Third Quarter 2026 Business and Financial Update - STOKE THERAPEUTICS INC

Explicit Guidance:

• Financial Outlook: Cash position of $358.8 million (as of Q3 2026) is projected to fund operations into early 2028, supported by Biogen reimbursement and potential development milestones.
• Spending Guidance: Q4 2026 and 2027 operating spend is expected to remain consistent with the observed quarterly increase in Q3 2026.
• Data Readout: EMPEROR Phase 3 primary and secondary endpoint data readout expected in Q3 2027.
• NDA Submission: Rolling NDA submission to begin in the first half of 2027, with completion targeted for the second half of 2027.
• Approval Target: Potential U.S. approval anticipated in early 2028.

Business-Segment Outlook:

• Zoriva-Nurson (Dravet Syndrome):
  • Pipeline/Clinical: Phase 3 EMPEROR study progressing well; 110/162 patients completed Week 28 visits, 20 completed Week 52. No treatment discontinuations to date.
  • Regulatory Strategy: FDA has agreed to accept a "multi-component" (MC4) assessment combining four Vineland-3 subdomains for the key secondary endpoint (cognition/behavior) in the U.S. NDA, avoiding a hierarchical assessment of individual domains.
  • Commercial Readiness: Adding field market access team; engaging top 50 U.S. treatment sites to ensure infrastructure and capacity for intrathecal administration; designing patient support program in collaboration with caregivers.
  • Additional Studies: Two non-registrational safety studies (one in adults, one in infants/toddlers) to initiate by end of 2026 to support broad labeling without age limits.
• STK002 (ADOA):
  • Clinical: Phase I OSPRY study dosing underway for Cohort 3; Cohort 4 dosing expected early 2027.
  • Data Readout: Initial safety and efficacy data for higher dose cohorts (Cohorts 3 & 4) expected in the first half of 2027.
  • Target: Aiming to demonstrate measurable effects on visual function and retinal OPA-1 protein levels to inform pivotal design.

Market and Competitive Outlook:

• Addressable Population: Estimated 38,000 patients with Dravet syndrome in major markets; ~16,000 in the U.S., with ~6,000 under age 25 (immediate launch target).
• Market Access: Anticipated growth in new diagnoses (500–600 annually) driven by increased genetic testing and awareness.
• Competitive Landscape: High awareness of Zoriva-Nurson among the Dravet community; growing recognition of "disease-modifying" potential across neurology, supported by the American Epilepsy Society's Presidential Task Force.
• Payer Dynamics: U.S. payers focused on "totality of data"; European markets expected to face more challenges regarding differential pricing and reliance on net treatment benefit scores for individual subdomains.

Macro / Industry Outlook:

• Disease Awareness: Significant shift in the field toward genetic epilepsies (DEEs) and the necessity of genetic testing, creating a favorable environment for haploinsufficiency-targeted therapies.
• Stakeholder Activity: Increased engagement from advocacy groups (e.g., American Epilepsy Society) preparing for the arrival of disease-modifying therapies.
• Regulatory Environment: FDA viewed as responsive and willing to accept complex, multi-component assessment strategies for neurodevelopmental endpoints; potential for OLE data (up to 5–6 years) to be included in labeling pending review.

Strategic Initiatives:

• Organizational Expansion: Scaling capabilities for 2028 commercial launch, hiring experienced personnel from high-science rare disease launches.
• Platform Focus: Continued emphasis on severe genetic diseases driven by haploinsufficiency, particularly in the CNS.
• Collaboration: Ongoing partnership with Biogen for U.S. commercialization; Biogen retains control of European filings and valuation strategies.
• Capacity Building: Active preparation of clinical sites to administer intrathecal treatments, addressing specific infrastructure needs for Zoriva-Nurson.

Risks and Headwinds to Outlook:

• Study Design Sensitivity: Reliance on the multi-component assessment; if individual subdomains show variability, the composite score must still meet statistical significance (p-value < 0.05).
• Data Gaps: 12-month data from earlier studies showed suboptimal dosing (gap in administration); future success depends on consistent 52-week dosing in EMPEROR.
• Commercial Execution: Risk of delayed market penetration if site infrastructure or payer education lags behind launch timing.
• External Factors: European reimbursement hurdles and potential pricing differentials compared to the U.S.

Management Tone on the Future:

• Confidence: High confidence in the 2027 data readout and 2028 launch trajectory, citing "great progress" in 2026 and strong clinical retention rates (0% discontinuations).
• Strategic Clarity: Reiteration of timelines remains firm; management expresses "unwavering" commitment to delivering the medicine to patients without delay.
• Hedges: Acknowledged that European markets present greater valuation challenges than the U.S.; no Advisory Committee Meeting (AdCom) anticipated for the U.S. NDA.

Miscellaneous:

• Statistical Methodology: Use of MMRM (Multivariate Mixed Model for Repeated Measures) for Vineland scoring to capture all visit data points and impute missing data, enhancing statistical power.
• Payer Education: Payer account team deployed to engage medical directors and insurers; educational efforts building on 5 years of clinical data and NEJM publications.