STK-001 (Stoke Therapeutics) — Dravet Syndrome Phase 1/2 Trial

STK001 Dravet Syndrome Phase 1/2

Executive Summary

STK001 Dravet Syndrome Phase 1/2

Executive Summary

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:

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[@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

Secondary Endpoints

Mechanism 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

• Promote RNase H-mediated degradation (most common mechanism)
• Sterically block translation
• Alter splicing patterns

Allele-Selective Approach

The key innovation of STK-001 is its allele-selectivity:

This 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:

Key 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

• 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