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. 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.
| 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 |
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.
| 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 |
- Q2-Q3 2026: Phase 2 efficacy data readout
- Q4 2026: BLA submission preparation
- 2027: Anticipated FDA decision
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)
- 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
Dravet syndrome is caused by loss-of-function variants in the SCN1A gene, 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 inhibition
The 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.
| 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 |
- Drug: STK-001 (antisense oligonucleotide)
- Route: Intrathecal administration (lumbar puncture)
- Dosing: Single dose with optional retreatment
- Dose escalation: Sequential cohort design
| 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.
- 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 formation
- 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 outcomes
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.
- 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
- Outcome: Reduced production of the target protein
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 channels
This approach differs from non-selective approaches that would reduce both mutant and wild-type channels, potentially worsening the deficit[@mill2023].
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 (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 spiking
| 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
- 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
- Dose-dependent increase in Nav1.1 expression in CSF (consistent with target engagement)
- Dose-proportional pharmacokinetics in CSF
- No accumulation with single dosing
| 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)
- 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
¶ 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 |
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 |
- 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
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
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
- CONNECT2: Additional safety data in different age groups
- Long-term extension: Open-label follow-up for participants
- FDA: Granted Orphan Drug Designation (2019)
- EMA: Granted Orphan Medicinal Product Designation (2020)
- 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
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)
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 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
- Enhanced delivery: Improving brain penetration
- Oral bioavailability: Future possibility
- Allele-selectivity 2.0: More precise targeting