Stoke Therapeutics

Stoke Therapeutics, Inc. (NASDAQ: STOK) is a biotechnology company headquartered in Bedford, Massachusetts, pioneering the use of antisense oligonucleotides (ASOs) to selectively upregulate gene expression for the treatment of severe genetic diseases. The company's lead program, STK-001, is in Phase 2 development for [Dravet syndrome](/diseases/dravet-syndrome) — a devastating developmental and epileptic encephalopathy caused by [SCN1A](/genes/scn1a) haploinsufficiency[@stoke2024].

Overview

Stoke Therapeutics, Inc. (NASDAQ: STOK) is a biotechnology company headquartered in Bedford, Massachusetts, pioneering the use of antisense oligonucleotides (ASOs) to selectively upregulate gene expression for the treatment of severe genetic diseases. The company's lead program, STK-001, is in Phase 2 development for [Dravet syndrome](/diseases/dravet-syndrome) — a devastating developmental and epileptic encephalopathy caused by [SCN1A](/genes/scn1a) haploinsufficiency[@stoke2024].

Overview

Stoke's mission is to address the root cause of severe genetic diseases by selectively increasing protein expression from the wild-type allele in patients with disease-causing loss-of-function mutations. Unlike traditional ASO approaches that target mRNA for degradation, Stoke's TANGO (Targeted Augmentation of Nuclear Gene Output) platform uses ASOs to restore levels of normally expressed but insufficient protein by increasing natural splicing of targeted transcripts["@stoke2023"].

The company's initial focus is on neurological diseases where increased expression of the wild-type allele can compensate for the loss of the mutant allele — a particularly compelling approach for conditions like Dravet syndrome where one functional copy of [SCN1A](/genes/scn1a) is insufficient to prevent disease["@stoke2024"].

TANGO Platform

Mechanism of Action

TANGO is a proprietary approach that uses allele-selective ASOs to increase natural mRNA splicing, thereby boosting production of the full-length, functional protein from the wild-type allele. Key features:

• Allele-selective: Targets only the wild-type allele for upregulation
• Splice-modulating: Redirects splicing to produce more full-length mRNA
• Disease-modifying: Addresses the underlying genetic cause rather than symptoms
• Repeatable: ASOs can be re-dosed, unlike AAV gene therapy

Technical Approach

Applications

TANGO is applicable to any gene where:

• Haploinsufficiency causes disease
• Natural (non-altered) splicing products would be beneficial
• The gene has naturally occurring "poison exon" or alternative splice events

Pipeline

STK-001 (Dravet Syndrome)

STK-001 is Stoke's lead product candidate for the treatment of Dravet syndrome, a severe developmental and epileptic encephalopathy characterized by treatment-resistant seizures, developmental delays, and significantly increased mortality risk[@stoke2024].

Mechanism: STK-001 is an ASO that selectively increases [SCN1A](/genes/scn1a) protein expression from the wild-type allele by promoting productive splicing of the target mRNA.

Clinical Development:

• Phase 1/2 (MONARCH): Dose escalation completed. Showed dose-dependent increases in [SCN1A](/genes/scn1a) expression with acceptable safety profile[@stoke2024]
• Phase 2 (SEQUOIA): Dose confirmation ongoing, initiated 2024
• Phase 2 (BEACON, NCT05482706): Registration-directed study, initiated 2025
• Long-term extension (ALbatross): Ongoing for patients who completed Phase 1/2

• Dose-dependent increases in [SCN1A](/genes/scn1a) mRNA in cerebrospinal fluid
• Encouraging seizure frequency reduction at higher doses
• Generally well-tolerated across dose range
• FDA granted Breakthrough Therapy Designation in 2024 based on preliminary evidence[@btd2024]

• Breakthrough Therapy Designation active
• BLA preparation underway
• Q2-Q3 2026: Expected Phase 2 registration data readout
• Q4 2026: Anticipated BLA submission

STK-002 (Dravet Syndrome - Alternative Indication)

STK-002 uses the same TANGO mechanism as STK-001 but is optimized for intrathecal delivery and may address different patient populations or administration preferences.

Status: Preclinical/IND-enabling

Additional Programs

Stoke has announced pipeline expansion into other genetic diseases where TANGO could be applied:

• Undisclosed neurological target: Early discovery
• Undisclosed metabolic target: Preclinical evaluation

Financial Overview

| Metric | Value |
|--------|-------|
| Exchange | NASDAQ |
| Ticker | STOK |
| IPO Date | July 2020 |
| IPO Proceeds | $125M |
| Market Cap | ~$800M-$1B (March 2026) |
| 2025 Follow-on | $65M (Phase 2 BLA prep, manufacturing investment) |
| 2023 Follow-on | $90M (STK-001/002 expansion) |
| Cash Position | ~$300M (estimated Q1 2026) |
| Employees | ~150-200 |

Funding History

• 2020: IPO — $125M raised on NASDAQ
• 2023: Follow-on offering — $90M
• 2025: Follow-on offering — $65M for BLA preparation and manufacturing scale-up

Investor Considerations

• Catalyst-rich 2026: Phase 2 data and BLA preparation represent significant value inflection points
• Platform validation: Successful STK-001 would validate TANGO for broader application
• Risk: Single-program concentration — STK-001 failure would materially impact company
• Manufacturing: BLA requires significant GMP manufacturing investment, partially addressed with 2025 funding

Competitive Position

Stoke competes in the Dravet syndrome therapeutic landscape with:

| Competitor | Approach | Stage |
|-----------|----------|-------|
| [Encoded Therapeutics](/companies/encoded-therapeutics) | AAV gene activation (ETX101) | Phase 1 |
| [Ultragenyx](/companies/ultragenyx) (GeneTx) | ASO for Angelman (GTX-102) | Phase 2 |
| Roche/Neurocrine | AAV gene therapy | IND-enabling |

Advantages:

• Clinical data available (Phase 1/2 complete)
• FDA Breakthrough Therapy Designation
• ASO approach well-understood by regulators
• Repeatable dosing flexibility

• Requires repeat dosing (quarterly maintenance)
• Limited to allele-selective gain-of-function targets
• Intrathecal delivery (lumbar puncture) required

Corporate Structure

• Headquarters: Bedford, Massachusetts
• Leadership: Experienced biotech executives with rare disease and CNS expertise
• Board: Mix of scientific, financial, and industry expertise
• Scientific Advisory Board: Leading epilepsy and genetics researchers

Key Publications and Presentations

Hub Page Cross-Links

• [AAV Gene Therapy for Neurodevelopmental Epilepsy — Hub](/therapeutics/aav-gene-therapy-neurodevelopmental-epilepsy)](/therapeutics)
• [Dravet Syndrome Disease Page](/diseases/dravet-syndrome)](/diseases/dravet-syndrome)
• [SCN1A Gene Page](/genes/scn1a)](/genes)
• [STK-001 Clinical Trial Page](/clinical-trials/)

See Also

• [Neuroinflammation and Microglia Pathway in Alzheimer's Disease](/wiki/mechanisms-ad-neuroinflammation-microglia-pathway) — inhibits