Pepinemab, a SEMA4D blocking antibody, is a novel potential treatment for neurodegenerative disease: clinical proof of concept in Phase 2 HD study supports clinical development in and ongoing Phase 1/2 AD study

Pepinemab, a SEMA4D blocking antibody, is a novel potential treatment for neurodegenerative disease: clinical proof of concept in Phase 2 HD study supports clinical development in and ongoing Phase 1/2 AD study

Terrence Fisher, PhD

SVP, Clinical Development

[e-mail]

October 24-27

Boston, MA

Rochester, New York

Disclosures

Terrence Fisher is a full-time employee, officer and shareholder at Vaccinex, Inc.

I will be discussing investigational drug and ongoing clinical trials.

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.

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Astrocytes reach out to touch and interact with other brain cells

Astrocyte "arms" provide essential functional support to neurons.

• Fully cover capillaries and facilitate glucose uptake from circulation

• Cradle synapses and recycle glutamate

• Positioned to couple energy metabolism with neuronal activity

	Pub Med search: "astrocytes & AD"	600
				# of articles
				0
1980	1990	2000	2010	2023
				3

SEMA4D IS OBSERVED TO BE UPREGULATED IN NEURONS DURING DISEASE PROGRESSION

Normal

Alzheimer's Disease

Huntington's Disease

Sema4D

Neuron

(HUC/HUD)

Semaphorin 4D is upregulated in neurons of diseased brains and triggers astrocyte reactivity

Elizabeth E Evans, Vikas Mishra, Crystal Mallow, Elaine Gersz, Leslie Balch, Alan Howell, Ernest S. Smith, Terrence L. Fisher, Maurice Zauderer*

Journal of Neuroinflammation, 2022.

Human autopsy sections of frontal lobe

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SEMA4Dregulatesneuron-astrocytecommunicationandinflammationindiseasedbrain

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HUNTINGTON'S DISEASE

Clinical Trial Design

Orphan Disease and

Fast Track Designations

Cohort B1

Early Manifest ("Mild") HD

n=179

	randomized 1:1	pepinemab
	or
	double-blind
CAG repeat ≥36	placebo
TFC 11-13, DCL 4

Cohort B2

Prodromal HD

n=86

	randomized 1:1	pepinemab
	or
	double-blind
CAG repeat ≥36	placebo
DCL 2 or 3

	Safety
Monthly	Follow-up
1 month
X18 months

	Safety
Monthly	Follow-up
1 month
X18 months

Data Analysis and Study Objectives

Safety and tolerability

Primary Efficacy Outcomes (mITT)

Cognitive Function

CGIC

Key Exploratory and

Biomarker Outcomes Metabolic imaging (FDG-PET) Brain Volume (vMRI)

GFAP

NCT02481674

Photo credit: Brown D . "Former TV reporter campaigns to bring Huntington's disease out of the shadows" Washington Post July 29, 2013

6

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Pepinemab is detected at expected levels in CSF

PK/PD

Most subjects dosed with pepinemab have at least saturating levels (100-300 ng/ml) in

CSF

	1000
PEPI	800
600
ng/ml
400
	200
	0

PEPI

sSEMA4D: PEPI complexes in subjects dosed with pepinemab - suggesting target engagement

sSEMA4D	10	***
6
	8
TOTAL	4
ng/ml	2
	0
	PEPI	PBO

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COGNITIVE ASSESSMENT BATTERY (HD-CAB)

Early Manifest HD: Intent to treat population (mITT)

HD-CAB Composite Index of 6 Cognitive Assessments

	PBO	88	84	82	80	79
	PEPI	90	86	82	80	79
Index	0.2
	Improve
CAB-HD
0.1
in	0.0
baseline
					*p=0.007
from	-0.1
Change		Worsen
	-0.2
		Baseline	Month 2	Month 6	Month 12	Month 17
				Study Months
		Treatment Groups	PBO B1	PEPI B1

HD-CAB Composite Score, MoCA<26

		PBO	36	34	32	33	32
-(Zscore)	0.2	PEPI 36	35	33	32	32
0.1
baseline	0.0	Improve					*p=0.0025
-0.1	Worsen
from	-0.2
Change
-0.3
			0		6	12	18
			BL
					Study Month
	HD-CAB Composite Score, MoCA ≥26
		PBO	50	50	50	47	47
-(Zscore)	0.2	PEPI 53	51	49	48	47
0.1
baseline	0.0	Improve
-0.1	Worsen
from	-0.2
Change
-0.3
			0		6	12	18
			BL

Study Month

8

HD-CAB, Change from Baseline at Month 17

HD-COGNITIVE ASSESSMENT BATTERY (HD-CAB)

Associated with Clinically Meaningful change

	HD-CAB cognitive score correlates with
	Clinical Global Impression of Change (CGIC)
Pepinemab delays disease progression	(CDF Analysis)

		Pepinemab	Proportion
		Placebo					CGIC worsen
								CGIC not worsen
				Cumulative				P=0.017
						HD-CAB, Change from Baseline at Month 17
Study Month
					Early Manifest Cohort B1 treated with Pepinemab

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FDG-PET CORRELATES WITH COGNITIVE FUNCTION

Pre-specified Exploratory Endpoint, Early Manifest cohort

1

2

FDG-PET measures brain metabolic activity.

Decline in FDG-PET is reported to correlate with cognitive impairment in neurodegenerative diseases.

Pepinemab treatment appears to reverse loss of metabolic activity.

Change in FDG-PET at Month 18

Difference (PEPI-PBO) at Month 18

Decline Increase

*p ≤ 0.05

n=31

n=28

Feigin, A et al. Nature Medicine (2022)

SUVR = standardized uptake value ratio

https://doi.org/10.1038/s41591-022-01919-8

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