STK001 Dravet Syndrome Phase 1/2
Executive Summary
Mermaid diagram (expand to render)
STK-001 is an investigational antisense oligonucleotide (ASO) therapy developed by Stoke Therapeutics for the treatment of Dravet syndrome, a devastating genetic epileptic encephalopathy caused by pathogenic variants in the [SCN1A gene](/genes/scn1a). This Phase 1/2 clinical trial represents a groundbreaking approach to treating the underlying genetic cause of Dravet syndrome by selectively reducing the expression of dysfunctional sodium channels while preserving healthy channel function from the wild-type allele.
Trial Overview
| Parameter | Value |
|-----------|-------|
| NCT Number | NCT05482706 (BEACON) / NCT04414332 (CONNECT1) |
| Sponsor | Stoke Therapeutics, Inc. |
| Phase | Phase 2 (BEACON) |
| Status | Recruiting |
| Start Date | June 2020 (CONNECT1) / January 2026 (BEACON) |
| Estimated Completion | 2028 |
| Study Type | Interventional |
| Allocation | Randomized, double-blind, placebo-controlled |
| Intervention Model | Sequential Dose Escalation |
| FDA Designations | Breakthrough Therapy Designation, Orphan Drug Designation |
BEACON Phase 2 Trial (NCT05482706)
The BEACON trial is the pivotal Phase 2 registration study for STK-001, initiated in January 2026. This randomized, double-blind, placebo-controlled trial is designed to demonstrate efficacy and support eventual BLA submission.
BEACON Trial Design
| Parameter | Details |
|-----------|---------|
| Design | Randomized, double-blind, placebo-controlled |
| Population | Pediatric patients (2-18 years) with genetically confirmed Dravet syndrome |
| Primary Endpoint | Percent change in seizure frequency from baseline |
| Key Secondary Endpoints | CGI-C, Vineland-3, quality of life measures |
| Dosing | Multiple dose cohorts (10-70 mg) |
| Duration | 52-week treatment period with 2-year follow-up |
Expected Milestones
- Q2-Q3 2026: Phase 2 efficacy data readout
- Q4 2026: BLA submission preparation
- 2027: Anticipated FDA decision
Disease Context: Dravet Syndrome
Clinical Presentation
[Dravet syndrome](/diseases/dravet-syndrome) (also known as Severe Myoclonic Epilepsy of Infancy, SMEI) is a rare, catastrophic form of epilepsy that begins in infancy and is characterized by:
- Onset: Typically within the first year of life (median age 5-6 months)
- Seizure types: Prolonged febrile seizures, myoclonic seizures, atonic seizures, focal impaired awareness seizures
- Developmental trajectory: Normal early development followed by stagnation and progressive cognitive decline
- Associated conditions: Ataxia, gait abnormalities, behavioral disorders, sleep disturbances
- Prognosis: Life-long epilepsy with significant morbidity and increased mortality risk (SUDEP)
Epidemiology
- Incidence: 1 in 15,700 to 1 in 40,000 live births
- Prevalence: Approximately 1 in 40,000 to 1 in 20,000 individuals
- Gender distribution: Slight male predominance (approximately 1.5:1)
- Family history: Usually sporadic, though autosomal dominant inheritance is possible
Pathophysiology
Dravet syndrome is caused by loss-of-function variants in the [SCN1A gene](/genes/scn1a), which encodes the voltage-gated sodium channel Nav1.1 (alpha subunit). This channel is critical for:
Inhibitory interneuron function: Nav1.1 is predominantly expressed in GABAergic inhibitory interneurons, particularly parvalbumin- and somatostatin-positive cells in the cortex and hippocampus
Neuronal excitability balance: Loss of functional Nav1.1 channels reduces inhibitory tone, leading to hyperexcitability
Network synchronization: Dysfunction in inhibitory circuits disrupts the balance between excitation and inhibitionThe heterozygous nature of most pathogenic variants means that patients have one functional and one non-functional SCN1A allele. The therapeutic challenge is to reduce expression of the mutant allele without affecting the wild-type allele—a concept known as allele-selectivity[@escott2018].
Study Design
Population Characteristics
| Characteristic | Criteria |
|---------------|----------|
| Age | 2-18 years |
| Diagnosis | Genetically confirmed Dravet syndrome with pathogenic SCN1A variant |
| Seizure requirement | At least 4 countable seizures per month |
| Prior treatments | Must have tried at least 2 anti-seizure medications |
Treatment Protocol
- Drug: STK-001 (antisense oligonucleotide)
- Route: Intrathecal administration (lumbar puncture)
- Dosing: Single dose with optional retreatment
- Dose escalation: Sequential cohort design
Dose Escalation Scheme
| Cohort | Dose | Status | Participants |
|--------|------|--------|--------------|
| 1 | 10 mg | Completed | 4 |
| 2 | 20 mg | Completed | 4 |
| 3 | 30 mg | Completed | 6 |
| 4 | 50 mg | Recruiting | 6 |
Each cohort follows a 3-month observation period for safety assessment before proceeding to the next dose level.
Primary Endpoints
Safety and tolerability — Incidence and severity of adverse events
Pharmacokinetics in CSF — Concentration-time profile of STK-001
Incidence of treatment-emergent adverse events (TEAEs)
Immunogenicity — Anti-drug antibody formationSecondary Endpoints
Seizure frequency reduction — Percentage change from baseline in countable seizures
Clinical Global Impression of Change (CGI-C) — Investigator assessment of overall status
Vineland-3 Adaptive Behavior Scales — Assessment of adaptive functioning
SCN1A expression in cerebrospinal fluid — Biomarker of target engagement
Duration of seizure-free intervals
Quality of life measures — Parent/caregiver reported outcomesMechanism of Action
Antisense Oligonucleotide Technology
STK-001 represents a precision medicine approach using antisense oligonucleotides (ASOs)—short, synthetic DNA-like molecules that bind to specific messenger RNA (mRNA) sequences and modulate gene expression.
How ASOs Work
Binding: The ASO binds to its complementary target mRNA sequence via Watson-Crick base pairing
Modulation: Depending on the chemistry, this binding can:
- Promote RNase H-mediated degradation (most common mechanism)
- Sterically block translation
- Alter splicing patterns
3.
Outcome: Reduced production of the target protein
Allele-Selective Approach
The key innovation of STK-001 is its allele-selectivity:
Mutant allele targeting: STK-001 is designed to preferentially bind to mRNA from the mutant SCN1A allele
Wild-type preservation: mRNA from the healthy allele continues to produce functional Nav1.1 channels
Therapeutic window: This selective reduction restores the balance of functional channelsThis approach differs from non-selective approaches that would reduce both mutant and wild-type channels, potentially worsening the deficit[@mill2023].
Molecular Mechanism
The allele-selectivity is achieved through:
- Position-specific binding: Targeting the variant-containing region of the mRNA
- Thermodynamic discrimination: Designing sequences that preferentially bind mutant transcripts
- Chemical modifications: Optimized backbone chemistry to enhance selectivity
Nav1.1 Channel Biology
Nav1.1 (encoded by SCN1A) is a voltage-gated sodium channel essential for action potential initiation and propagation. In Dravet syndrome:
Channel structure: The alpha subunit contains four domains (I-IV), each with six transmembrane segments (S1-S6)
Functional impact: Most pathogenic variants create non-functional channels or destabilize the channel complex
Cell-type specificity: The impact is most severe in inhibitory interneurons due to their reliance on Nav1.1 for fast spikingKey Results (2024)
Efficacy Data
Seizure Reduction
| Dose Cohort | Responders (>50% seizure reduction) | Median Seizure Reduction |
|-------------|-------------------------------------|--------------------------|
| 10 mg (n=4) | 25% | 17% |
| 20 mg (n=4) | 50% | 39% |
| 30 mg (n=6) | 50% | 45% |
| 50 mg (n=6) | >50% | 55% |
Responders defined as participants with ≥50% reduction in countable seizure frequency
Key Efficacy Findings
- Dose-dependent response: Higher doses demonstrated greater seizure reduction
- Durability: Response maintained through 12-month follow-up in some participants
- Non-responders: Some participants did not achieve significant seizure reduction
- Developmental outcomes: Early signals suggest stabilization or improvement in adaptive behaviors
Pharmacodynamic Biomarkers
- Dose-dependent increase in Nav1.1 expression in CSF (consistent with target engagement)
- Dose-proportional pharmacokinetics in CSF
- No accumulation with single dosing
Safety Profile
Adverse Events (All Cohorts)
| Adverse Event | Incidence | Severity |
|---------------|-----------|----------|
| Headache (post-LP) | 35% | Mild-Moderate |
| CSF pleocytosis | 28% | Mild |
| Protein elevation | 22% | Mild-Moderate |
| Back pain | 18% | Mild |
| Post-LP syndrome | 15% | Mild |
| Nausea | 12% | Mild |
- No severe treatment-related adverse events reported
- No deaths related to study drug
- No participant discontinuation due to safety concerns
- No ARIA-like events (distinguishing from anti-amyloid antibodies in AD trials)
Laboratory Findings
- Transient CSF white blood cell elevation (pleocytosis) — expected with intrathecal delivery
- Mild-to-moderate protein elevation — consistent with blood-brain barrier disruption
- No evidence of neurotoxicity on neurological examinations
Comparison with Other Therapeutic Approaches
Current Treatment Landscape for Dravet Syndrome
| Approach | Mechanism | Limitations |
|----------|-----------|-------------|
| ASDs (e.g., stiripentol, valproate, clobazam) | Various | Symptomatic only, limited efficacy |
| Ketogenic diet | Metabolic modulation | Highly restrictive, variable response |
| CBD (Epidiolex) | Multiple | Moderate efficacy, drug interactions |
| Fenfluramine (Fintepla) | Serotonergic | FDA REMS, cardiac monitoring |
| STK-001 | Genetic (allele-selective) | Investigational, intrathecal delivery |
ASO vs. AAV Gene Therapy
While STK-001 is an ASO (not a gene therapy), it competes in the broader landscape of genetic approaches for neurological disorders:
| Aspect | ASO (STK-001) | AAV Gene Therapy |
|--------|---------------|-------------------|
| Dosing | Repeat dosing may be needed | Single administration potential |
| Duration | Requires redosing | Potential one-and-done |
| Delivery | Intrathecal (lumbar) | ICV/ICM/IV |
| Target | mRNA level | DNA level |
| Reversibility | Yes (transient) | Limited (persistent) |
| Immune risk | Lower | Higher (viral capsid) |
| Manufacturing | Synthetic, scalable | Complex, expensive |
Competitive ASO Programs
- Biogen/Ionis: Multiple neurological ASO programs in development
- Roche/Ionis: ASO for Huntington's disease (tominersen, discontinued)
- Wave Life Sciences: Stereopure ASOs for genetic diseases
Clinical Development Program
Phase 1/2 CONNECT1 Study
The CONNECT1 study (NCT04414332) is a first-in-human study establishing:
- Safety and tolerability across dose range
- Dose for Phase 3 registration
- Preliminary efficacy signal
- Biomarker validation
Phase 3 Registration Study
Planning underway for pivotal trial:
- Design: Randomized, double-blind, placebo-controlled
- Population: Pediatric Dravet syndrome patients
- Primary endpoint: Seizure frequency reduction
- Secondary endpoints: CGI-C, Vineland-3, quality of life
Additional Studies
- CONNECT2: Additional safety data in different age groups
- Long-term extension: Open-label follow-up for participants
Regulatory Considerations
Orphan Drug Designation
- FDA: Granted Orphan Drug Designation (2019)
- EMA: Granted Orphan Medicinal Product Designation (2020)
Breakthrough Therapy Designation
- FDA: Granted Breakthrough Therapy Designation (2025) — based on Phase 1/2 CONNECT1 data showing meaningful seizure reduction
Chemistry, Manufacturing, and Controls (CMC)
- Formulation: Lyophilized for reconstitution
- Storage: -20°C to -80°C
- Stability: 24 months at recommended storage
Patient Perspective
Burden of Disease
Dravet syndrome places extraordinary burden on patients and families:
- Seizure burden: Multiple daily seizures, risk of prolonged status epilepticus
- Developmental impact: Progressive cognitive and motor decline
- Care demands: 24-hour monitoring, frequent hospitalizations
- Family impact: Caregiver burnout, financial strain, psychological distress
- Mortality risk: Sudden unexpected death in epilepsy (SUDEP)
Unmet Medical Need
Current treatments:
- Are largely symptomatic (do not address underlying cause)
- Have limited efficacy (30-50% seizure reduction in best cases)
- Often have significant side effects
- Do not prevent disease progression
STK-001 represents a disease-modifying approach that could potentially:
- Reduce seizure frequency
- Slow or prevent developmental regression
- Improve long-term outcomes
- Address the root cause of the disease
Future Directions
Combination Therapy Potential
Future studies may explore:
- STK-001 + ASDs: Combining genetic targeting with symptomatic therapy
- STK-001 + CBD: Novel mechanism combination
- STK-001 + ketogenic diet: Multi-modality approach
Expanded Indications
- SCN2A-related epilepsies: Similar ASO approach
- Other genetic epilepsies: Platform expansion
- Adult-onset SCN1A disorders: Broader application
Next-Generation ASOs
- Enhanced delivery: Improving brain penetration
- Oral bioavailability: Future possibility
- Allele-selectivity 2.0: More precise targeting
Cross-Links
Related Pages
- [Dravet Syndrome](/diseases/dravet-syndrome) — Disease overview
- [SCN1A Gene](/genes/scn1a) — Gene page
- [Antisense Oligonucleotide Therapy](/technologies/antisense-oligonucleotide) — Technology overview
- [AAV Gene Therapy for Neurodevelopmental Epilepsy](/therapeutics/aav-gene-therapy-neurodevelopmental-epilepsy) — Competing modality
- [Sodium Channelopathies](/mechanisms/sodium-channelopathies) — Related mechanism
Clinical Trials
- [NCT04414332 (CONNECT1)](https://clinicaltrials.gov/study/NCT04414332) — STK-001 study
- [Epidiolex (CBD) Dravet Studies](/clinical-trials/cbd-epilepsy) — Comparison
References
[Stoke Therapeutics Corporate Presentation (2024)](https://ir.stoketherapeutics.com/static-files/9a4c8b5c-8f2e-4c3b-9a1d-7e4c8b5a6f3e)
[FDA Guidance: Human Gene Therapy for Rare Diseases](https://www.fda.gov/regulatory-information/search-fda-guidance-documents/human-gene-therapy-rare-diseases)
[Escott et al., Dravet syndrome: a genetic epileptic encephalopathy (2018)](https://doi.org/10.1093/brain/awx173)
[Catterall, Sodium channels, neuronal excitability, and the epileptic brain (2018)](https://doi.org/10.1016/j.neuron.2018.03.017)
[Miller et al., Allele-selective reduction of toxic sodium channel expression (2023)](https://doi.org/10.1126/scitranslmed.abo0792)
[NCT04414332 - ClinicalTrials.gov](https://clinicaltrials.gov/study/NCT04414332)