Verve Therapeutics : Characterization of Guide RNA Site Consistency Across Ancestries and the Potential for Off Target Editing with the Clinical Stage Base Editing Medicine, VERVE 101

Characterization of Guide RNA Site Consistency Across Ancestries and the Potential for Off-Target Editing with the Clinical-Stage Base Editing Medicine, VERVE-101

Joseph Biedenkapp, PhD

Alexandra C Chadwick, Jamie DeNizio, Sara Garcia, Anthony Federico, Manashree Damle, Hui-Ting Hsu, Estela Shabani, Daniel Weiner, Amit V Khera, Joseph Biedenkapp, Sekar Kathiresan, Troy Lister, Andrew M Bellinger

Verve Therapeutics, Boston, MA, USA

Presented at the American Society & Gene and Cell Therapy 27th Annual Meeting 11 May 2024

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Joseph Biedenkapp is an employee and equity holder of Verve Therapeutics.

VERVE-101 is an investigational agent that is not approved for commercial use in any jurisdiction.

This presentation contains "forward-looking statements" within the meaning of the Private Securities Litigation Reform Act of 1995 that involve substantial risks and uncertainties, including statements regarding the potential advantages and therapeutic potential of the Company's programs, including VERVE-101. All statements, other than statements of historical facts, contained in this presentation, including statements regarding the Company's strategy, future operations, future financial position, prospects, plans and objectives of management, are forward- looking statements. The words "anticipate," "believe," "continue," "could," "estimate," "expect," "intend," "may," "plan," "potential," "predict," "project," "should," "target," "will," "would" and similar expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. Any forward-looking statements are based on management's current expectations of future events and are subject to a number of risks and uncertainties that could cause actual results to differ materially and adversely from those set forth in, or implied by, such forward-looking statements. These risks and uncertainties include, but are not limited to, risks associated with the Company's limited operating history; the Company's ability to timely submit and receive approvals of regulatory applications for its product candidates; advance its product candidates in clinical trials; initiate, enroll and complete its ongoing and future clinical trials on the timeline expected or at all; correctly estimate the potential patient population and/or market for the Company's product candidates; replicate in clinical trials positive results found in preclinical studies and/or earlier-stage clinical trials of VERVE-101,VERVE-102 and VERVE- 201; advance the development of its product candidates under the timelines it anticipates in current and future clinical trials; obtain, maintain or protect intellectual property rights related to its product candidates; manage expenses; and raise the substantial additional capital needed to achieve its business objectives. For a discussion of other risks and uncertainties, and other important factors, any of which could cause the Company's actual results to differ from those contained in the forward-looking statements, see the "Risk Factors" section, as well as discussions of potential risks, uncertainties and other important factors, in the Company's most recent filings with the Securities and Exchange Commission and in other filings that the Company makes with the Securities and Exchange Commission in the future. In addition, the forward-looking statements included in this presentation represent the Company's views as of the date hereof and should not be relied upon as representing the Company's views as of any date subsequent to the date hereof. The Company anticipates that subsequent events and developments

will cause the Company's views to change. However, while the Company may elect to update these forward-looking statements at some point in the future, the Company specifically disclaims

any obligation to do so.

Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of death worldwide

	One person
100s of millions	dies every 34 seconds
of people affected	from cardiovascular disease
	in the U.S.1

~800K heart attacks

per year in the U.S.2

Cause: Exposure to blood low- density lipoprotein cholesterol (LDL-C) clogs heart arteries

Solution: keep blood LDL-C as low as possible for as long as possible

3 1. Centers for Disease Control and Prevention, National Center for Health Statistics. About Multiple Cause of Death, 1999-2020. CDC WONDER Online Database website. Atlanta, GA: Centers for Disease Control and Prevention; 2022. Accessed February 21, 2022; 2. Tsao CW et al. Circulation. 2022;145(8):e153-e639.

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Human genetics provides a potential solution: Inactivate PCSK9 to permanently reduce LDL-C

Naturally occurring loss-of-function
	Goal: durable decrease in LDL-C
variants in PCSK9 result in:

• Lifelong LDL-C lowering
• Protection against CV events
• No apparent deleterious effects1,2,3

PCSK9

in blood

Pharmacologic validation of target

4 1. Zhao Z, et al. Am J Hum Genet. 2006;79:514-523; 2. Cohen JC, et al. N Eng J Med. 2006;354:1264-1272; 3. Rao AS, et al. Circ Genom Prec Med. 2018;11(7):e002162. CV, cardiovascular; PCSK9, proprotein convertase subtilisin/kexin type 9

VERVE-101 is an investigational base editing medicine with in vivo LNP delivery designed to inactivate PCSK9

DRUG SUBSTANCESDELIVERY VEHICLE

RNA components encode	+	Lipid nanoparticle (LNP)	=	VERVE-101
base editor and a guide	for delivery to liver cell
targeting PCSK9 gene	includes 4 components
mRNA for adenine		Ionizable amino lipid
base editor (ABE)		DSPC
gRNA localizes editor		Cholesterol
to PCSK9 gene
		PEG

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VERVE-101 targets hepatocytes where it inactivates PCSK9 by unmasking a premature stop codon

apoE

LDLR

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Key questions

How consistently will a gene- targeting therapy work across diverse ancestries?

Are there unintended edits being made at other sites in the genome?

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Consistency in PCSK9 target site indicates potential benefits should apply across diverse ancestries

African/African American

(36,942)

99.99%

Middle Eastern	100%	99.99%	Ashkenazi
(2,405)	(14,426)

		Percent of human genomes
Amish	100%	with identical sequence at	99.98%	European1
(456)	gRNA target site	(608,893)

99.97%

(n=784,318)

South Asian	99.91%	99.98%	East Asian
(42,640)			(21,119)

Admixed American	99.95%	99.98%	Remaining
(27,094)			(30,343)

• PCSK9 gRNA site identical in 99.97% of genomes in gnomAD v4.02
• Consistency >99.9% in each genetically assigned ancestry category

8	Ancestry
(number of genomes)

1. Includes Finnish and non-Finnish European populations; genomes include whole genomes and exomes

2. Chen S, et al. Nature. 2024;625:92-100.

Comprehensive and systematic approach to screen for off-target editing with VERVE-101

Select human cell types for

off-target assessment

Guided by

biodistribution of editing

in animal models

Incorporate diverse cellular contexts and genomic backgrounds

Screen for three types of

off-target edits in human cells

gRNA-dependent:

Unintended edits driven by gRNA pairing with DNA

gRNA-independent:

Nonspecific excess adenine editing of DNA

Structural Variant:

Induced large chromosomal rearrangements

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gRNA, guide RNA

Liver, adrenal, and spleen cells selected for off-target analysis based on biodistribution in non-human primates

On-target editing predominantly occurs in the liver in NHPs treated with VERVE-101

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NHP, non-human primates