VERVE-101 – an investigational singlecourse gene editing medicine targeting
PCSK9 – durably and potently lowers
PCSK9 and LDL-C concentrations innon-human primates
Amit V. Khera MD, MSc
Verve Therapeutics
Paul Dudley White International Scholar Awardee
ATVB Council Outstanding Research Awardee
American Heart Association Scientific Sessions
November 6, 2022
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Forward looking statements
This press release contains “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995 that involve substantial risks anduncertainties, including statements regarding the company’s research and development plans and the potential advantages and therapeutic potential of thecompany’s programs, including VERVE-101. All statements, other than statements of historical facts, contained in this press release, 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 timing of and the company’s ability to submit 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 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 toachieve 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 todiffer from those contained in the forward-looking statements, see the “Risk Factors” section, as well as discussions of potential risks, uncertainties and otherimportant 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 press release represent the company’s views as of the datehereof 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 pointin the future, the company specifically disclaims any obligation to do so.

2Solution to ASCVD revealed by human genetics and pharmacology:
get LDL-C as low as possible for as long as possible

3Unmet need: current chronic care model for ASCVD results inpoor control of cumulative blood LDL-C exposure

Illustrative graphic depicts the journey of a hypothetical patient with familial hypercholesterolemia who began
standard-of-care treatment after suffering a heart attack at age 44
4Single-course treatment for ASCVD could address key unmet need:getting LDL-C as low as possible for as long as possible

Illustrative graphic depicts the journey of a hypothetical patient with familial hypercholesterolemia who began
standard-of-care treatment after suffering a heart attack at age 445

VERVE-101 designed to turn off PCSK9 gene with base editing
to durably lower LDL-C and treat ASCVD

6VERVE-101 precursor study demonstrated potential for
potent hepatic PCSK9 inactivation in non-human primates

4 non-humanprimates treatedwith 3.0 mg/kg ofVERVE-101 precursor

Musunuru et al. | Nature | 2021

~90% reduction
In blood PCSK9 protein

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Having demonstrated proof-of-concept in non-human primates,
4 key questions prior to initiation of a clinical trial
Potency: what degree of liver PCSK9 editing can be achieved?

Durability: what evidence supports potential for permanent effect?

Tolerability: what is the safety profile of VERVE-101 in nonclinical studies?

Biodistribution: Does VERVE-101 edit get transmitted to offspring?

8In non-human primates, a single infusion of VERVE-101 achieved
mean liver PCSK9 editing of 70% at higher dose
Study of 36 Non-human Primates

Efficient Liver PCSK9 editing

GROUP 1

Vehicle control(N = 10)GROUP 2

Intravenousinfusion

VERVE-101
0.75 mg/kg(N = 4)
GROUP 3VERVE-101
1.5 mg/kg(N = 22)9

In non-human primates, a single infusion of VERVE-101 achieved
blood PCSK9 reduced up to 83%*, durable out to 476 days

A subset of animals underwent scheduled necropsy 1 year following dosing* Measured as time-weighted average % change from baseline from days 28 and up to 476 days following dosing.
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In non-human primates, a single infusion of VERVE-101 achieved
blood LDL-C reduced up to 69%*, durable out to 476 days

A subset of animals underwent scheduled necropsy 1 year following dosing* Measured as time-weighted average % change from baseline from days 28 and up to 476 days following dosing.
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In non-human primates dosed with single infusion of VERVE-101,transient impact on alanine aminotransferase (ALT) observed
Vehicle control (N = 10)
VERVE-101 0.75 mg/kg (N = 4)
VERVE-101 1.5 mg/kg (N = 22)

Liver safety monitoring•Maximal ALT and AST concentrations
noted within 48 hours after dosing,with normalization by day 14.

•Normal ALT and AST noted in each of
26 NHPs treated with VERVE-101 oneyear after dosing.

•Normal total bilirubin observed with nochange from baseline.

•Normal liver histopathology one yearafter dosing in subset of 10 treatedUpperunderwent
limit of normal scheduled
NHPs whonecropsy

12In non-human primates dosed with single infusion of VERVE-101,
no impact on total bilirubin observed
Vehicle control (N = 10)
VERVE-101 0.75 mg/kg (N = 4)
VERVE-101 1.5 mg/kg (N = 22)

Liver safety monitoring•

Maximal ALT and AST concentrations
noted within 48 hours after dosing,with normalization by day 14.

•

Normal ALT and AST noted in each of
26 NHPs treated with VERVE-101 oneyear after dosing.

•Normal total bilirubin observed with nochange from baseline.

•Normal liver histopathology one year
after dosing in subset of 10 treated
NHPs who underwent scheduled
necropsy13

In non-human primates dosed with single infusion of VERVE-101,
no impact on fasting glucose observed*

Upper limit of normalVehicle control (N = 10)
VERVE-101 0.75 mg/kg (N = 4)VERVE-101 1.5 mg/kg (N = 22)* No impact of VERVE-101 was observed on additional biomarkers of glucose homeostasis, including fasting insulin and hemoglobin A1c.

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In non-human primates dosed with a single infusion of VERVE-101,
on-target PCSK9 editing occurred mostly in the liver** PCSK9 editing assessed using targeted amplicon sequencing in tissues isolated at scheduled necropsy 1 year after dosing

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In sexually mature male NHPs treated with VERVE-101,
No evidence of PCSK9 editing in sperm
6 NHPs treated with VERVE-101
Mean liver PCSK9 editing 79%

Sequencing of sperm noted
no detectable PCSK9 editing

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F1 progeny study of VERVE-101mu treated female miceProblem Not technically feasible toreliably dissect oocytes fromovarian tissue to assess forgermline editing

Liver PCSK9 editing confirmed inVERVE-101mu treated female dams

Solution Assess editing in offspring of90 female mice treated with
0.1 mg/kg VERVE-101mu
saturating dose56%

Data from 67 out of 90 treated females who became pregnant.
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F1 progeny study of VERVE-101mu treated female mice observes
no evidence of germline transmission of the PCSK9 edit
436 offspring of treated females
No detectable transmission

0 of 436 translates into upperbound of the 95% CI of 0.8%.

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VERVE-101: base editing medicine designed to inactivate PCSK9;
Phase 1 clinical trial underway, interim data expected in 2023
• Mean 83% reduction in blood PCSK9 protein and 69% reduction in LDL-C was observedin NHPs treated with 1.5 mg/kg of VERVE-101, durable out to 476 days
• VERVE-101 was well-tolerated in NHPs, with normal liver function tests andhistopathology 1 year following dosing and no detectable impact on glucose homeostasis• No detectable evidence of germline transmission of PCSK9 edit to offspring in study ofNHPs and a F1 progeny mouse mouse study• The ongoing heart-1 clinical trial is studying VERVE-101 in patients with heterozygous
familial hypercholesterolemia and atherosclerotic cardiovascular disease
Additional details available inpublication online inEfficacy and safety of an investigational single-course CRISPR baseediting therapy targeting PCSK9 in non-human primate and mouse models

https://doi.org/10.1161/CIRCULATIONAHA.122.062132

Richard G. Lee, PhD; Anne Marie Mazzola, MS; Maurine C. Braun, MS;
Colin Platt, PhD; Scott B. Vafai, MD; Sekar Kathiresan, MD; Ellen Rohde, PhD;
Andrew M. Bellinger, MD PhD; Amit V. Khera, MD MSc
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