Vaccinex Provides Update on Biomarkers Associated with Response to Treatment of Early Stage AD with Pepinemab at CTAD (Clinical Trials on Alzheimer's Disease)

Regulatory Role of Semaphorin 4D in the Nervous System Vaccinex, Inc. Maurice Zauderer, PhD President & CEO December 3, 2025 Unique Targets Novel Mechanisms New Medicines Current Employee and Stock Shareholder of Vaccinex, Inc. Disclosures Maurice Zauderer, PhD Forward Looking Statements To the extent that statements contained in this presentation are not descriptions of historical facts regarding Vaccinex, Inc. (“Vaccinex,” “we,” “us,” or “our”), they are forward-looking statements reflecting management’s current beliefs and expectations. Such statements include, but are not limited to, statements about the Company’s plans, expectations and objectives with respect to the results and timing of clinical trials of pepinemab in various indications, the use and potential benefits of pepinemab in Head and Neck cancer, Huntington’s and Alzheimer’s disease and other indications, and other statements identified by words such as “may,” “will,” “appears,” “expect,” “planned,” “anticipate,” “estimate,” “intend,” “hypothesis,” “potential,” “advance,” and similar expressions or their negatives (as well as other words and expressions referencing future events, conditions, or circumstances). Forward-looking statements involve substantial risks and uncertainties that could cause the outcome of the Company’s research and pre-clinical development programs, clinical development programs, future results, performance, or achievements to differ significantly from those expressed or implied by the forward-looking statements. Such risks and uncertainties include, among others, uncertainties inherent in the execution, cost and completion of preclinical and clinical trials, uncertainties related to regulatory approval, the risks related to the Company’s dependence on its lead product candidate pepinemab, the ability to leverage its ActivMAb® platform, the impact of the COVID-19 pandemic, and other matters that could affect the Company’s development plans or the commercial potential of its product candidates. Except as required by law, the Company assumes no obligation to update these forward-looking statements. For a further discussion of these and other factors that could cause future results to differ materially from any forward-looking statement, see the section titled “Risk Factors” in the Company’s periodic reports filed with the Securities and Exchange Commission (“SEC”) and the other risks and uncertainties described in the Company’s most recent year end Annual Report on Form 10-K and subsequent filings with the SEC. This presentation involves discussion of unapproved, experimental or investigational use of pepinemab. SEMA4D signaling pathway regulates cellular morphology, gene expression, and communication in both the immune and nervous systems Mature Dendritic Cell Facilitates interactions with other immune cells: T and B lymphocytes, macrophage, endothelial cells Healthy Astrocyte Reaches out to touch and interact with other brain cells: neurons, microglia, pericytes, endothelial cells Astrocytes in brain and Dendritic Cells in immune tissue express PlexinB1/B2 receptors and change form and function in response to SEMA4D signaling, “SEMA4D Reactive Regulators” Stressed or Damaged NeuronsActivated lymphocytes SEMA4D is expressed by 3 ASTROCYTE FORM and FUNCTION SEMA4D/PLXN signaling regulates astrocyte morphology and metabolic activity PLXNB1 PLXNB2 Blue= anti-PLXN Red= isotype control A B C Evans et al. Journal of Neuroinflammation, (2022) 19:200. 4 SEMA4D signaling through PlexinB1/B2 receptors leads to depolymerization of the actin cytoskeleton and collapse of cytoplasmic projections. Mature Dendritic Cell Facilitates interactions with other immune cells: T and B lymphocytes, macrophage, endothelial cells (Courtesy of Rut Olivar and Josep M. Aran. IDIBELL). U Barcelona Cortadellas N, Fernandez E, Garcia A. Biomedical and Biological Applications of Scanning Electron Microscopy Mature Dendritic Cell Facilitates interactions with other immune cells: T and B lymphocytes, macrophage, endothelial cells Fewer, shorter dendrites limit cell-cell interactions SEMA4D/PlexinB1 signaling promotes morphological and functional change 5 SEMA4D is progressively upregulated with increasing pathologic stage of HD and in AD Evans et al. Journal of Neuroinflammation, (2022) 19:200. A B SEMA4D in HD neurons SEMA4D in AD neurons 6 Pepinemab treatment prevents a chain of pathogenic events downstream of astrocyte reactivity in AD and HD 7 Pepinemab treatment prevents a chain of pathogenic events downstream of astrocyte reactivity that drive disease progression in both AD and HD: ▪ Pepinemab blocks crosstalk between reactive astrocytes and microglia that amplifies glial reactivity leading to inflammation and glial scars. ▪ Pepinemab preserves vascular integrity in brain. ▪ Pepinemab downregulates expression of AD related proteins in CSF: SNAP25 associated with synaptic loss and GAP-43 that promotes tau spreading and accumulation. Synaptic loss and tau spreading are pathologies common to both AD and HD. ▪ Data from randomized Phase 2 studies in HD (n=179) and a recently completed phase 1b/2a study in MCI and mild AD (n=49) suggest that early in disease pepinemab treatment has favorable effects on biomarkers related to disease progression and appears to slow cognitive decline. Clark … and Quintana, Barcoded viral tracing of single-cell interactions in central nervous system inflammation Science 372, 360 UnnecessaryUU ALZHEIMER’S DISEASE Phase 1b/2 Trial Design NCT04381468 Funding by MCI and Mild AD dementia Key eligibility criteria: • CDR-GS = 0.5 or 1.0 • MMSE = 17-26 • Amyloid positive (PET or CSF) N=50 n=24 n=26 Placebo Q4W Pepinemab 40 mg/kg, IV Q4W Objectives: Primary Safety and Tolerability Secondaries • Biomarkers: • Fluid Biomarkers • FDG-PET • Cognitive and Functional measures: Including change in CDR-SB, iADRS, and ADAS-Cog13 Exploratory • Subgroup analysis: including MMSE 22-26 and MMSE 17-21 (MCI or mild dementia) • PK/PD Screening Double-blind Treatment period 48 weeks Safety Follow-up 4 weeks 8 FDG-PET MRI CSF FDG-PET FDG-PET MRI CSF R 1:1 Pepinemab was well-tolerated No discontinuations Pepinemab reduces levels of CSF proteins associated with synaptic loss and tau pathology in patients with AD-related mild dementia NCT04381468 -0.6 -0.4 -0.2 0.0 0.2 0.4 0.6 TNFRSF10C SERPINE1 COMP COL3A1 CD14 IL1R1 CD164 TNFRSF11A CSF1 CD74 LAMP2 IL6ST CTSL OLR1 ITGB5 CXCL13 CXCL1 PDIA3 BCL2 CAMK4 LILRB4 TREM2 MARCO Immune Related Pathways* Mean Change from Baseline LOG2 FOLD CHANGE NPx Placebo Pepinemab * * # * * * p-value: PEPI-PBO t-test (adjusted age, sex) -0.6 -0.4 -0.2 0.0 0.2 0.4 0.6 (YKL40) CHI3L1 SOD1 Total Tau MAPT SPON1 KYAT1 Neurogranin NRGN Neurofilament Light Chain NEFL APOE TREM2 GFAP SNAP25 GAP43 AD-related Biomarkers MMSE 22-26 Mean Change from Baseline LOG 2 FOLD CHANGE NPx p=0.008 p=0.009 p=0.098 p=0.119 p=0.030 p=0.095 Select AD-related biomarkers reported to be elevated in AD cerebrospinal fluid (CSF) are reduced in patients treated with pepinemab. Olink analysis of CSF , change from baseline at 48 weeks in Baseline MMSE 22-26 prespecified subgroup. Olink Explore 5000 panel was performed in collaboration with group of Charlotte Teunissen at UMC, Amsterdam. 9 UnnecessaryUU SEMA4D/PLXNB1 Pathway Regulates a Key Astrocyte Subset, Ast10, Associated with Cognitive Decline 10 bioRxiv preprint doi: https://www.biorxiv.org/content/10.1101/2025.02.24.639868v1 QR code below PLXNB1 and other signaling drives a pathologic astrocyte state contributing to cognitive decline in Alzheimer’s Disease Natacha Comandante-Lou, Tsering Lama, Kevin Chen, Jinglong Zhang, Bin Hu, Shuhui Liu, Sarah Heuer, Kristen J. Brennand, Julie Schneider, Lisa Barnes, Bin Zhang, Minghui Wang, Hongyan Zou, Roland H. Friedel, Yiyi Ma, Tracy Young-Pearse, Aiqun Li, Masashi Fujita, David Bennett, Ya Zhang, Vilas Menon, Hans-Ulrich Klein, Mariko Taga, Philip L. De Jager* *Correspondence: Philip L. De Jager, MD PhD Professor of Neurology and Chief, Division of Neuroimmunology [email protected] Reactive astrocyte signature driven by PLXNB1 correlates with cognitive decline and is reduced by pepinemab treatment • Investigators at Columbia/Mount Sinai (NY)/Harvard/Yale,and Rush University identified a genetic signature for an astrocyte subset termed Ast10 that was quantified in 4 sets of single-nucleus transcriptomic data (snRNAseq) derived from a total of 869 brains. Volunteer donors were also characterized as to amyloid and tau burden and slope of cognitive decline late in life. • Ast10 cells were found to be significantly associated with rapid AD and aging-related cognitive decline. • SEMA4D-PLXNB1 was identified as a top ligand-receptor pair that strongly regulates Ast10 representation in brain increasing frequency from <1% in cognitively normal individuals to as much as 25 to 80% of all astrocytes in AD. In collaboration with Philip De Jager, Columbia University Ast10 Z-score Changed by Treatment Change = week 48 – week 0 Pepinemab Placebo p = 0.0058 NCT04381468 11 → Analysis of Ast10 Ligands represented in SIGNAL-AD Olink CSF data set showed a significant decline with pepinemab treatment: Ast10 correlates with inflammatory and synaptic fluid biomarkers in CSF at Baseline rS = 0.700 p <0.0001 rS = 0.364 p = 0.01 rS = 0.663 p <0.0001 SEMA4D GFAP YKL40 rS = 0.658 p <0.0001 Neurogranin NCT04381468 12 Ast10 CSF Biomarker (pg/ml) Ast10 Z-score derived from Olink proteomics analysis of CSF , collaboration with group of Philip De Jager, Columbia University. Soluble biomarker concentration determined by SIMOA assay of CSF . Ast10 increasingly correlates with NfL, Tau and Aβ during disease progression NCT04381468 13 In collaboration with Philip De Jager, Columbia University 0.020.040.060.08 -2 -1 0 1 2 48 week Ast10 x Aβ 42/40 Aβ42/40 ratio 48 wk Ast10 Z-score 48 wk Placebo at 48 weeks 0.020.040.060.08 -2 -1 0 1 2 Baseline Ast10 x Aβ 42/40 Aβ42/40 ratio wk 0 Ast10 Z-score wk 0 All at Baseline Ast10 Z-score v Biomarker in CSF: Baseline Week 48 PBO Spearman r= p- value # pairs Spearman r= p- value # pairs pTau-181 0.33 * 49 0.83 *** 15 tTau 0.42 ** 48 0.83 *** 15 NfL 0.19 ns 49 0.68 ** 16 Aβ 42/40 ratio -0.29 ns 30 -0.76 ** 14 rS = -0.20 p = 0.12 rS = -0.76 p = 0.002 Ast10 Biomarker worsening Pepinemab treatment disrupts the accumulation of Tau, Aβ and NfL Pepinemab treatment for 48 weeks reduced correlation with Tau and Aβ suggesting that pepinemab disrupts the accumulation of Aβ, Tau and neurodegeneration biomarkers driven by reactive astrocytes. Week 48 Pepi Spearman r= p-value # pairs 0.44 ns 17 0.33 ns 17 0.40 ns 16 -0.057 ns 15 NCT04381468 14 In collaboration with Philip De Jager, Columbia University 0.020.040.060.08 -2 -1 0 1 2 48 week Ast10 x Aβ 42/40 Aβ42/40 ratio 48 wk Ast10 Z-score 48 wk Pepinemab Placebo Ast10 Z-score v Biomarker in CSF: Baseline Week 48 PBO Spearman r= p- value # pairs Spearman r= p- value # pairs pTau-181 0.33 * 49 0.83 *** 15 tTau 0.42 ** 48 0.83 *** 15 NfL 0.19 ns 49 0.68 ** 16 Aβ 42/40 ratio -0.29 ns 30 -0.76 ** 14 rS = -0.76 p = 0.002 rS = -0.057 p = 0.842 0.020.040.060.08 -2 -1 0 1 2 48 week Ast10 x Aβ 42/40 Aβ42/40 ratio 48 wk Ast10 Z-score 48 wk Pepinemab Placebo 0.020.040.060.08 -2 -1 0 1 2 48 week Ast10 x Aβ 42/40 Aβ42/40 ratio 48 wk Ast10 Z-score 48 wk Pepinemab Placebo Ast10 Biomarker worsening Baseline Ast10 correlates with Change in Clinical Outcome Assessments Pepinemab treatment appears to alter trajectory of disease progression driven by Ast10 astrocytes NCT04381468 15 Placebo Pepinemab iADRS ADAS-Cog13CDR-SB rS = 0. 46, p = 0.06 rS = 0. 44, p = 0.05rS = 0. 31, p = 0.26 Ast10 BL Δ COA 48 wks, worsening p=0.169 p= 0.067 p= 0.122 % slowing by pepinemab at week 48 99% 76% 70% NCT04381468 Pepinemab improved assessments of cognition and function in MMSE 22-26 subgroup MMSE 22-26 and MMSE 17-21, prespecified subgroup analysis MMSE 22-26 at baseline MMSE 17-21 at baseline p=0.592 p=0.492 p=0.339 0 12 24 36 48 -1 0 1 2 3 CDR-SB in MMSE 17-21 Weeks of Treatment Change from Baseline 13 11 7 9 8 13 10 11 11 9 worsen 0 12 24 36 48 -20 -15 -10 -5 0 5 iADRS in MMSE 17-21 Weeks of Treatment LS Mean CHG from Baseline (SEM) 13 11 11 9 9 13 12 11 10 9 worsen 0 12 24 36 48 -5 0 5 10 ADAS-Cog13 in MMSE 17-21 Weeks of Treatment Change from Baseline worsen 13 11 11 9 9 13 13 12 11 9 16 Appreciation and Thanks 17 Vaccinex Research and Clinical Development Colleagues SIGNAL-AD study investigators and staff Charlotte Teunissen, et al., UMC, Amsterdam Neuroscience WCG Clinical Services/Statistics Collaborative Initiative Participants, caregivers and their families! Philip De Jager, Natacha Comandante-Lou, et al.

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