Stifel 2026 Healthcare Conference - VOYAGER THERAPEUTICS INC

Financial Performance:

• No specific revenue, earnings, or cash flow figures disclosed; company is a clinical-stage biopharmaceutical firm not yet generating commercial revenue.
• Management noted that future cost of goods for AAV therapies is declining as companies scale production.
• Emphasis on a potential "volume-based" commercial model for Alzheimer's treatment, contrasting with the high-price, low-volume model typical of rare disease gene therapies.

Guidance and Future Outlook:

• Expect to read out Tau antibody data in Q4 (current quarter).
• First-in-human dosing for the Tau gene therapy (tau knockdown) program anticipated in the coming months, with a formal IND recently submitted.
• Acute safety data for the gene therapy expected in Q1.
• Pharmacodynamics (CSF Tau levels) expected to be measurable approximately one year after dosing initiation.
• PET imaging readouts expected to lag behind CSF biomarkers by a year or more due to the slow turnover of Tau protein and the accumulation of signal in pathological regions.
• Neurocrine is advancing a Voyager capsid into Friedreich's ataxia trials to validate BBB penetration.

Business Segments and Product Lines:

• Tau Antibody (Dark Horse): Differentiated by targeting pathological Tau forms rather than normal Tau; validated by a proprietary animal model (P301S mouse) that has correctly predicted clinical outcomes for three failed assets and one positive asset (Pramanab); study powered to show effect on Tau PET.
• Tau Gene Therapy: Uses a novel capsid to deliver siRNA intracellularly for Tau knockdown; approach aims for irreversible, long-term reduction (targeting 50-70% knockdown); utilizes a capsid that detargets the liver 30-fold relative to AAV9.
• ALP Shuttle Technology: A non-TfR1 blood-brain barrier (BBB) shuttle targeting ALPL; offers restricted distribution (brain bias), longer half-life, and potentially fewer hematologic issues compared to TfR1 shuttles; data to be presented at the Antibody Engineering meeting in San Diego.
• Neurocrine Partnership: Capsid technology being utilized in Neurocrine's Friedreich's ataxia program.

Market and Competitive Landscape:

• Analysis of competitor data (BIB80, Novartis ASO, Arrowhead siRNA) suggests that intrathecal ASOs face a therapeutic index challenge due to transient neurological side effects (confusional states) rather than target failure.
• Voyager's gene therapy approach avoids extracellular ASO toxicity by generating siRNA intracellularly.
• Anti-Amyloid therapies (e.g., Lecanemab) have limitations regarding ARIA risk, particularly for APOE4 homozygotes, creating a market opportunity for Tau-targeting therapies.
• Potential for a "once-and-done" intravenous gene therapy to replace frequent intrathecal dosing or subcutaneous injections.

Risks and Challenges:

• BIB80 Trial Results: Failed primary endpoint (dose-response) primarily attributed to off-target neurotoxicity from high-dose intrathecal ASOs rather than lack of target engagement; highest dose only achieved 50% Tau reduction.
• Safety Concerns: Capsid-related safety (e.g., liver toxicity) and acute confusional states associated with intrathecal delivery of negatively charged oligonucleotides.
• Biomarker Lag: Difficulty in correlating CSF biomarker reduction with PET imaging outcomes and clinical functional endpoints (CDR-SB, ADAS-Cog).
• Regulatory Path: Need for larger Phase 3 trials for Alzheimer's compared to rare diseases, potentially requiring a partner for late-stage commercialization.

Management Commentary and Tone:

• CEO Al Sandrock expressed confidence in the platform, citing the "catalyst-rich" period ahead and the unique ability to safely cross the BBB.
• Tone was described as "eternal optimist," particularly regarding the Tau antibody which is viewed as an underdog.
• Acknowledged his upcoming departure as CEO in the next few months, with Robin Schwartz named as successor.
• Emphasized that the severity of Alzheimer's justifies aggressive therapeutic development despite risks.

Analyst Questions and Answers:

• BIB80 Dose Response: Management explained the lack of dose-response was due to a ceiling effect on Tau reduction (50%) and the emergence of confusional states masking efficacy; suggested systemic/siRNA approaches (like Arrowhead) avoid this.
• Tau PET vs. CSF: Differentiated between soluble, reversible Tau pools (affected by synthesis inhibition) and permanent neurofibrillary tangles (NFTs) which PET may struggle to reduce quickly.
• Therapeutic Index: Confirmed comfort with irreversible Tau knockdown (50-70%) based on genetic variants and animal models, noting redundancy of microtubule stabilizing proteins in adults.
• Capsid Safety: Disclosed plans to lower dose (max 5E13 VG/kg vs. industry standard 1E14) and liver detargeting to mitigate risks seen in previous AAV therapies (e.g., Sarepta).
• Commercial Strategy: Discussed the feasibility of a high-volume, lower-price model for Alzheimer's versus the high-cost model of rare diseases.

Other Key Points:

• The proprietary animal model has a 4-for-4 track record in predicting clinical trial failures (3) and successes (1).
• Future data on the ALP shuttle's safety profile and lack of hematologic issues will be shared in December.
• Voyager views itself as a multi-modality neurotherapeutics company, not solely a gene therapy firm.
• The company is open to partnering for the antibody program but intends to retain control over the gene therapy development.