Stifel 2026 Healthcare Conference - VOYAGER THERAPEUTICS INC

Explicit Guidance:

• Q1 2024: Expected readout for the tau antibody program (BIB80 competitor data context) and acute safety data for the gene therapy tau knockdown program.
• Coming Months: First-in-human (FTH) dosing expected for the tau knockdown gene therapy program.
• ~1 Year Post-Dosing: Anticipated measurement of CSF tau pharmacodynamic (PD) data for the gene therapy program.
• >1 Year Post-Dosing: Anticipated tau PET imaging readout to confirm brain-level impact (specific timeline not provided).
• Q4 2024 (Implied "Any Day Now"): Primary data readout for the tau antibody program (powered to show effect on tau PET).
• December (Upcoming): Presentation of in vivo pharmacology data regarding the ALPL shuttle capsid at the antibody engineering meeting in San Diego.
• Next Few Months: CEO transition; Al Sandrock stepping down to allow Robin Schwartz to assume CEO role and make decisions regarding future development pathways.

Business-Segment Outlook:

• Tau Gene Therapy: Expectation that capsid-related safety issues will declare themselves early; success hinges on validating the blood-brain barrier (BBB) penetrant capsid and achieving gene expression.
• Tau Antibody: Viewed as a "dark horse" with a "decent chance" of success; success requires demonstrating efficacy superior to the benchmark (Pranumab) with >50% effect on slowing tau accumulation/spread.
• Capsid Platform: Two "shots on goal" to validate newly discovered BBB-penetrant capsids: one in Voyager's Alzheimer's program and one in Neurocrine's Friedreich's ataxia program.
• ALPL Shuttle: Differentiated from TFR1 approach due to more restricted distribution (brain-biased vs. muscle/other tissues), longer half-life, and lack of hematologic issues; plans to share data confirming ALPL necessity for brain crossing.

Market and Competitive Outlook:

• Tau Target Validation: Recent data from Biogen (BIB80), Novartis, and Arrowhead supports tau as a viable target, though intrathecal ASOs face transient neurological toxicity (confusional state/encephalopathy) limiting dose escalation.
• Delivery Landscape: Intrathecal ASOs face steep CSF-to-brain concentration gradients requiring excessive doses; systemic delivery via gene therapy (Voyager) and shuttle mechanisms (Arrowhead) offers a solution to avoid off-target effects and maximize central exposure.
• Competitive Benchmarking: Voyager's antibody aims to outperform Pranamab (approx. 50% effect on spread), which had secondary endpoint success but failed primary endpoints; Voyager's animal model has a 4-for-4 prediction record for clinical outcomes.
• Commercial Strategy: Anticipated shift toward high-volume, lower-cost-of-goods models for Alzheimer's (similar to Zolgensma baseline therapy) rather than rare disease pricing, potentially combining with adjunct therapies.

Macro / Industry Outlook:

• Safety Paradigm Shift: Industry is recognizing that transient neurological toxicity (confusional state/encephalopathy) in intrathecal ASOs is a class effect related to high extracellular concentrations of negatively charged oligonucleotides, not necessarily target-specific.
• Regulatory Expectations: FDA engagement is robust; pre-IND meetings have occurred to incorporate feedback from recent gene therapy safety signals (e.g., Capsida patient), with confidence that safety protocols are optimized.
• Market Demand: High unmet need in Alzheimer's, particularly for patients ineligible for anti-amyloid therapies (e.g., APOE4 homozygotes) due to ARIA risk; tau targeting is viewed as the "next big thing" to fill this gap.

Strategic Initiatives:

• Partnership Strategy: Explicit need for a commercial partner for the Alzheimer's antibody program due to the scale of late-stage trials required; potential for Phase 2 trials or shuffling the antibody with the ALPL shuttle.
• Pipeline Expansion: Continued validation of the ALPL shuttle platform for broader neurotherapeutic applications; plans to leverage the shuttle for the tau antibody.
• Leadership Transition: Upcoming succession of CEO from Al Sandrock to Robin Schwartz to potentially drive strategic decisions regarding partnership and development scale.

Risks and Headwinds to Outlook:

• Safety Risks: Capsid-related toxicity (historically seen with AAV9 liver failure or HLH); potential for transient confusional states with intrathecal delivery methods (ASOs); potential liver targeting issues mitigated by detargeting (30-fold reduction vs. AAV9).
• Biomarker Limitations: Difficulty in correlating CSF tau reduction with clinical endpoints; PET imaging may lag significantly (requiring >1 year) and may only detect reduction in reversible tau pools (condensates) rather than irreversible neurofibrillary tangles.
• Clinical Efficacy: The "flat part of the dose-response curve" for tau knockdown (maxing out at ~50% with ASOs); risk that the antibody fails to meet the "tall order" of >50% effect on tau spread.
• Regulatory/Development Risks: Potential for long-term safety concerns in humans not seen in animals; uncertainty regarding the size of the safety database required for a common disease like Alzheimer's versus rare diseases.

Management Tone on the Future:

• Confidence Level: High confidence in the biological validity of tau targeting and the safety profile of the gene therapy approach (supported by animal data and genetic variants); optimistic ("eternal optimist") regarding the antibody program despite skepticism.
• Strategic Outlook: Views the current period as "catalyst-rich" with multiple imminent data points; believes the ability to deliver systemically with a BBB-penetrant capsid represents a significant structural advantage over current intrathecal standards.
• Caveats: Acknowledges the "dark horse" nature of the antibody and the difficulty of proving clinical efficacy; notes that while the gene therapy provides a "baseline" treatment, patients may still require adjunctive therapies.

Miscellaneous:

• Technology Differentiation: Voyager's gene therapy utilizes intracellular siRNA production (avoiding high extracellular concentrations) vs. intrathecal ASO delivery; ALPL shuttle offers tissue-biased distribution compared to TFR1.
• Safety Data: Animal studies have shown tau knockdown up to 70% without untoward effects; human genetic variants support tolerance of reduced tau levels in adults.
• Commercial Potential: Vision for a "once-and-done" IV treatment that could become a baseline standard of care for Alzheimer's, similar to Zolgensma in SMA, supported by decreasing cost of goods for AAV therapies.