AdventHealth Involved in Research to Evaluate First Potential Disease-Modifying Treatment for Epileptic Patients with Dravet Syndrome

Under the leadership of principal investigator Ki Hyeong Lee, MD, MS, medical director of AdventHealth for Children’s pediatric epilepsy center in Orlando, AdventHealth Orlando has been one of two Florida sites participating in multi-center Phase II and extended study clinical trials to evaluate STK-001, an antisense oligonucleotide (ASO), designed to address the genetic cause of Dravet syndrome. A severe and progressive genetic epilepsy, Dravet syndrome is characterized by frequent, prolonged and refractory seizures that typically begin within the first year of life. Up to 20% of children and adolescents living with Dravet die before adulthood due to sudden unexplained death in epilepsy (SUDEP), prolonged seizures or seizure-related accidents.

Recently released data from two open-label Phase I/IIa studies and two open-label extension studies of children and adolescents ages 2 to 18 with Dravet syndrome who were treated with STK-001 showed clinically meaningful effects, including substantial and durable reductions in convulsive seizure frequency and improvements in multiple measures of cognition and behavior that support the potential for disease modification. Specific findings included the following:

• In the Phase I/IIa end-of-study data, 70 mg doses of STK-001 demonstrated substantial and sustained reductions in convulsive seizure frequency on top of the best available anti-seizure medicines. This included median reductions of 85% (n=10) at 3 months and 74% (n=9) at 6 months after the last dose.
• In the open-label extension studies, durable reductions in seizures and clinically meaningful improvements in multiple measures of cognition and behavior were maintained over 12 months with continued dosing at 30 mg and 45 mg.
• STK-001 was generally well-tolerated.

“These are groundbreaking studies because we are evaluating the first-ever medication designed to actually modify the disease course of Dravet Syndrome, a genetic cause of epilepsy,” shares Dr. Lee “For decades we have tried treating the symptoms — mainly seizure frequency and severity — with minimal success so the 74-85% reductions achieved so far with this new approach are significant and exciting.”

Dravet Syndrome and its Effects

A rare disease, Dravet syndrome impacts an estimated 1:15,700 infants in the U.S., and over 80% of those diagnosed carry a mutation in the sodium channel gene SCN1A, which results in a 50% decrease in expression of the Nav1.1 protein.

“Seizures are uncontrolled in 90% of people with Dravet syndrome, and children do not outgrow the condition,” explains Dr. Lee. “It is a horrible disease that typically begins around 3 to 4 months of age and results in tremendous suffering for patients and their families. Dravet also carries a high rate of premature death.”

Beyond seizures, additional complications of the disease that can negatively impact a patient’s quality of life include:

• Intellectual disability
• Developmental delays
• Movement and balance issues
• Language and speech disturbances
• Growth defects
• Sleep abnormalities
• Disruptions of the autonomic nervous system
• Mood disorders

Understanding the STK-001 Treatment Technology

STK-001 was designed by Stoke Therapeutics using their TANGO (Targeted Augmentation of Nuclear Gene Output) research platform. The researchers are targeting genetic diseases in which the patient has one functional copy of the gene and one mutated copy, causing the patient to produce only half the amount of protein needed. The genes are transcribed into pre-messenger RNA (pre-mRNA), and using TANGO, researchers design antisense oligonucleotides (ASOs) that bind to the pre-mRNA and help the healthy target gene to produce more protein. This increased protein output from the healthy gene compensates for the non-functioning copy of the gene.

Using TANGO, STK-001 was designed to upregulate NaV1.1 protein expression by leveraging the non-mutant (wild-type) copy of the SCN1A gene to restore physiological NaV1.1 levels, reducing both occurrence of seizures and the non-seizure comorbidities. Because STK-001 does not cross the blood-brain barrier, it is injected directly into the cerebrospinal fluid via a lumbar puncture (spinal tap). The U.S. Food and Drug Administration (FDA) has granted STK-001 orphan drug designation and rare pediatric disease designation as a potential new treatment for Dravet syndrome.

The Importance of Genetic Testing to Guide Epilepsy Treatment

Dr. Lee emphasizes the importance of genetic testing to properly diagnose and treat children with epilepsy.

“Epilepsy has many etiologies, and genetic mutation is one of the common causes in children. Early genetic evaluation helps us identify the root cause of the epilepsy, as in the case of Dravet syndrome, so that we can take the most targeted and effective treatment approach. Genetic testing is also critical to advancing care as researchers work to develop new precision medicine and gene-based therapies that could enhance outcomes and quality of life for our patients who suffer from epilepsy.”

Plans for Future Dravet Syndrome Research

Stoke Therapeutics has been meeting with regulatory agencies to discuss a randomized, controlled Phase III registrational study for STK-001 that includes initial doses of 70 mg followed by continued dosing at 45 mg. They hope to launch the trial later this year, and AdventHealth Orlando plans to participate when it becomes available.

“This is one of the most exciting medical developments in epilepsy care in more than 100 years,” comments Dr. Lee. “It is opening a new horizon, and if successful, this platform technology could lead to potential new disease-modifying treatments for other genetic neurological diseases as well. We are excited to be a part of pioneering research efforts that could significantly improve care for the patients and families we are privileged to serve.”