Vaccinex : Corporate Presentation

SEMA4D blocking antibody, pepinemab, is a novel potential treatment for neurodegenerative disease:

clinical proof of concept in Phase 2 HD study supports ongoing clinical development in Phase 1 / 2a AD Study

Terrence Fisher1, E. Evans1, M. Boise1, A. Foster1, V. Mishra1, C. Mallow1, E. Smith1, J. Leonard1, A. Feigin2, E. Siemers3, K. Walters4, E. Sheldon5, R. Turner6, M. Farlow7, A. Porsteinsson8, W. Bond9 , M. Zauderer1.

1 Vaccinex, Inc.; 2 for the Huntington Study Group, and SIGNAL-HD investigators and coordinators; 3 Siemers Integration LLC; 4 for Statistics Collaborative; 5 for JEM Research; 6 for Re-Cognition Health; 7 for Indiana University; 8 for University of Rochester; 9 for Neuropsychiatric Research Center of Southwest Florida

July 31-August 4	Contact: [e-mail]

Poster: 65554

Pepinemab is an antibody that blocks a key driver of

neurodegenerative disease pathology

Alzheimer's Disease: SIGNAL-AD

SEMA4D Blockade Safety and Brain Metabolic Activity in Alzheimer's Disease (AD): A Multi-center, Randomized,

Double-Blind,Placebo-Controlled Safety and Biomarker Study of Pepinemab Anti-SEMA4D Antibody in early-AD

UPDATE from SIGNAL-AD

Phase 1 Safety segment is complete

Mechanism of Action

SEMA4D is upregulated in Alzheimer's Disease (AD) and Huntington's Disease (HD) in response to stress in CNS. SEMA4D signals to receptors on glial cells to trigger reactive inflammation and loss of normal homeostatic functions (Evans et al., J. Neuroinflammation, 2022, In Press)

Antibody blockade of SEMA4D can reduce neuroinflammation, restore normal function of astrocytes and improve synaptic function and behavioral deficits in HD (Feigin et al., Nature Medicine, 2022, In Press) and in a preclinical model of AD.

Phase 1/2a Trial Design

Inclusion Criteria

Phase 1 Safety

Phase 2a: Expansion

	placebo		Monthly	up-
		X12 months
		n=20
			Follow
Mild AD	Randomized 1:1
Double-blind
(CDR=0.5 or 1.0, MMSE 17-26)	pepinemab		40 mg/kg	Safety
			Monthly
	n=4	n=20	X12 months

Site Map

Objectives

Safety and tolerability

Cognitive Function measures

CDR-SB,ADAS-Cog13,

MMSE, CDRS

Biomarker Outcomes

Brain Volume (vMRI),Metabolic imaging

Enrollment in Phase 2 expansion segment is ongoing

• First randomized participant successfully completed study with no safety concerns
• 12 participants randomized to date

Funded in part by the Alzheimer's Drug Discovery Foundation and by a grant from the Alzheimer's Association under its 2020 Part the Cloud Program.

LESSONS LEARNED from SIGNAL-HD

SIGNAL-HD study established safety and proof of concept for pepinemab

✓ Well tolerated

✓ Target engagement and CNS penetration

Clinical Experience

Pepinemab was well tolerated, showed promise of slowing or preventing cognitive decline and a striking increase in brain metabolic activity in most brain regions as measured by FDG-PET in a Phase 2 clinical trial of participants with early HD.

Alzheimer's Disease

Amherst, NY

Rochester, NY

Dent Neurological Research

University of Rochester

Anton Porsteinsson

Horacio Capote

Asa Widman

Shanita Jones

New York, NY

Columbia University Irving

Medical Center

Lawrence Honig

Indianapolis, IN

Katrina Cuasay

Washington, DC

Indiana University SOM

Martin Farlow

Georgetown University

Isabell Mwaura

Fairway, KS

Raymond Turner

Jessica Mallory

University of Kansas Medical Center

Research Institute

Fairfax, VA

Jeffrey Burns

Re-Cognition Health

Ryan Townley

Raymond Turner

Monica Bland

Lady Lake, FL

Stuart, FL

Brain Matters Research-

Charter Research

Satellite Site

Alexander Smirnoff

Mark Brody

San Diego, CA

Jessica Sletten

Jennifer Blasi

Pacific Research Network,

West Palm Beach, FL

Inc

Premiere Research Institute Palm

Stephen Thein

Beach Neurology

Dixie Creager

Fort Myers, FL

Paul Winner

Neuropsychiatric Research

Ashley Poulette

Delray Beach, FL

Center of Southwest Florida

Lake Worth, FL

Wendy Bond

Brain Matters Research

JEM Research Institute

Mark Brody

Mark Goldstein

Jennifer Blasi

Valerie Nevins

1Q, 2022

2Q, 2022

Data Safety Monitoring	First randomized participant
Smith, et.al. Neurobiology of Disease, 73:254-268. 2015
Board meeting	successfully completed study
Complete	with no safety concerns

2H 2023

Topline Data

(FDG-PET)

NCT04381468

SIGNAL-HD study informed study design for SIGNAL-AD

• Patient population: data supports the potential cognitive benefit, particularly in patients with mild cognitive deficits -> Exclude MCI
• KEY Exploratory endpoints: Improved metabolic activity via FDG-PET

FDG-PET CORRELATES WITH COGNITIVE FUNCTION IN AD

Pre-specified Exploratory Endpoint, Early Manifest cohort, HD

The ongoing SIGNAL-AD study is evaluating the safety, tolerability and the effects on cognition and brain metabolism of pepinemab in early AD.

Huntington's Disease

NCT02481674

Early Manifest HD *

COGNITIVE ASSESSMENT BATTERY (HD-CAB)

Co-Primary and pre-specified Exploratory analysis

1 FDG-PET measures brain

50 μm

metabolic activity.

Decline in FDG-PET is

Targeting common pathology in Neurodegeneration

		Data Analysis and Study Objectives
placebo	Monthly
X18 months
n=88	month1	Safety and Tolerability	Key Exploratory and
-up
Randomized 1:1 Double-blind		Biomarker Outcomes
Follow		Brain Volume (vMRI)
		Metabolic imaging (FDG-PET)
	Primary Efficacy Outcomes	PK/PD - target engagement

HD-CAB Index

	PBO	88	84	82	80	79
	PEPI	90	86	82	80	79
Index	0.2
	Improve
CAB	0.1

Two-item HD Cognitive Assessment: Pre-specifiedCo-Primary

LS Mean	One-sided	Favors	Critical
Difference
p-value	Pepinemab	value
Estimate (95% CI)
OTS:
-1.98(-4.00, 0.05)	0.028

2 reported to correlate with cognitive impairment in AD

Pepinemab treatment

Many current intervention strategies

targeting disease-associated biomarkers

have had limited efficacy.

An alternative and

potentially complementary strategy

may target inflammation and underlying

Targeting dysregulated proteins

• AD: antibodies to Aβ, Tau; BACE inhibitors
• HD: gene therapy to reduce mHTT
• Most have not demonstrated significant disease modifying effects in the clinic

Pepinemab: Targets reactive glia

• Neurons under stress upregulate

semaphorin 4D (SEMA4D)

• Astrocytes and microglia express

plexin B1/B2 receptors for

SEMA4D, which triggers activation

and inflammation

• Pepinemab anti-SEMA4D antibody

blocks its activity and the glial cell

activation that contributes to and

pepinemab		Monthly	Safety	(mITT)
	n=91	X18 months
		Cognitive Function	Post-hoc Subgroup Analyses
			CGIC

The Phase 2 double-blind,placebo-controlled SIGNAL trial of pepinemab in patients with early manifest Huntington's disease (HD) has been completed and we believe the program is Phase-3 ready.

-HD
in
baseline	0.0
from	-0.1
ngeCha	Worsen

		Yes	No
		[0.025]
PTAP:
1.43 (-0.37,	3.23)	0.060

HD-CAB Composite Index: Pre-specified Exploratory

While the Phase 2 study did not meet the prespecified primary endpoints, pre-specified exploratory and post-hoc analyses supports

-0.2
Baseline Month 2	Month 6	Month 12	Month 17

LS Mean

One-sided Favors Critical

the potential cognitive benefit of treatment with pepinemab in HD patients, particularly those with mild cognitive deficits:

Study Months

Difference

p-value Pepinemab value

• Highly significant improvement (p=0.007) in the (Huntington's Disease Cognitive Assessment Battery (HD-CAB) Index score
•	Significant benefit in reducing apathy severity (p=0.017, 1-sided)
•

Treatment Groups

PBO B1

PEPI B1

Estimate (95% CI)

0.13 (0.03, 0.23) 0.007 Yes

Yes

Reduced atrophy (p=0.017) in caudate region of striatum

• A striking increase in brain metabolic activity as measured by FDG-PET in most brain regions

Andrew Feigin et al. Nature Medicine, 2022, In Press.

[0.025]

appears to reverse loss of metabolic activity in most brain regions.

*p ≤ 0.05

Placebo, n=31

Pepinemab, n=28

Andrew Feigin et al.

Nature Medicine, 2022, In Press.

disease pathology.

aggravates pathogenesis

* Note 86 subjects with Late Prodromal HD were also included in the study

PEPINEMAB APPEARS TO

DRUG PENETRATION and

SEMA4D regulates Glia activation

Smith, et.al. Neurobiology of Disease, 73:254-268. 2015

SEMA4D IS UPREGULATED IN NEURONS DURING ALZHEIMER'S AND HUNTINGTON'S DISEASE

COGNITIVE ASSESSMENT BATTERY (HD-CAB)

Exploratory and Post-hoc analysis to characterize patient populations

Normal

Alzheimer's Disease Huntington's Disease

Sema4D

Neuron

(HUC/HUD)

1	"Learning effect" is lost when HD
symptoms become manifest
2	Pepinemab treatment restores the
ability to benefit from experience

(ie, to learn)

Potential cognitive benefit of pepinemab is more evident in subjects with greater cognitive deficits at baseline

pepinemab

prodromal

early manifest

placebo

pepinemab

pepinemab

p=0.0025

placebo

REDUCE BRAIN ATROPHY

Volumetric MRI- Boundary Shift Integral Analysis (BSI) Pre-specified Exploratory Endpoint, Early Manifest cohort

Caudate Atrophy (CBSI)

Ventricular Expansion (VBSI)

TARGET ENGAGEMENT

Most subjects dosed with	sSEMA4D complexes
pepinemab have ≥	increase in subjects dosed
saturating levels (100-	with pepinemab - suggesting
300 ng/ml) in CSF	target engagement

Evans et al. Journal of Neuroinflammation, 2022, In Press.

Evans et al. Journal of Neuroinflammation, 2022, In Press.

Human autopsy sections of frontal lobe

Andrew Feigin et al. Nature Medicine, 2022, In Press.

placebo

LS Mean Difference Estimate (95% CI):
CBSI: -1.54(-2.79,-0.29);p = 0.017	VBSI:-2.47(-5.04, 0.10); p = 0.060
	Andrew Feigin et al. Nature Medicine, 2022, In Press.	Andrew Feigin et al. Nature Medicine, 2022, In Press.

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 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 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.