Epilepsy Society meeting, we reported the first results from that trial. As of today, 19 patients had been dosed at various dose levels. The intervention was very safe and well tolerated. The most common treatment emergent adverse event was transaminase elevation in 4 patients, all of whom were clinically asymptomatic. And all 3 resolved without treatment with 1 requiring some steroid treatment. This is very much consistent with what we know from AAV9-based therapy as a class effect. Then moving on to the efficacy, again, this was primarily a safety and tolerability study. 

(01:58): 

So we started out at a low dose and then did dose escalation over time. And we have 32 week follow-up for patients through dose level 3, and what we saw was a really nice dose-response curve, with the dose level 3 achieving a median of 78% reduction in seizures. And again, that's through 7 through 32 weeks of treatment with a one time therapy. And then again, in the spirit of being disease modifying and why the ENVISION natural history study was so important, we're also looking at developmental outcomes in  these patients because we want to get to the “D” part in “DEE”. When we looked at the subdomains in the Vineland and specifically expressive and receptive communication, what we saw is when we looked at how the patients did in the 52-week natural history study, the patients at the 16-week time point actually had caught up. 

(02:56): 

So they actually were performing the same number of skills in 16 weeks as what we saw in the natural history study over 52 weeks. And then in the small group of patients where actually did have 52 week neurodevelopmental follow-up data, we saw a magnitude of improvement that really we haven't ever seen before and specifically in the areas of receptive and expressive communication, which is what we hear from families is one of the developmental domains that has the most impact on their day-to-day quality of life. And then lastly, knowing from the natural history study, again, that cognition is something that changes quite dramatically early in the course of the disease. We looked at the Bayley measure of cognition, specifically in the younger group of children that were dosed prior to 24 months of age. And what we saw in that small cohort was this acceleration in their acquisition of skills, such that it actually surpassed the rate of what we actually see in neurotypical patients. 

(04:00): 

So not to say that they are developing better than neurotypical patients, but rather they were able to catch up. And in some of the earliest dose patients where we have the 52-week follow-up, there's one patient that is now just over 2 years old and tracking normal neurodevelopment, which is really, really inspiring to see that there's this potential for disease modification. So we're really excited about these preliminary data in the lower dose levels and are excited to follow the children that receive the higher dose levels for a longer period of time, because that is actually going to set the stage for part two of this study, which will, again, be an interventional study, but will have a sham control. So we're really excited to continue following this cohort and especially, those that have received some of the higher doses to see if they have a even more incremental gain, not only with regard to reduction seizures, but in terms of improving their overall developmental trajectory. 

(05:01): 

And this is really gonna inform part two of the trial, which will include the intervention and then also a sham control arm so that we can actually really define what the effect size is, both with regard to seizure reduction and neurodevelopmental improvement. And that trial should hopefully be enrolling in early 2026. This has been a really exciting time in pediatric epilepsy as we enter into this world of genetic testing being available in the clinic. We are now able to arrive at precise diagnoses for these patients that are just lumped into this DEE, developmental and epileptic encephalopathy category. And that's so important because not only is there a value in having a specific diagnosis just to counsel and for parents and families to have an identity, there are now some really novel approaches to treating these genetically based DEEs that are targeting the underlying cause. 

(06:00): 

So we're moving from an era of anti-seizure symptom management into precision medicine and potentially disease modification for a whole host of these neurogenetic disorders. So I'm super excited about the direction our field is going.