ESC 2022 Poster: Nomination of VERVE-201 ANGPTL3 Product Candidate

An in vivo CRISPR base editing therapy to inactivate ANGPTL3: nomination of a development candidate for VERVE-201

Amit V. Khera, MD MSc; Richard G. Lee, PhD; Ellen Rohde, PhD; Hari Jayaram, PhD; Sekar Kathiresan, MD; Andrew M. Bellinger, MD PhD

Verve Therapeutics, Cambridge, MA, USA

ESC CONGRESS 2022 BARCELONA / 26 - 29 AUGUST

GOAL	GOAL OF VERVE'S ANGPTL3 PROGRAM: turn off gene (permanently)
in liver with base editing to lower LDL-C and treat ASCVD

2	DELIVERY: Can Verve's proprietary GalNAc lipid
	nanoparticle technology enable efficient delivery
	in both wild-type and HoFH NHP models?

3 POTENCY AND POTENTIAL OFF-TARGET EDITING:

Can chemically modified base editing / gRNA configurations preserve potency while minimizing potential off-target editing?

1x		150	Single
ABE
			course
	mg/dl	100	treatment

Addition of proprietary GalNAc targeting ligand to LNP enables hepatic delivery through ASGPR instead of LDLR

VERVE-201 is designed to inactivate ANGPTL3 in the liver with a precise A-to-Gbase-pair DNA change

Challenge: A standard ABE with ANGPTL3 precursor gRNA identified potential off-target editing at up to 3 sites

Potential solution: Screened >200 rationally engineered and chemically modified ABE / gRNA configurations

EXON 5 EXON 6	INTRON	EXON 7	-C
			50
	sgRNA		LDL
				0
				40	45	50	55	60	65	70
						Age
BASE
EDITING	ANGPTL3
A>G	ANGPTL3						BloodLDL-C
							Blood TG
		in blood

mRNA gRNA GalNAc

GalNAc

mRNA

gRNA

Lipid nanoparticles (LNP)

ABE

sgRNA

gDNA

Exon 5 Exon 6	Intron Exon 7
G T C C A T

	base editing
G T C C GA T	A>G

Key features of ANGPTL3 target DNA site:

•	Precise A-to-G base-pairchange: disrupts splice
	donor site and introduces a downstream
	premature stop codon
•	Site is unique: 23 DNA base pair
	protospacer/PAM sequence not found anywhere
	else in the human genome, expected to minimize
	potential off-target editing
•	Site is consistent: >99.98% of sequenced
	individuals have two ANGPTL3 alleles that
	perfectly match the protospacer/PAM sequence,
	expected to maximize consistency of treatment
	response
•	Silent bystander editing: at the single additional A
	in the editing window-should it occur-does not
	affect protein-coding sequence or ANGPTL3

Adenine Editing (%)

100

80

60

40

20

0

On-targetANGPTL3 editing

Potential off-target

editing at 3 sites

• 600+ candidate sites nominated by ONE-seq

• 600 evaluated using

nom SureSelect screening

eval

assay in adult primary Sure

human hepatocyte cells

• assa

As compared to on-targethum

editing of 82%, potential off-targeting• As c editing at 3 additionaleditisites ranging

from 0.2offto-t7.1%addi from

Data aggregated from 2 representative screening experiments assessing on-targetANGPTL3 editing in adult primary human hepatocytes.

Site selected based on results of screening assays Site selected based on results of screening assays

performed for 29 potential sites in the ANGPTL3 gene. performed for 29 potential sites in the ANGPTL3 gene.

inactivation

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20 2122

X

Chromosomal Location

Data aggregated from 2 representative screening experiments assessing on-targetANGPTL3 editing in adult primary human hepatocytes. As compared to mean editing of 45% with standard ABE and ANGPTL3

BACKGROUND:

1 LIVER SAFETY: Is long-term and potent

ANGPTL3	GalNAc	Asialoglycoprotein	mRNA	gRNA
Receptor (ASGPR)

precursor gRNA, noted editing ranging from 1.6 to 61% with 41 alternate ABE / gRNA configurations.

• Lowering cumulative exposure to low-density

lipoprotein cholesterol (LDL-C) is the primary

treatment for atherosclerotic cardiovascular

disease (ASCVD)

• The majority of patients in the current chronic

care model fail to achieve adequate LDL-C

suppression of ANGPTL3 in NHPs associated with any detectable liver toxicity?

GalNAc LNP ANGPTL3 precursor enables

efficient liver editing in LDLR-deficient*non-human primates

Screening of ABE / guide RNA configurations in vitro	Optimized ABE / gRNA configuration with preserved potency and
Goals: maximize on-target editing, minimize off-target editing	no detectable off-target editing at 3 candidate sites in PHH cells

ANGPTL3 precursor and modified ABE/gRNA configurations assessment in non-human primates

lowering.

• Durable inactivation in the liver of a cholesterol-

raising gene with a one-time therapy offers

potential to address this unmet need.

TWO PATIENT POPULATIONS

WITH HIGH UNMET NEED:

• ASCVD not at LDL-C goal on oral standard of

care (SOC) therapy + PCSK9i: in the ORION-9,

-10, and -11 studies of inclisiran, 32% of patients

did not attain LDL-C <70 mg/dl even on oral

(statin) + PCSK9 siRNA (inclisiran)ev (Wright et

al. 2021)

• Homozygous familial hypercholesterolemia:

In a global registry of HoFH patients, 47% did

ANGPTL3 precursor: potent and durable in NHPs

2-year data: >90%↓ in blood ANGPTL3, >60% liver editing

Blood ANGPTL3 protein	Liver ANGPTL3 editing
96% reduction* from baseline	•	Day 15 biopsy: 61%
ANGPTL3 Precursor	•	Day 730 necropsy: 61%

3.0 mg/kg N = 4

* Measured as time-weighted average % change from baseline from days 28 to 730

*Verve's NHP model of homozygous familial hypercholesterolemia with >90% reduction in liver LDLR protein (Kasiewicz et al., biorXiv, 2021)

Liver ANGPLT3 editing displayed represent values for non-human primates treated with 2 mg/kg of an ANGPTL3 precursor using a standard orGalNAc LNP (N = 3 in each treatment group). Reductions in ANGPTL3 reported as time- weighted average % change from baseline from days 26 to 45.

ditingEdtarget-ffO MMinimizef ##2:Goal

Goal #1: Maximize On-targetANGPTL3 Editing

Data aggregated from 2 representative screening experiments in primary human hepatocytes of a standard ABE and ANGPTL3 precursor gRNA and >50 alternate ABE / gRNA configurations.

Data display mean adenine editing noted at the on-targetANGPTL3 site and 3 potential off-target editing sites assessed using a SureSelect assay of primary

Data display mean adenine editing noted at the on-targetANGPTL3 site and 3 potential off-target editing sites assessed using a SureSelect assay of primary human hepatocytes treated with a standard ABE and ANGPTL3 gRNA, an optimized ABE / gRNA configuration, or untreated cells averaged across two replicates. No detectable differences in editing with the optimized configuration at any of the three potential off-target editing sites versus untreated cells was observed.

Data aggregated across two experiments In non-human primates treated with 2 mg/kg of the ANGPTL3 precursor or modified ABE/cyno surrogate gRNA configurations (N = 3 for each treatment group). Reductions in blood ANGPTL3 assessed 15 days were >90% for 3 of 7 configurations screened.

not attain LDL-C goal even on 5 lipid-lowering

therapies (Tromp et al. 2022)

ANGPTL3 precursor in non-human primates

2-year data: no change from baseline in liver biomarkers detected

GalNAc LNP ANGPTL3 precursor enables similar editing efficiency in wild-type and LDLR-deficient* NHPs

Optimized ANGPTL3 precursor is well-toleratedin NHPs at

a range of doses and potent in reducing blood ANGPTL3 >90%

VERVE-201 ANGPTL3 drug candidate: IND-enablingactivity ongoing,on track for first-in-humantrial initiation in 'H1 2024

Inactivation of ANGPTL3 with a single-course treatment

to lower LDL-C has potential to address unmet need in ASCVD

ANGPTL3 - VALIDATION FROM

HUMAN PHARMACOLOGY

• ASCVD not at LDL-C goal on oral SOC + PCSK9i: LDL-Creduced by 50% with evinacumab in trial of ASCVD patients with LDL-C≥ 70 mg/dl on oral+PCSK9i therapy (Rosenson et al. 2020)
• Homozygous familial hypercholesterolemia: LDL-Creduced by 52% in registrational trial of evinacumab (Evkeeza™) in HoFH patients on maximum lipid-loweringtherapy (Raal et al. 2020)
• Blood ANGPTL3 reduction of ~90% has lowered LDL-Cby ~40% in prior studies of an antisense oligonucleotide or siRNA targeting ANGPTL3

Mean and individual values displayed reflect measurement in each of 4 NHP prior to dosing with an ANGPTL3 precursor at 3 mg/kg and at time of necropsy.

*Verve's NHP model of homozygous familial hypercholesterolemia with >90% reduction in liver LDLR protein (Kasiewicz et al., biorXiv, 2021)

Liver ANGPLT3 editing displayed represent values for wild-type or LDLR-deficientnon-human primates treated with 2 mg/kg of an ANGPTL3precursor (N = 3 in each group). Reductions in ANGPTL3 reported as time-weighted average % change from baseline from days 28 to 90.

In NHPs dosed with 2, 3, or 4 mg/kg of VERVE-201cyno (N = 3 in each dosing group), observed liver ANGPTL3 editing ranging from 54 to 57% and blood ANGPTL3 protein reduction assessed at day 15 ranging from 95 to 98%. Transient increases in ALT and AST resolved by day 7, no change in total bilirubin.

Significant unmet need for

SignificantadditionalunmetLDLneed-C loweringfor in

additional LDL-C loweringonin

ASCVD not at goal oral +

ASCVD not at goal on oral +

PCSK9i therapy & HoFH

PCSK9i therapy & HoFH

Precise A-to-G DNA edit designedPrecisetoAinactivate-to-GDNAliveredit

ANGPTL3designedwithoutto inactivatedouble- liver

strand DNA breaks

ANGPTL3 without double- strand DNA breaks

Durable and potent effect: >90%↓ in ANGPTL3 2 years after single dosing of

ANGPTL3Durableprecursorand potentin NHPeffect: >90%↓ in ANGPTL3 2 years after single dosing of ANGPTL3 precursor in NHP

Safety: No detectable

Safety: No detectablelong-termimpact of long-term impact of

ANGPTL3 suppression on

ANGPTL3 suppression on

liver biomarkers in NHP

liver biomarkers in NHP

Verve's proprietary GalNAc

LNP expected to enableVerve's proprietary GalNAc

efficient liver deliveryLNPinexpectedall to enable patients, includingHoFH

efficient liver delivery in all patients, including HoFH

Chemically modified ABE+gRNA preserves potency while minimizing risk of off-

target modificationsChemicallyin PHH modified

ABE+gRNA preserves potency while minimizing risk of off- target modifications in PHH

HEART ATTACK

Oral Therapy

PCSK9i

VERVE-201

Illustrative graphic of a hypothetical patient with ASCVD and hypercholesterolemia treated with serial

Illustrative graphic of a hypothetical patient with ASCVD and hypercholesterolemia treated with serial addition of lipid-lowering therapies to achieve goal LDL-C after suffering a heart attack at age 44.

ANGPTL3 - VALIDATION FROM HUMAN GENETICS

• Homozygous ANGPTL3 deficiency ('human knockout') individuals with very low LDL- cholesterol and no known adverse effects (Minicocci et al. 2012)
• Heterozygous ANGPTL3 deficiency individuals with lower LDL-Cand resistant to ASCVD (Stitziel et al. 2017)

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 initiation, and timing, of the Company's planned regulatory submissions, future clinical trial, its research and development plans and the potential advantages and therapeutic potential of the Company's programs. 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 timing of and the Company's ability to submit applications for, and obtain and maintain regulatory approvals for, its product candidates; continue to advance its product candidates in clinical trials; initiate and enroll patients in 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 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. 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.