– Baseline data from the BUTTERFLY observational study provide initial validation of standard measures of cognition (BSID-III and WPPSI-IV) for use in evaluating non-seizure comorbidities in people with Dravet syndrome –
– The current design for the ongoing MONARCH Phase 1/2a study to assess both single and multiple ascending doses of STK-001 in children and adolescents with Dravet syndrome will be presented –
– New data in a mouse model of Dravet syndrome demonstrate that TANGO ASOs can help restore normal function of nerve cells which correlate to reductions in seizure frequency and extended survival –
BEDFORD, Mass.--(BUSINESS WIRE)-- Stoke Therapeutics, Inc. (Nasdaq: STOK), a biotechnology company pioneering a new way to treat the underlying cause of genetic diseases by precisely upregulating protein expression, today announced highlights from presentations being made at the American Epilepsy Society (AES) 2020 Virtual Annual Meeting December 4-8, 2020 related to the Company’s work to advance STK-001, the first potential new medicine to target the underlying cause of Dravet syndrome. Dravet syndrome is a severe and progressive genetic epilepsy characterized by frequent, prolonged and refractory seizures that usually begin within the first year of life. The disease is classified as a developmental and epileptic encephalopathy due to the developmental delays and cognitive impairment associated with the disease. Highlights from the Company’s presentations include:
BUTTERFLY Observational Study – Baseline Analysis
Abst. 81. Observational Study to Investigate Cognition and Quality of Life in Children and Adolescents with Dravet Syndrome: Baseline Analysis of the BUTTERFLY Study
December 5, 2020 9:00 AM – 10:30 AM; Track: 4. Clinical Epilepsy / 4B. Clinical Diagnosis
22 children and adolescents with Dravet syndrome were enrolled in the Company’s BUTTERFLY observational study and included in a baseline analysis.
All study participants evaluated are representative of patients with Dravet syndrome. The majority of patients were able to complete commonly used cognition assessments including either the BSID-III (Bayley Scales of Infant and Toddler Development) or the WPPSI-IV (Wechsler Preschool and Primary Scale of Intelligence Fourth Edition), indicating that these measures are valid and appropriate for use in patients with Dravet syndrome. An initial analysis of data from 17/22 patients who completed one of these assessments showed substantially decreased neurocognitive abilities compared to children of the same age level despite the use of multiple anti-epileptic therapies. The assessment also demonstrated an apparent widening in overall intellectual development that increases with age. In addition, a gap in adaptive functioning was noted using the Vineland Adaptive Behavior Scales.
“We have long known that Dravet syndrome is far more than seizures and the BUTTERFLY study is providing quantifiable information on cognition and quality of life that fill gaps in our understanding of this disease and its progression as children age,” said Joseph Sullivan, M.D., Professor of Neurology at UCSF Benioff Children's Hospitals and Director of the UCSF Pediatric Epilepsy Center of Excellence. “Initial results from the study show significantly diminished neurocognitive abilities in children with Dravet syndrome such that 10 year-olds are functioning below the level of a healthy 1 year-old even while they are being treated with available anti-epileptic medicines. The fact that the majority of patients in this study were able to complete standard assessments of neurocognition gives us confidence that we can objectively assess whether potential new disease-modifying medicines have an effect on the non-seizure comorbidities that make Dravet so devastating.”
“Dravet syndrome is characterized by an array of effects that go beyond seizures and include motor and speech impairment, intellectual and developmental disabilities, behavioral deficits and abnormal sleep patterns,” said Barry Ticho, M.D., Ph D., Chief Medical Officer of Stoke Therapeutics. “We continue to generate strong preclinical evidence supporting the potential for STK-001 to address the underlying cause of Dravet syndrome and reduce seizure frequency. Our goal is to develop a medicine that goes beyond seizure control to address many of the other comorbidities associated with Dravet syndrome. As we look to future clinical studies of STK-001, we are encouraged by data showing the ability to diagnose children earlier as well as the validation of tools that will help us measure the potential impact of STK-001 on cognition and quality of life.”
MONARCH Phase 1/2a Current Study Design
Abst. 344. Safety and Pharmacokinetics of Antisense Oligonucleotide STK-001 in Children and Adolescents with Dravet Syndrome: Single and Multiple Ascending Dose Design for the Open-Label Phase 1/2a MONARCH Study
December 6, 2020 12:00 PM – 1:30 PM; Track: 7. Antiepileptic Drugs / 7B. Clinical Trials
A review of the study design for MONARCH, the Company’s ongoing Phase 1/2a study of STK-001 in children and adolescents with Dravet syndrome will be presented during a poster session by Linda Laux, M.D., Associate Professor of Pediatrics (Neurology and Epilepsy), Northwestern University Feinberg School of Medicine. Following a recent protocol amendment, MONARCH is designed to evaluate both single and multiple ascending doses of up to 30mg of STK-001 in children and adolescents with Dravet syndrome. The primary endpoints are safety, tolerability and pharmacokinetic (PK) profile of STK-001 in Dravet syndrome patients. The impact of STK-001 on frequency of convulsive seizures and quality of life are secondary endpoints of this study. Patient enrollment and dosing in MONARCH is ongoing and preliminary safety and PK data are anticipated in 2021.
Restoration of Interneuron Firing Frequency in a Dravet Mouse Model
Abst. 236. Targeted Augmentation of Nuclear Gene Output (TANGO) of SCN1A Reduces Seizures and Rescues Parvalbumin Positive Interneuron Firing Frequency in a Mouse Model of Dravet Syndrome
December 5, 2:00 PM – 3:30 PM; Platform A: Translational Research / Genetics
December 6, 12:00 PM – 1:30 PM; Track: 2. Translational Research / 2B. Devices, Technologies, Stem Cells
New preclinical data provide additional evidence of the potential for TANGO antisense oligonucleotides (ASOs) to provide a gene-specific, disease-modifying treatment for Dravet syndrome. In this study, Dravet syndrome mice treated with a TANGO ASO had significantly decreased seizure frequency and increased survival. Data presented by Eric Wengert, graduate student at the University of Virginia, show that 100% of mice treated with a TANGO ASO were seizure free between postnatal day 16 and postnatal day 19 compared to 50% of vehicle-treated control mice. The data also provide evidence that decreases in seizures and mortality are, in part, due to restoration of excitability of parvalbumin (PV) expressing interneurons. PV interneurons are commonly hypoexcitable in Dravet syndrome. In this study, treatment with a TANGO ASO restored Dravet syndrome mouse PV interneuron firing frequency to that of wild-type mice.
Additional Work in a Dravet Mouse Model
Antisense Oligonucleotides Increase Scn1a Expression and Reduce Seizures and SUDEP Incidence in a Mouse Model of Dravet Syndrome
December 8, 1:30 PM – 4:00 PM; Annual Fundamentals Symposium: Fundamentally New Ideas in Epilepsy Treatment and Research
Lori Isom, Ph.D., Maurice H. Seevers Professor and Chair of Pharmacology, University of Michigan Medical School, will present a review of data from experiments conducted with TANGO ASOs in a mouse model of Dravet syndrome.
Early Diagnosis of Dravet Syndrome
Abst. 392. Reducing the Time to Diagnosis and Increasing the Detection of Individuals with SCN1A-related Disease Through a Sponsored Epilepsy Genetic Testing Program
December 6, 12:00- 1:30 PM; Track: 12. Genetics / 12A. Human Studies
Data from an analysis of 6,874 children who participated in a no-cost epilepsy genetic testing program co-sponsored by Stoke showed that 152 had a positive molecular diagnosis related to the SCN1A gene, accounting for 2.2% of all patients. Results demonstrated a substantial decrease in the time to diagnosis from >6 years of age (2011-2015) to