Verve Therapeutics : Proof of concept for in vivo Base Editing to Inactivate the PCSK9 Gene and Lower LDL Cholesterol in Humans

Proof-of-concept for in vivo Base Editing to

Inactivate the PCSK9 Gene and

Lower LDL-Cholesterol in Humans

Sekar Kathiresan, MD

CEO, Verve Therapeutics

Boston, MA, USA

Presented at TIDES USA

May 17, 2024

Forward looking statements and disclaimers

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 Company's ongoing Heart-2 clinical trial; expectations for the Company's Heart-1 trial; the receipt of regulatory clearances and timing of initiating the clinical trial of VERVE-201; the timing and availability of clinical data from the Company's PCSK9 and ANGPTL3 programs; and the Company's strategic plans and prospects. 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.

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Conflict of Interest Declaration

I am an employee of and hold equity in Verve Therapeutics.

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What causes atherosclerotic cardiovascular disease (ASCVD) and

what's a solution?

High cumulative life-long

exposure to blood cholesterol

clogs heart arteries

Cholesterol carried in 3 lipoproteins:

Cholesterol		Triglycerides	Apolipoprotein B Apolipoprotein(a)

4	LDL, low-density lipoprotein; TRL, triglyceride-rich lipoprotein; Lp(a), lipoprotein(a)

What causes atherosclerotic cardiovascular disease (ASCVD) and

what's a solution?

High cumulative life-long	Solution: keep blood
exposure to blood cholesterol	cholesterol as low as possible
clogs heart arteries	for as long as possible

Cholesterol carried in 3 lipoproteins:

Cholesterol		Triglycerides	Apolipoprotein B Apolipoprotein(a)

5	LDL, low-density lipoprotein; TRL, triglyceride-rich lipoprotein; Lp(a), lipoprotein(a)

How is ASCVD treated today and is there an unmet need? Current treatment options lower LDL-Cby about 40% to 60% & intended to be taken lifelong

PCSK9 PCSK9

statin siRNA mAb

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But, up to 50% of patients discontinue CVD medications within 12 months1,2 Unmet need: for many, real-world LDL-Clowering is close to zero

PCSK9 PCSK9

statin siRNA mAb

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2

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About 50% of ASCVD patients not on a statin3

Only about 2% of eligible patients

are currently on a PCSK9 agent4

Only 3% of patients with heterozygous familial hypercholesterolemia

are at LDL-C goal5

7	1. Nelson A et al., Nature Reviews Cardiology 2024. https://doi.org/10.1038/s41569-023-00972-1; 2. Naderi SH et al., Am J Med. 2012;125, 882-887.e1; 3. Nelson AJ et al., J Am Coll Card. 2022;79(18):1802-13; 4. Dayoub EJ et al., J Am Heart Assoc.
2021 May 4; 10(9): e019331; 5. EAS Familial Hypercholesterolaemia Studies Collaboration (FHSC). Lancet. 2021;398(10312):1713-1725

How might we address this unmet need?

A new treatment option: one-time procedure, lifelong cholesterol lowering

Potential for

in vivo

base editor

1

2

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Differentiation:

Single treatment versus chronic care

Goal is broad access for highly prevalent disease

LNP/RNA product now precedented for mass use

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Verve is advancing a pipeline of in vivo gene editing programs designed to lower cholesterol lifelong after a single treatment

TARGET

INDICATION

TECHNOLOGY

DEVELOPMENT STATUS

Research	IND-enabling	Clinical

RIGHTS

	Heterozygous familial
PCSK9	hypercholesterolemia	Base Editor
(VERVE-101)
ASCVD
	Heterozygous familial
PCSK9	hypercholesterolemia	Base Editor
(VERVE-102)
ASCVD
	Homozygous familial
ANGPTL3	hypercholesterolemia	Base Editor
(VERVE-201)	Refractory
	hypercholesterolemia
LPA	ASCVD patients with	Novel Editor
high blood Lp(a)
Undisclosed	Undisclosed ASCVD	Base Editor
Undisclosed	Undisclosed	Novel Editor
liver disease

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Rationale for permanent gene inactivation of PCSK9, ANGPTL3, and LPA

Human Genetics	Pharmacological Validation
People with naturally occurring loss of function	Potent target inhibition and cholesterol lowering
variants are protected from cardiovascular	appears safe in real-world use and/or
disease and otherwise healthy1,2,3,4	third party clinical trials5,6,7

PCSK9

ANGPTL3

LPA

PCSK9

ANGPTL3

LPA

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1. Zhao Z, et al. Am J Hum Genet. 2006; 2. Musunuru K, et al. NEJM. 2010; 3. Stitziel NO, et al. JACC. 2017; 4. Lim ET, et al. PLOS Genet. 2014; 5. O'Donoghue ML et al. Circulation. 2022; 6. Raal FJ, et al. NEJM. 2020; 7. O'Donoghue ML, NEJM. 2022.