Voyager Therapeutics, Inc. · NASDAQ:VYGR
Voyager Therapeutics — Technical Presentation (May 2025)
19 slides from Voyager Therapeutics's technical presentation, May 2025
Slide 1: Intravenous delivery of VY1706, a CNS penetrant AAV gene therapy for Alzheimer's disease, provides broad Tau lowering in NHP
Intravenous delivery of VY1706, a CNS penetrant AAV gene therapy for Alzheimer’s disease, provides broad Tau lowering in NHP Rajeev Sivasankaran, PhD Vice President, Neuroscience Voyager Therapeutics 1 |
Slide 2: Disclosures
Disclosures • Rajeev Sivasankaran is a full‐time employee of Voyager Therapeutics 2 |
Slide 3: Tau Burden Correlates with Alzheimer's disease progression
Tau Burden Correlates with Alzheimer’s disease progression Tau PET imaging‐based staging aligns with neuropathological staging1 • ~ 7M Alzheimer’s disease patients Alzheimer’s disease in U.S.2 progression (Braak Staging) Worsening of disease • Multiple clinical trials now show slowing tau accumulati
Slide 4: Voyager capsids offer targeted solutions to Alzheimer's and Tau-related Therapeutic challenges
Voyager capsids offer targeted solutions to Alzheimer’s and Tau‐ related Therapeutic challenges CHALLENGE SOLUTION SOLUTION Pathological forms of Tau that drive disease Silence all forms of Tau via a potent siRNA‐mediated remain poorly defined silencing approach Efficient BBB crossing is essential f
Slide 5: Pan-species BBB-penetrant Gen2 TRACER Capsids demonstrate enhanced CNS Tropism and Liver detargeting
Pan‐species BBB‐penetrant Gen2 TRACERTM Capsids demonstrate enhanced CNS Tropism and Liver detargeting Gen1 TRACER Capsids: Gen2 Capsids: Increased Brain Tropism and Liver Detargeting in NHP Pan‐Species CNS Targeting via ALPL Binding Gen 1 Gen 2 AAV9 VCAP‐102 VCAP‐Gen2 Cortex AAV‐Gen1 Liver ALPL VCA
Slide 6: Therapeutic Approach for Targeting Tau
Therapeutic Approach for Targeting Tau: Single IV Dose of BBB penetrant AAV Gene Therapy to knockdown Tau mRNA and Protein Vectorized Tau mRNA Tau Protein Neurofibrillary Prevention of pri‐amiRNA silencing Reduction Tangle Reduction Neuronal Loss amiRNA Prevention of AD Progression & Improvement of
Slide 7: Selection of VY1706
Selection of VY1706 – screening for high amiR potency, specific, processing and broad NHP biodistribution Screening Workflow Selection Criteria siRNA Design & Screening • Favorable human, rhesus, cyno on‐target In silico Design and • Stringent off‐target profile siRNA in vitro • No seed match to end
Slide 8: Lead siRNA candidate shows high potency and selectivity
Lead siRNA candidate shows high potency and selectivity Highly Potent lead siRNA identified Dose dependent reduction of Tau Minimal off‐targets in Global Transcriptomics In BT‐474 cell line mRNA in HEK293T at > 30 times Tau KD IC50 dose 0.2nM siRNA530 vs Mock IC50 = 7pM BE(2)‐M17 cells 8 |
Slide 9: IV-delivered VY1706 shows dose dependent delivery of VGs and reduction of Tau mRNA in P301S mice
IV‐delivered VY1706 shows dose dependent delivery of VGs and reduction of Tau mRNA in P301S mice Biodistribution P301S mice Cortex Hippocampus ✱✱✱✱ ✱✱✱✱ Study Scheme ✱✱✱✱ ✱✱✱✱ Doses: ✱✱ VY1706 1E12 vg/kg IV Injection 3E12 vg/kg 1E13 vg/kg Necropsy Male + Female P301S Mouse Age 12 wks 20 wks mRNA Kno
Slide 10: VY1706 shows dose dependent reduction of total and pathological Tau and rescues body weight loss in P301S mice
VY1706 shows dose dependent reduction of total and pathological Tau and rescues body weight loss in P301S mice Tau Protein Pathological Tau Cortex Hippocampus Cortex Hippocampus ✱✱✱✱ ✱✱✱✱ ✱✱ ✱✱ ✱✱✱ ✱✱✱ Body Weight Percentage of body weight change vs Day 0 (%) W ne W 1 W 2 W 3 W 4 W 5 W 6 W 7 8 k k k
Slide 11: IV-delivered VY1706 shows good CNS biodistribution, robust mRNA knockdown and reduced distribution to the liver
IV‐delivered VY1706 shows good CNS biodistribution, robust mRNA knockdown and reduced distribution to the liver Necropsy VG, Tau Necropsy mRNA, Tau protein, small RNA‐seq VY‐1706 5 wks 11 wks ISH, FISH for Tau IV Infusion mRNA KD Liver Biodistribution CNS Biodistribution Tau mRNA Knockdown EC HC TC
Slide 12: VY1706 treatment in NHPs results in robust Tau mRNA knockdown within cells of AD-related brain regions
VY1706 treatment in NHPs results in robust Tau mRNA knockdown within cells of AD‐related brain regions Singleplex Tau in situ hybridization (ISH) Vehicle VY1706 (High dose) 5‐week 5‐week 11‐week Average Cellular tau mRNA KD Entorhinal cortex (% of vehicle) Hippocampus 3. V wk 3. V wk 3. V wk k 1 k 1
Slide 13: Relative Total Tau Protein Level
13 | Relative Total Tau Protein Level (% of Vehicle) 3. V 1 1e eh 1. .3e12‐ icle 3e 13 5w 13 ‐5 k ‐1 w k 3. V 1wk 1 1e eh 1. .3e12‐ icle 3e 13 5w 13 ‐5 k ‐1 w k 3. V 1wk 1 1e eh 1. .3e12‐ icle 3e 13 5w 13 ‐5 k ‐1 w k 3. V 1wk 1 1e eh 1. .3e12‐ icle 3e 13 5w 13 ‐5 k ‐1 w k 3. V 1wk 1 1e eh 1. .3e12‐
Slide 14: VY1706 demonstrates translatable cross-species pharmacology
VY1706 demonstrates translatable cross‐species pharmacology P301S mouse ‐ Tau Protein KD IC50 NHP ‐ Tau Protein KD IC50 IC50 = 1.9 IC50 = 2.7 95%CI = 1.4‐2.9 95%CI = 1.1 ‐ 3.5 R2 = 0.67 R2 = 0.76 14 |
Slide 15: VY1706 shows robust Tau protein knockdown in neurons across AD-relevant brain regions
VY1706 shows robust Tau protein knockdown in neurons across AD‐relevant brain regions Strong Neuronal Tau protein Knockdown observed across brain regions at 11 weeks Vehicle VY1706 Neuronal tau protein reduction EC HC TC EC normalized to that of vehicle 150 % neuronal Tau intensity 100 43% 47% 57% 4
Slide 16: VY1706 shows favorable in vivo miR processing in NHPs
VY1706 shows favorable in vivo miR processing at 1.3 E13 vg/kg in NHPs No differentially expressed endogenous miRNA were observed % relative to Guide / Passenger 5’ End (TX vs Vehicle) endogenous miRNA Guide/Passenger Ratio ratio Processing (%) Dose TX Up Down (vg/kg) Target 49.5 Threshold VY1706 3.
Slide 17: Clinical Chemistry and Time-course Serum NfL analysis of VY1706-treated NHPs indicate a clean profile
Clinical Chemistry and Time‐course Serum NfL analysis of VY1706‐ treated NHPs indicate a clean profile out to 11 weeks Clinical Chemistry Serum NfL Timecourse CK (U/L) LDH (U/L) ALT (U/L) AST (U/L) No TA‐related clinical observations or histopathology findings (5 or 11 weeks) 17 |
Slide 18: VY1706: Overall Summary
VY1706: Overall Summary • Potent vectorized siRNA achieves up to 73% MAPT mRNA reduction at 5 weeks and 55% Tau protein reduction at 11 weeks in AD‐relevant brain regions, with a clean off‐target profile at a low dose of 1.2e13 vg/kg. • Up to 57% MAPT protein reduction within neurons in key, AD‐rele
Slide 19: Team Acknowledgements
Team Acknowledgements Key Contributors: Wencheng Liu Johnny Yao Dhiral Shah Mathieu Nonnenmacher Kavitha Bodige Todd Carter Joydeep Ghosh Rouhong Zhou Tyler Moyer Kevin Nguyen Dinah Sah Yasuhiro Ito Jeyashree Natasan Amanda Ibe-Enwo Kumar Dhanasekharan Hechen Bao Joydip Kundu Alex Kubiak Andrew Joyc
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