NeuroVoices: Barry Ticho, MD, PhD, on the Disease-Modifying Potential of STK-001 in Treating Dravet Syndrome

Barry Ticho, MD, PhD

There are several therapeutic limitations in the treatment of Dravet syndrome (DS), including seizure refractoriness, cognitive and developmental decline, heterogeneity of response and treatment-related adverse events, among others. Industry leaders have begun to test new mechanisms of action, such as antisense oligonucleotides, to try to break through some of the challenges with DS drug development. One such therapy in development, STK-001 (Stoke Therapeutics), has demonstrated promising data in 2 early-stage studies, MONARCH (NCT04740476) and ADRIMAL (NCT04442295).

At the 2024 American Epilepsy Society (AES) Annual Meeting, held December 6-10 in Los Angeles, California, Stoke led a number of presentations highlighting STK-001, otherwise known as zorevunersen. The new data included 9 patients who received 2 or 3 initial doses of 70 mg of STK-001 in a phase 1/2 study and then continued treatment in an open-label extension where they received at least 2 doses of 45 mg. To better understand the totality of the findings, NeurologyLive® sat down with Barry Ticho, MD, PhD, chief medical officer at Stoke.

As part of a new iteration of NeuroVoices, Ticho gave insight on the mechanism and promise behind this new therapeutic, and why it could potentially be the first “disease-modifying” treatment for DS. Ticho, a pediatrician and cardiologist, discussed the greater effects of the drug seen on cognition and activities of daily living, as well as the plans for a registrational phase 3 trial. Additionally, he spoke on the significance of the recent breakthrough therapy designation for the agent, the drug’s encouraging safety to date, and how this drug could shake up the DS treatment landscape for good going forward.

NeurologyLive: Discuss more about this drug's mechanism of action. Why do we believe it can be successful?

Barry Ticho, MD, PhD: Stoke Therapeutics is a company focused on RNA medicines, specifically for severe diseases with a genetic basis. We use our proprietary technology, called TANGO, which stands for Targeted Augmentation of Nuclear Gene Output. The goal of TANGO is to increase protein levels inside cells using antisense oligonucleotides (ASOs).

ASOs work by binding to messenger RNA (mRNA) and increasing its level, which in turn increases the corresponding protein. Now, some people may be familiar with ASOs as a way to lower proteins, which is the mechanism behind several approved drugs. But what we’re doing is the opposite—increasing protein levels.

We achieve this by manipulating a part of the mRNA that normally signals the cell to degrade that message. This degradation process is part of the body’s natural protein regulation and happens in about half of all mRNAs. What we’ve figured out is how to remove this signal for certain genes. By preventing degradation, we’re able to produce more mRNA, and that translates directly into more protein.

Can you give insight on the data presented at AES 2024; what were the greatest takeaways?

At AES 2024, we were excited to share data on STK-001, also called zorevunersen. This antisense oligonucleotide targets the SCN1A gene, which is the genetic cause of Dravet syndrome. In patients with Dravet syndrome, only half the normal amount of a critical sodium channel is produced, leading to what’s called haploinsufficiency. This sodium channel deficit causes the cascade of effects seen in the disease.

STK-001 is delivered intrathecally, allowing the oligonucleotide to reach the brain and restore sodium channel levels back to normal. We’ve demonstrated this mechanism in multiple animal models and have now moved into clinical trials.

We’ve treated 81 children with Dravet syndrome, aged 2 to 18 years, across the U.S. and U.K., all of whom had the SCN1A mutation and were on multiple anti-seizure medications at baseline. These children were highly refractory, experiencing frequent major motor seizures—on average, about one seizure every other day.

Our results show a dose-dependent reduction in seizures. At the highest tested dose—70 mg administered multiple times—we observed up to an 85% reduction in seizure frequency compared to baseline. Importantly, this effect was sustained for up to 6 months after the last dose. That’s because STK-001 has a long half-life in the brain—over 4 months—allowing for lasting benefits.

The other key point is that restoring sodium channel function doesn’t just suppress seizures; it also helps rebuild disrupted neural networks. Once these networks are restored, they remain stable, which is likely why we see such prolonged effects.

How does the safety of STK-001 look thus far?

Safety is always our top priority, and it’s the primary endpoint of our trials. So far, the safety profile for STK-001 has been encouraging. We’ve treated 81 children, administered over 600 doses, and some children have been on treatment for over 3 years—receiving up to 12 doses.

The main safety finding has been an elevation in cerebrospinal fluid (CSF) protein levels in some patients. This is a lab finding with no clinical manifestations—no signs of inflammation or adverse symptoms. This elevation is considered a class effect for intrathecal ASOs, as it has been observed with other approved drugs in this category.

We did have one serious adverse event (SAE) identified as related to the medication, but after thorough investigation, we haven’t seen any similar events across the rest of the treated population. Overall, STK-001 appears to be well-tolerated with a favorable safety profile.

Discuss the significance of the breakthrough therapy designation and the future plans for the drug.

The Breakthrough Therapy designation from the FDA is incredibly meaningful. It’s reserved for therapies that demonstrate significant benefits over existing treatments, and it reflects the unique, disease-modifying potential of STK-001.

What sets this drug apart is that it addresses the underlying cause of Dravet syndrome. Standard anti-seizure medications can reduce seizure frequency, but they don’t impact the cognitive and behavioral challenges associated with the condition. STK-001 has shown improvements in both areas—cognition and behavior—something never achieved before in Dravet syndrome.

For example, in our Phase 1/2 studies, we saw improvements on the Vineland Adaptive Behavior Scales, which measure communication, motor skills, and interpersonal abilities. Typically, children with Dravet syndrome plateau in these skills after age two. But with STK-001, scores increased—children were able to say "mommy" and "daddy," sing songs, help with tasks, and improve gross and fine motor skills like running or buttoning a shirt. These changes are transformative for families and patients.

Looking ahead, our phase 3 study will build on these findings. We’ll treat children aged 2 to 18 years with a 70 mg loading dose followed by a 45 mg maintenance dose. Data from our open-label extension study supports this approach, showing sustained seizure reduction and continued improvements in cognition and behavior.

This drug has the potential to revolutionize the treatment landscape—not just reducing seizures but improving the overall quality of life for children with Dravet syndrome and their families.

If this drug were to continue to progress, how would it fit in the treatment landscape of Dravet syndrome?

In the future, STK-001 could become a cornerstone therapy for Dravet syndrome. Our Phase 3 study will focus on children aged 2 to 18 who continue to have seizures despite being on optimized background therapy.

What’s unique about STK-001 is its potential to offer rapid and lasting benefits. By administering a 70 mg loading dose, we aim to achieve a quick onset of effect, followed by a 45 mg maintenance dose to sustain the benefits. The data we’ve seen so far suggest not only seizure reduction but also continued improvements in cognition and behavior over time. For example, patients treated for 12 months showed significant gains, and by 24 months, these improvements were even greater.

If successful, STK-001 would be the first disease-modifying therapy for any form of epilepsy. It could transform the lives of patients and families—helping children develop communication skills, gain independence, and experience a more normal childhood. For families, it could mean the ability to go on vacations, have their child attend school, or simply play outside—all things that many take for granted but are often out of reach for those living with Dravet syndrome.

This breakthrough therapy represents hope for a completely new standard of care.

Transcript edited for clarity. Click here for more AES 2024 coverage.