Intellia is Leading theGene Editing Revolution
Corporate Overview
October 2024

Intellia Therapeutics’ Legal Disclaimer
This presentation contains “forward-looking statements” of Intellia Therapeutics, Inc. (“Intellia”, “we” or “our”) within the meaning of the Private Securities Litigation Reform Act of1995. These forward-looking statements include, but are not limited to, express or implied statements about Intellia’s beliefs and expectations regarding: our ability to build aworld-class gene editing toolbox to develop an unsurpassed gene editing pipeline; the safety, efficacy and advancement of our clinical programs for NTLA-2001, also known as
nexiguran ziclumeran or “nex-z”, for the treatment of transthyretin (“ATTR”) amyloidosis, NTLA-2002 for the treatment of hereditary angioedema (“HAE”) and NTLA-3001 for thetreatment of alpha-1 antitrypsin deficiency (“AATD”)-associated lung disease pursuant to our clinical trial applications (“CTA”) and investigational new drug (“IND”) submissions,
including the expected timing of data releases, regulatory filings, and the initiation and completion of clinical trials, such as initiating the Phase 3 study for the treatment of ATTR
amyloidosis with polyneuropathy in 2024, presenting updated data from the ongoing Phase 1 study of NTLA-2001 in 2024, presenting additional data from the Phase 2 portion of
the Phase 1/2 study of NTLA-2002 in 2024, and dosing the first patient in the Phase 1 study of NTLA-3001 in 2024; the execution of its strategic priorities for 2024-2026,
including the completion of patient enrollment for pivotal studies of NTLA-2001 and NTLA-2002, the planned BLA submission for NTLA-2002 for HAE in 2026, demonstrating
human proof-of-concept for targeted in vivo gene insertion, initiating clinical development for its allogeneic ex vivo program, demonstrating preclinical proof-of-concept of editingin tissues outside the liver, and advancing DNA writing technology; the ability to generate data to initiate clinical trials and the timing of CTA and IND submissions; theadvancement, expansion and acceleration of our CRISPR/Cas9 technology and related technologies, including DNA writing, base editing, manufacturing and delivery
technologies, to advance and develop additional candidates and treatments; our ability to demonstrate our platform’s modularity and replicate or apply results achieved in
preclinical studies, including those in its NTLA-2001, NTLA-2002 and NTLA-3001 programs, in any future studies, including human clinical trials; our ability to optimize the impactof our collaborations on our development programs, including, but not limited to, collaborations with Regeneron Pharmaceuticals, Inc. (“Regeneron”), including our codevelopment programs for ATTR amyloidosis and hemophilia A, with AvenCell Therapeutics, Inc. (“AvenCell”) for the development of universal CAR-T cell therapies, with
SparingVision SAS (“SparingVision”) for the development of ophthalmic therapies, with ReCode Therapeutics, Inc. (“ReCode”) for the development of novel genomic medicines
for the treatment of cystic fibrosis, with Kyverna Therapeutics, Inc. (“Kyverna”) for the development of KYV-201, and with ONK Therapeutics Ltd. (“ONK”) for the development ofengineered NK cell therapies; the potential commercial opportunities, including value and market, for our product candidates, including the potential of NTLA-2001, NTLA-2002
and NTLA-3001 to be a single-dose treatment, the potential of NTLA-2001 to halt and reverse disease and result in lifelong, stable TTR reduction, the potential of NTLA-2002 toeliminate significant treatment burden; and the potential of NTLA-3001 to achieve normal human levels of alpha-1 antitrypsin protein and halt progression of lung disease; andour use of capital and other financial results.
Any forward-looking statements in this presentation are based on management’s current expectations and beliefs of future events, and are subject to a number of risks anduncertainties 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 related to our ability to protect and maintain our intellectual property position; risks related to valid third party intellectual property; risks related
to our relationship with third parties, including our licensors and licensees; risks related to the ability of our licensors to protect and maintain their intellectual property position;
uncertainties related to regulatory agencies’ evaluation of regulatory filings and other information related to our product candidates; uncertainties related to the authorization,
initiation and conduct of studies and other development requirements for our product candidates, including uncertainties related to regulatory approvals to conduct clinical trials;
risks related to the development and/or commercialization of any of Intellia’s or its collaborators’ product candidates, including that they may not be successfully developed andcommercialized; risks related to the results of preclinical or clinical studies, including that they may not be positive or predictive of future results; risks related to the developmentof novel platform capabilities, including technologies related to editing in tissues outside the liver, base editing and DNA writing; risks related to Intellia’s reliance on
collaborations, including that its collaborations with Regeneron, AvenCell, SparingVision, ReCode, Kyverna, ONK or its other collaborations will not continue or will not be
successful. For a discussion of these and other risks and uncertainties, and other important factors, any of which could cause Intellia’s actual results to differ from thosecontained in the forward-looking statements, see the section entitled “Risk Factors” in Intellia’s most recent Annual Report on Form 10-K and Quarterly Report on Form 10-Q as
well as discussions of potential risks, uncertainties, and other important factors in Intellia’s other filings with the Securities and Exchange Commission. All information in thispresentation is as of the date on its cover page, and Intellia undertakes no duty to update this information unless required by law.

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TABLE OF CONTENTS

1
2
3
4
3

Intellia Investment Overview
In Vivo Portfolio
Ex Vivo Portfolio
AppendixIntellia is Leading a New Era of Medicine
Turning Nobel-Prize-Winning Science into Medicine• Poised to bring first-ever in vivo CRISPR therapy to market• Initiated first-ever, pivotal Phase 3 program for an in vivo CRISPR therapy• Three active Phase 3 studies expected by the end of 2024

Robust pipeline ofin vivo and ex vivo programs

4150+ patients

dosed with Intellia’s
investigational in vivo
CRISPR-based therapies

Comprehensive
gene editing toolbox

Advancing a Full-Spectrum Genome Editing Company
CRISPR-Based
Modular Platform
EMPLOY NOVEL EDITING AND DELIVERY TOOLSIn Vivo

CRISPR is
the therapy
FIX THE TARGET GENE

Genetic diseases

5

Ex Vivo

CRISPR creates
the therapy
REWIRE & REDIRECT CELLS

Immuno-oncology
Autoimmune diseases

Intellia is Developing Potentially Curative Gene Editing
Treatments to Transform the Lives of Patients
Full-Spectrum Strategy
Pipeline of in vivo and ex vivo CRISPR-based therapies
for life-threatening diseases with high unmet need

Clinically Validated Modular Platform
Modular technology enables a reproducible pathto drug discovery and development

Deploying Novel Tools
Continued innovation across editing and delivery
modalities for future therapeutic applications
6

Therapeutic Strategies to Treat Life-Threatening Diseases
Have Advanced Over TimeINNOVATION TIMELINE

Small Molecule Drugs

Biologics

PROTEINS

7

RNAi

RNA

Gene Therapy

DNA

Genome Editing

Gene Editing Starts with CRISPR/Cas9,
a Two-Part, Programmable System
FOUNDATIONAL CRISPR MACHINERYINSIDE CELL
NUCLEUS
Target gene1

Guide RNA (gRNA)

Identifies genetic target

2

Cas Protein

Responsible for thetargeted DNA editing andprovides platform for otherenzymatic activities

KEY FEATURES OF CRISPR/CAS9 SYSTEM
 Selectivity8

 High potency

 Address any site Target multiple DNA sites

CRISPR/Cas9 and Derivative Gene Editing Technologies
Can Be Used to Make Any Type of Edit
INTELLIA’S EDITING TOOLSDERIVATIVETECHNOLOGIES

Base Editor

CRISPR/
Cas9

DNA Writer
Other Technologies

KNOCKOUT

Inactivation/deletion of
disease-causing DNA sequence

INSERT

Insert new DNA sequence tomanufacture therapeutic protein

REPAIR
Correction of “misspelled”
disease-driving DNA sequence

INTELLIA SELECTS THE BEST TOOL FOR EACH THERAPEUTIC APPLICATION
9A Tailored Approach to Maximize the Reach of Gene Editing
Across Multiple Tissues
INTELLIA’S DELIVERY TOOLSLNP:Livertargeted

LNP:
Bone marrowtargeted

TARGET TISSUES*
LNPs are well-suited for delivery
to the liver and blood cells

Liver

AAV

Other
technologies

AAV and other technologies are
well-suited for delivery to other tissues

CNS/PNS

10* This is a representative list of target tissues and does not include all future opportunities.

Bone Marrow

Eye

MuscleCRISPR-Based Editing Technologies are a Promising
New Therapeutic Modality
Potential of CRISPR-Based Editing Technologies

1x
Treat patientsat the root causeof their disease

11

Single dosetreatment with potential
lifelong benefit

Reduce burden
to the healthcare systemover a patient’s lifetime

In Vivo Leader: First to Demonstrate Systemic CRISPR
Gene Editing in Humans

August 5, 2021

12

N Engl J Med 2021; 385:493-502; DOI: 10.1056/NEJMoa2107454
N Engl J Med 2024; 390:432-441; DOI: 10.1056/NEJMoa2309149

January 31, 2024

Intellia’s Strategic Priorities for 2024 – 2026

1 Execute pivotal trials

for first two in vivo
CRISPR-based therapies• Complete patient enrollment
for pivotal studies of
NTLA-2001, now known as
nexiguran ziclumeran(nex-z), and NTLA-2002• Planned BLA submission for
NTLA-2002 for HAE in 2026

13

2

Launch next wave
of in vivo and ex vivo
clinical programs• Demonstrate humanproof-of-concept for targetedin vivo gene insertion• Initiate clinical development
for first allogeneic ex vivo
program

3 Deploy newgene editing anddelivery modalities• Demonstrate preclinicalproof-of-concept ofediting in tissues
outside the liver• Advance DNA writing
technology

Upcoming 2024 Key Clinical Program Milestones
NTLA-2001(nex-z)ATTR

Dose first patient in pivotal Phase 3 MAGNITUDE trial for ATTR-CM in Q1 2024
Continue to open new sites and enroll patients
Initiate a pivotal Phase 3 study for ATTRv-PN by year-end
Present updated data from the ongoing Phase 1 study in 2H 2024

NTLA-2002

HAE

Present updated data from the Phase 1 portion in 2024
Initiate the Phase 3 study in 2H 2024
Present data from the Phase 2 portion in 2H 2024

NTLA-3001

AATD
14Dose first patient in Phase 1 study of NTLA-3001 in 2H 2024

Broad Development Pipeline Fueled by Robust Research Engine
PROGRAMAPPROACH

Research andPreclinical

Early-Stage
ClinicalLate-Stage
ClinicalPARTNERSIn Vivo: CRISPR is the therapy
NTLA-2001 (nexiguran ziclumeran*):Transthyretin Amyloidosis

Knockout

NTLA-2002: Hereditary Angioedema

Knockout

NTLA-3001: AATD-Lung Disease

Insertion

Hemophilia A / B***

Insertion

Research Programs

Knockout,
insertion or repair

Research Programs

Tissues outside
the liver

LEAD

LEAD

**

Ex Vivo: CRISPR creates the therapy
Research Programs

15

Allogeneic and other

Lead refers to lead development and commercial party.
* NTLA-2001 is now known as nexiguran ziclumeran (nex-z)** Intellia is advancing both wholly owned and partnered programs.
*** Hemophilia A program is in the research stage; Hemophilia B is being advanced by Regeneron – Intellia is eligible for milestones and royalties.

**

TABLE OF CONTENTS

1
2
3
4
16

Intellia Investment Overview
In Vivo Portfolio
Ex Vivo Portfolio
AppendixIn Vivo

CRISPR is the therapy
GENETIC DISEASESStrategic Advantages:
Potential curative therapy from a single dose
Systemic non-viral delivery of CRISPR/Cas9 provides
transient expression and potential safety advantages
Potential for permanent gene knockout or gain offunction by targeted insertion
Capable of delivering to multiple tissue types forvarious therapeutic applications
17

LNP

Modular Delivery Platform Enables Rapid and Reproducible
Path to Clinical Development

gRNA identifies
genetic target

LNP Delivery System:

Key Advantages of LNP Delivery• Clinically-proven delivery to liver• Large cargo capacity

TTR
gRNA

• Transient expression• Biodegradable• Low immunogenicity

KLKB1
gRNA

• Well-tolerated• Redosing capability

TargetspecificgRNA• Scalable synthetic manufacturing
AAAA
Cas9
mRNA

18

• Tunable to other tissues

NTLA-2001 (nex-z*) for
Transthyretin (ATTR) Amyloidosis
About ATTR Amyloidosis•

Caused by accumulation of misfolded TTR protein•

Primarily affects the nerves and/or the heart•

Chronic dosing is required with current treatment options

Our Approach
Knock out TTR gene with a single-dose CRISPR-based treatment•

Reduces wild-type and mutant TTR protein•

Aims to address polyneuropathy and cardiomyopathy

Key Advantages Includes Potential to:

19

NANCY
Living with ATTR
amyloidosis withpolyneuropathy•

Halt and reverse disease with deep and consistent TTR reduction•

Be a single-dose treatment•

Expect lifelong, stable TTR reduction* NTLA-2001 is now known as nexiguran ziclumeran (nex-z)

ATTR Amyloidosis:
Large Commercial Opportunity with Significant Unmet Need

NTLA-2001(nex-z)Potential to be thebest-in-class TTR
reduction agent
and only singledose treatment

Prevalence1,2Life
Expectancy3
DiseaseBurden4
Commercial
Opportunity5,6

1 Hawkins et al. Ann Med. 2-15; 47(8): 625–638
2 Compiled from various sources.

3 Luigetti et al. Ther Clin Risk Manag. 2020; 16:109-123

20

4 Griffin et al. JACC 2021; Intellia Patient Survey 2022
5 GlobalData 2023
6 Redbook 2023

50,000~200-500K

ATTRv patients worldwide

ATTRwt patients worldwide

2-7 years

10+ years

after diagnosis for
ATTR-CM patients

after diagnosis for
ATTRv-PN patients

Patients experience highly burdensome symptoms,
including heart failure, shortness of breath, muscle weakness
and sensory deficits$11B+

global market size
expected by 2029

$450K+

average annual cost of TTR
reduction treatment in
the U.S.

NTLA-2001 (nexiguran ziclumeran) Phase 1 Study in ATTR Amyloidosis
Two-part, open-label, multicenter study in adults with hereditary ATTR amyloidosis withpolyneuropathy (ATTRv-PN) or ATTR amyloidosis with cardiomyopathy (ATTR-CM)
PART I: Single-Ascending Dose Escalation

Intervention:
Single-dose
CRISPR/Cas9based gene editing
therapy administered
via an intravenous(IV) infusion

21

ATTRv-PN
patients(n=36)
ATTR-CMpatients(n=36)

0.1 mg/kg (n=3)

PART II: Dose Expansion
55 mg (n=16)

0.3 mg/kg (n=3)

N=15

0.7 mg/kg (n=3)

N=2180 mg (n=5)

1.0 mg/kg (n=6)

N=72

0.7 mg/kg NYHA Class I/II (n=3)

55 mg NYHA Class I/II (n=12)

1.0 mg/kg

N=12

0.7 mg/kg NYHA Class III (n=6)

N=2455 mg NYHA Class III (n=12)

1.0 mg/kg NYHA Class I/II (n=3)

PRIMARY OBJECTIVES
Evaluate safety, tolerability, PK and PD

SECONDARY OBJECTIVES
Evaluate efficacy on clinical measures of: Measure serum TTR levels

Clinicaltrials.gov ID: NCT04601051* NTLA-2001 is now known as nexiguran ziclumeran (nex-z)

Neurologic function in subjects with ATTRv-PN
Cardiac disease in subjects with ATTR-CM

Most Frequent Treatment-Emergent Adverse Events
TEAEs by Maximum Toxicity Grade and Preferred Term Reported in>5% of All ATTRv-PN and ATTR-CM Patients (N=65)

22

AE, Preferred Term, n (%)

Any Grade

Grade 1

Grade 2

Grade ≥3

Infusion-related reaction

25 (38)10 (15)14 (22)1 (2)Headache12 (18)12 (18)

Diarrhea

11 (17)10 (15)Back pain

7 (11)

7 (11)

COVID-19 infection

6 (9)

5 (8)

1 (2)

Cardiac failure

6 (9)

2 (3)

2 (3)

2 (3)

Upper respiratory tract infection

6 (9)

6 (9)

AST increased

5 (8)

3 (5)

1 (2)

1 (2)

Dizziness

5 (8)

5 (8)

Fatigue

5 (8)

5 (8)

Muscle spasms

5 (8)

4 (6)

Vision blurred

5 (8)

5 (8)

Atrial flutter

4 (6)Constipation

4 (6)

2 (3)

Rash

4 (6)

4 (6)

•

This includes all reported
events, including thoseunrelated to NTLA-2001 (nex-z)(e.g., atrial flutter and cardiac
failure hospitalizations)•

Infusion-related reactions weremost common; nearly all wereconsidered mild, and all
resolved without sequelae,
and all patients received thecomplete, planned dose•

Any liver enzyme elevations
resolved spontaneously, wereasymptomatic, and required
no intervention (e.g., steroids)or hospitalization

1 (2)

1 (2)
1 (2)

3 (5)

2 (3)

Data cutoff May 11, 2023.
Patients reporting more than one AE related to NTLA-2001 (nex-z) are counted only once using the maximum toxicity grade. AEs coded to preferred term using
Medical Dictionary for Regulatory Activities (MedDRA), version 23.0 for PN and version 24.0 for CM. Interim data presented are from the initial 65 of 72 patients
dosed. Results from the final 7 patients enrolled after the data cutoff will be reported at a future date.

Regardless of Baseline TTR Levels, NTLA-2001 (nex-z) Led toConsistently Low and Sustained Absolute Serum TTR in All Patients
ATTR-CM

350

NYHA I-II 0.7 mg/kg (N=3)
NYHA III 0.7 mg/kg (N=6)
NYHA I-II 1.0 mg/kg (N=3)
NYHA I-II 55 mg (N=11)
NYHA III 55 mg (N=6)

Baseline IQR:
155 to 234 µg/mL

Serum TTR (µg/mL)
Mean ± SD

250

250

200

150

150

100

50

50

0

1

2

3

4

5

6
7
MonthsMedian (IQR)
Serum TTR at
Day 28 (n=62)

8

9

10

11

12

Baseline IQR:
160 to 300 µg/mL

0.3 mg/kg (N=3)
0.7 mg/kg (N=3)
1.0 mg/kg (N=6)
55 mg (N=16)80 mg (N=5)

200

100

0

23

300

Serum TTR (µg/mL)
Mean ± SD

300

ATTRv-PN

350

0

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24MonthsResidual absolute TTR concentration at day 28

17 µg/mL (11 to 24 µg/mL)% Change from baseline in serum TTR at day 28-91% (-88 to -94%)

Data cutoff May 11, 2023.
Figure notes: Results for each dose level are shown out to the last time point with complete follow-up for the entire cohort. Interim data presented excludes the 0.1 mg/kg cohortfrom the dose-escalation of the polyneuropathy arm. The three patients in the 0.1 mg/kg cohort have been re-dosed at 55 mg and results will be shared in a future presentation.
The 55 mg and 80 mg doses are the fixed doses corresponding to 0.7 mg/kg and 1.0 mg/kg, respectively.

A Phase 3, Randomized, Double-blind, Placebo-controlled Studyto Evaluate NTLA-2001 (nexiguran ziclumeran*) in Patients with
ATTR Amyloidosis with Cardiomyopathy (ATTR-CM)

Randomization
2:1

nexiguran ziclumeran*Single 55 mg IV infusion

N = ~765

24

Primary Endpoint• Composite endpoint of CV-related
mortality and CV-related events

Key Secondary Endpoints

Placebo• Serum TTR• KCCQ-OS score

Key Eligibility Criteria:

Stratification:

Study Duration:• Adult patients with diagnosis of either
hereditary or wild-type ATTR-CM• NYHA Class I – III• NT-proBNP baseline ≥ 1000 pg/mL• NAC stage• TTR genotype:wild-type vs. mutant• Concomitant tafamidis use
vs. no tafamidis• Dependent on occurrence of prespecified number of CV events and aminimum of 18 months follow-up• Majority of patients are expected tohave ≥ 30 months of follow-up for the
primary analysis

Clinicaltrials.gov ID: NCT06128629* NTLA-2001 is now known as nexiguran ziclumeran (nex-z)NTLA-2002 for
Hereditary Angioedema (HAE)
About HAE•

Genetic disease characterized by recurring, severe and unpredictable
swelling in various parts of the body•

Despite availability of existing therapies, significant unmet need persists•

Chronic dosing is required with current treatment options

Our Approach
Knock out KLKB1 gene with a single-dose CRISPR-based treatment•

Reduce kallikrein activity to prevent attacks

Key Advantages Includes Potential to:•

Be a single-dose treatment•

Provide extensive and continuous reduction in kallikrein activity‒

25

DAMIAN
Living with HAE•Intended to minimize the risk of breakthrough attacks

Eliminate significant treatment burden

HAE: Large Commercial Opportunity with Significant Unmet Need

NTLA-2002
Potential to be thebest-in-class HAEprophylaxis agent
and only single-dose
treatment

Prevalence1

150,000+

HAE patients worldwide

Diagnosis2

20 years old

DiseaseBurden350-60%

Commercial
Opportunity4,5

average age of diagnosis

patients continue to have
HAE attacks despite
existing therapies$6B+

global market size
expected by 2029

1 Zuraw BL. Clinical practice. Hereditary angioedema. N Engl J Med. 2008 Sep 4;359(10):1027-36. doi: 10.1056/NEJMcp0803977. PMID: 18768946.
2 Farkas et al. Allergy. 2017. 72;300-313

3 Banjerii et al. Ann Allergy Asthma Immunol. 2020. 124;600-607

26

4 GlobalData 2023
5 Redbook 2023

Symptom onset typicallyoccurs by 12 years old• Attacks can result in
hospitalizations• Patients subject to lifetimeof attack risk and chronic
treatment$500K+

annual U.S. cost of leading
prophylactic treatment

NTLA-2002 Phase 1/2 Trial Design
International, multicenter study to assess safety, tolerability, PK, PD andeffect of NTLA-2002 on attacks in adults with Type I or Type II HAE

Up to 55 patients,
age 18 and older

Intervention:

Single dose
administered via
an intravenous(IV) infusion

KEY ENDPOINTS27

Clinicaltrials.gov ID: NCT05120830

75 mg (n=3)
50 mg (n=4)
25 mg (n=3)

PHASE 2
Expansion study toconfirm recommended dose
Randomized

Total
Enrollment:

PHASE 1Open-Label,
Single-Ascending Dose

50 mg (n=10)
25 mg (n=10)
Placebo arm (n=5)• Evaluate safety and tolerability• Change in plasma kallikrein protein and activity levels• Change in attack rates (Phase 2)

NTLA-2002 Continues to Be Well-Tolerated Across All Dose Levels
25 mg
(n=3)

50 mg
(n=4)

75 mg
(n=3)

All
Patients(N=10)

Any TEAE

3

4

3

10

Infusion-related reaction

2

2

3

7

COVID-19

3

1

2

6

Fatigue132Upper respiratory tract infection

1

1

Myalgia0

Oropharyngeal pain

TEAEs Occurring in ≥2 Patients

28

With a median follow-up time of 20.1 months:•

No treatment-emergent AEs ≥ Grade 3•

No treatment-emergent SAEs

6•

No AESIs other than IRRs

3

5

•

0

3

3

No liver enzyme elevations or platelet countdecreases > Grade 1

2

0

1

3

•

No clinically significant shifts in coagulation
parameters

Abdominal discomfort

0

2

0

2

Headache

0

0

2

2

Viral upper respiratory tract
infection

0

0

2

2

Data cutoff date: 12Feb2024

A Single Dose of NTLA-2002 Continues to Show Dose-Dependent andDurable Reductions in Plasma Kallikrein Protein Over Time
Kallikrein Protein % Change From Baseline(Mean ± SD)

0
-10
-20
-30
-40

-60%

-50
-60

*

-70
-80

*

-90
-100

-88%

0

4

8

12

16

20

24

28

32

-95%

*
36

40

44

48

52

56

60

64

68

72

76

80

Time on Study (Weeks)29

All doses
achieved>60% mean
kallikrein
reduction

Data cutoff date: 12Feb2024.
Baseline value is the average of 2 samples on separate days during the screening period and 1 predose on study Day 1. Only visits completed by all patients within a cohort are presented.
Asterisks indicate the start of additional ongoing follow-up since the previous datacut of 17Feb2023.

84

88

92

A Single Dose of NTLA-2002 Led to a 98% Reduction in HAE Attack Rate,
With 8 of 10 Patients Attack-Free in Post-Primary Observation Period
Administration of

50 mg

75 mg

25 mg

Pt

Mild

Moderate

SevereProphylaxis Withdrawal:

Post-primary Observation Period

Months sincelast attack

13.9

1

1.9

2

14.0

3

2.2

Berotralstat withdrawn, Week 16

26.3

1

16.8

No concomitant prophylaxis

20.4

2

1.9

No concomitant prophylaxis

21.9

3

4.4

Berotralstat withdrawn, Week 13

11.7

1

1.9

2

0.9

No concomitant prophylaxis

18.8

3

0.9

Danazol withdrawn, Week 16

19.0

4

0.9

Danazol withdrawn, Week 16

19.1

Week

30

Attack Severity:

NTLA-2002
Historic
monthly attack
Primaryrate prior to Screening
Observation Period
screening

No concomitant prophylaxis

23.5

Danazol withdrawn, Week 22

18.9

Stanozolol withdrawn, Week 11-8-4Data cutoff date: 12Feb2024.
A month is defined as 28 days.

0

4

8

12

16

20

24

28

32

36

40

44

48

52

56

60

64

68

72

76

80

84

88

92

96

100 104 108

A Phase 3, Randomized, Double-blind, Placebo-Controlled Study to Evaluate theEfficacy and Safety of NTLA-2002 in Patients with Hereditary Angioedema (HAE)
WEEK 28
Primary Analysis

DAY 1
PRIMARYOBSERVATION

Data to support
planned BLA
submission
in 2026

NTLA-2002 (N = 40)
4 – 18 weeks

Optional
BlindedCrossoverR
2:1

Placebo (N = 20)
PRIMARY ENDPOINT:
Time-normalized number ofinvestigator-confirmed HAE attacks overweeks 5 through 28

31

LONG-TERMOBSERVATION

NTLA-2002

Single 50 mg IV infusion

Screening*

WEEK 104* Patients on long-term prophylaxis are required to wash out of therapy prior to the run-in period of screening.

NTLA-2002

NTLA-3001 for Alpha-1 Antitrypsin Deficiency(AATD)-Associated Lung Disease
About AATD•

Genetic disorder leading to progressive lung and/or liver disease1•>60K AATD patients in the U.S.2*•~250K AATD patients globally3*

Our Approach
Targeted insertion of a functional SERPINA1 gene into the albumin locus•

Continuous expression of functional AAT protein at normal levels

Key Advantages•

Designed to be a single-dose treatment•

Aims to achieve normal human levels of AAT protein andhalt progression of lung disease

1 Remih et al. Curr Opin Pharmaco 2021; 59:149-156

32

2 Brantly M. Clin Chem. 2006; 52:2180-2181

3 Blanco et al. Int J Chron Obstruct Pulmon Dis. 2017; 12:561-569* In severe AATD patients defined as individuals with Pi*ZZ genotype.

Durable Production of Physiologic Levels of hAAT Through One Year in NHP
Insertion Platform Enables Targeted, Stable
Gene Insertion in the Albumin Locus

LNP

Deliver Insertion
Template
Circulating hA1AT (µg/mL)
Circulating hAAT (µg/mL)

Precisely Create
Insertion Site

AAV

Promoter
Exon 1

Human AAT (hAAT) Expression

Gene of Interest

Exon 2

2000
2000

Insertion (n=3)
Buffer control (n=3)

1500
1500
Normalrange1

1000
1000
500
500
0

Therapeutically relevant1

00 4
8 12
12 16
16 20
20 24
24 28
28 32
4 8
32 36
36 40
40 44
44 48
48 52
52
Weeks
Post InsertionTime(weekspost insertion)

33

1 Stoller & Aboussouan. The Lancet, 2005

Normal range: ~1000-2700 µg/mL, or 20-53 µM; Therapeutically relevant: 571 µg/mL, or 11 µM
This presentation includes data for an investigational product not yet approved by regulatory authorities.

NTLA-3001 Phase 1/2 Study Design
International, multi-center, open-label study to evaluate NTLA-3001 in adults
with alpha-1 antitrypsin deficiency (AATD)-associated lung disease

Total Enrollment:
Up to 30 patients,
age 18-75 years with
AATD-associatedlung disease

Key Eligibility:•

ZZ or Z/null genotype•< 11 µM AAT
serum concentration•

FEV1 > 35% to < 65%

Intervention:

Singleadministration of
intravenous (IV)AAV and LNP
infusions* Minimum of 3 patients per cohort

PHASE 2
Expansion study

N = Up to 18 patients*

N = ~12 patients

AAV
Dose 1
Dose 2
Dose 3KEY ENDPOINTS34

PHASE 1
Single-Ascending Dose
LNP
Up to
3 doseescalation
cohorts

Fixed
dose(50 mg)• Evaluate safety, tolerability• Measure change in serum AAT levels

Administer dose
selected from Phase I

Significant Opportunities to Unlock Full Potential of In Vivo Platform
CRITERIA USED TO SELECT POTENTIAL FUTURE CANDIDATES:
Unmet need

• Population size

Potential Liver Development Programs*
RARE DISEASES **• Blood disorders• Lysosomal
storage diseases• Metabolic diseases

PREVALENTDISEASES **• Chronic viral diseases• Technical feasibility

Unlocking Full Potential of Genome Editing
TARGET TISSUESBone marrow• Dyslipidemia

CNS/PNS**• Hypertension

Eye***• NASHHeart
Muscle**Lung ****

35* This is a selection of potential liver targets and does not represent all future opportunities.
** Individual targets could be developed by Intellia, Regeneron or through collaborations.
*** In collaboration with SparingVision**** In collaboration with ReCode

Expansion into
tissue-specificdiseasesTABLE OF CONTENTS

1
2
3
4
36

Intellia Investment Overview
In Vivo Portfolio
Ex Vivo Portfolio
AppendixEx Vivo

CRISPR creates the therapy
IMMUNO-ONCOLOGY / AUTOIMMUNE DISEASESStrategic Advantages:
Utilizing proprietary CRISPR engineering platform to create
differentiated cell therapies for IO and AI diseases
Targeting modalities, such as TCR, with broad potential
in multiple indications
Focused on reproducing natural cell physiology for potential
improvements to safety and efficacy in immuno-oncology

37

CELL

Proprietary Engineering Platform to Power Next-Generation Engineered
Cell Therapies
LNP-BASED CELL ENGINEERING PLATFORM
Highly efficient sequential editing

Optimal cell performance

Scalable manufacturing process

ENABLES VERSATILE SOLUTIONS BY “MIXING AND MATCHING,” INCLUDING:

38

Cell Type

Targeting Modality

Rewiring Instructions

HSCs, T cells

TCRs

Immune-enhancing edits

Differentiated Approach to Cell Therapy Genome Engineering
Other Approaches

Gene
Editing
Approach

Key
Questions
From
Preclinical
Data

Delivery

LNP

Electroporation

Electroporation

Editing Mode

Sequential

Simultaneous

Simultaneous

Knockout (KO)

Cleavase or Base Editor

Cleavase

Base Editor

Insertion

CRISPR insertion

Lenti/Retroviruses

Lenti/Retroviruses

Minimize random DSB?
Minimize random insertion?
Minimize genotoxicity risk?

LNP-based,sequential process

39

Precise CRISPR
KOs & insertion(s)Slide based on preclinical data disclosed by Intellia. Intellia’s cell product to be further explored in additional preclinical and clinical studies.

Quality cell productSequential Editing with LNP Approach Minimizes Translocations
While Retaining Robust Cell Viability and Expansion
ddPCR assay todetect TRAC-TRBC
translocations

40

LNP Approach:
Cell Expansion
at D10Three Immune Concerns Must Be Addressed by Allogeneic Cell Therapies
1
1
Patient

TCR
HLA
class I2
Patient
T cells

T cell therapy

Patient NK cell
activation

Low or no
HLA class I
41

T cell receptor (TCR) from allogeneic T cells recognizes
and kills recipient (host) cells.

Largely solved with knockout (KO) of endogenous TCR

2

Rejection via host T cells

3

Rejection via host natural killer (NK) cells

HLA
class II

3

Graft-versus-host disease (GvHD)

Human leukocyte antigen (HLA) molecules must match
between donor and recipient to prevent rejection from:• Host CD8 (HLA class I) T cells• Host CD4 (HLA class II) T cells

NK cells will attack cells that lack HLA-I expressionor have low HLA-I.

No validated solution yet

Intellia’s Differentiated Allogeneic Approach Aims to Address
All Three Immune Concerns
1aIntellia’s Editing Strategy

1bMain Objective of Edit

1a

Knockout endogenous TCR

Prevent Graft-versus-Host
Disease (GvHD)

1b

Insert target CAR or TCR

Direct T cell for tumor killing

2aKnockout HLA Class II

Prevent CD4-mediated rejection

2bKnockout HLA-A only

Prevent CD8-mediated rejection

3

Partial HLA Class I match

Block NK cell activation andavoid NK-mediated rejection

2a

3
2b

Key Potential Advantages
 Approach is applicable to CAR and TCR
 Solves for host NK and T cell rejection
 Avoids long-term immunosuppression
42Realizing the Promiseof Gene Editing
At Intellia, we innovate every day
to make CRISPR-based medicinesa reality for patients.
This is just the beginning of thegene editing revolution.

43

TABLE OF CONTENTS

1
2
3
4
44

Intellia Investment Overview
In Vivo Portfolio
Ex Vivo Portfolio
Appendix

APPENDIX TABLE OF CONTENTS

1
2
3
4
5
6
7
45

Re-dosing with Intellia’s LNP Delivery Platform
Persistence of In Vivo Edits
In Vivo Editing of Hematopoietic Stem Cells
Intellia’s Allogeneic Solution
Platform: Identifying Potent and Highly Specific Guide RNAs
Strategic Collaborations
Abbreviations

Re-dosing with Intellia’s LNP
Delivery Platform

Return to Appendix Table of Contents

Clinical Proof-of-Concept that Redosing with Intellia’s LNP-Delivered Gene
Editing Technology Led to a Targeted Additive Pharmacodynamic EffectInitial Dosing Period

Follow-on Dosing Period
ATTRv-PN

Change from baseline in serum TTR (%)
Mean +/- SE

0

0.1 mg/kg
(N=3)

-10

-52%

-20

0.1 mg/kg + 55mg
(N=3)

-30
-40

Median (IQR)
serum TTR at
day 28

-50
-60

-90%

-95%

-70
-80
-90

-100

47

0

1

2

4

6

9

12

18

Data cutoff April 12, 2024.
This presentation includes data for an investigational product not yet approved by regulatory authorities.

24

Months

0

1

2

4

6

9

0.1 mg/kg(N=3)

130 µg/mL(81 to 133)

0.1 mg/kg+ 55 mg(N=3)

13 µg/mL(9 to 14)

Follow-on Dosing Was Well-Tolerated and Did Not Lead to Any Safety Findings
TEAEs by Maximum Toxicity Grade and Preferred Term Reported
in Patients After Receipt of a Follow-On Dose (n=3)
Preferred Terma, n (%)
Any TEAE

48

0.1 mg/kg + 55 mg(n=3)

Maximum CTCAE
Toxicity Grade•8 – 12 months of follow-up
for patients who received
a follow-on dose•

No clinically significant
changes in liver enzymes,
platelets or coagulation
parameters

2 (67%)

COVID-19

1 (33%)

1

Fatigue

1 (33%)

1

Hand fracture

1 (33%)

1

Headache1 (33%)

1

Infusion-related reaction

1 (33%)

1

Nausea1 (33%)

1

Vulvovaginal candidiasis

1 (33%)

2

Data cutoff April 12, 2024. Note: For each preferred term, patients reporting more than one adverse event are counted only once.
A Grade 1 AE of “Hereditary neuropathic amyloidosis” was reported for one patient at the time of the data cutoff and confirmed to be entered in error.
a Adverse events are coded to preferred term using MedDRA, version 26.0.
This presentation includes data for an investigational product not yet approved by regulatory authorities.

Persistence of In Vivo Edits

Return to Appendix Table of Contents

Protein Reduction Remains Unchanged Following PHx Murine Modelof Liver Regeneration
1500

Control

Serum TTR Levels (µg/mL)

Serum TTR Levels (μg/mL)

KO via CRISPR/Cas9 Gene
Editing

Control

2/3 Liver
Removed

2/3 Liver
Removed

1000

500

0

ay

PH
x

Po
st

17
:P
os
t

Ed
it,

di
t,

Pr
e

PH
x

Ed
it

Po
st
E

0:

D

ay

7:

ay

D

Ed
it,

Po
st

Pr
e

PH
x

PH
x

Pr
e

di
t,

17
:P
os
t

ay

ay

7:

* Similar results obtained for control and LNP when sham surgery was performed.
Next generation sequencing (NGS) analysis to evaluate the frequency of insertion and deletion events (edits)

D

50

Po
st
E

D

ay

0:

Pr
e

Ed
it

Day 0: Day 7:
Day 17:
Day 0: Day 7:
Day 17:
Pre-Edit Post-Edit, Post-Edit, Pre-Edit Post-Edit, Post-Edit,
Pre-PHx Post-PHx
Pre-PHx Post-PHx

Knockout via CRISPR/Cas9 Gene Editing

Gene Insertion Provides a Durability Advantage Over Conventional
AAV Episomes in a PHx Murine Model of Rapid Liver Growth
2/3 Liver
Removed

2/3 Liver
Removed

EpisomeLiver Regrowth

Human FIX (µg/mL)

Liver Regrowth

Post-Dosing
51

Post-PHx

Post-Dosing

Post-PHx

Insertion

In Vivo Editing of
Hematopoietic Stem Cells

Return to Appendix Table of Contents

Editing HSCs In Vivo Requires LNPs with Bone Marrow Tropism
LNPs designed, formulated and tested in vivo to identify
compositions with enhanced delivery to bone marrow and HSCs

Infusionof LNP

Liver-tropic LNPInfusionof LNP

Bone marrow-tropic LNP

53

Editing of Mouse Bone Marrow and HSCs is Durable ThroughAt Least One Year
• Editing was similar across all time points assessed, in both whole bone marrow and HSCs populations• Results highlight the potential for a single-course, long-lasting therapy
Editing Over One Year Period
10

Buffer

E d itin g (% )Whole bone marrow
Hematopoietic stem cells*
5

4

6

4

2

3

5

2
1

1

0

W eeks Post LN P D ose
54* Lin-Sca-1+c-Kit+CD34-Flk2- cell population

Editing of Mouse Bone Marrow and HSCs Increases with Multidosing• Non-immunogenic LNP delivery platform may enable stepwise “treat-to-target” approach60

50

E d itin g (% )40

Whole bone marrow
Hematopoietic stem cells**

30

Level predicted to be
curative for SCD*

20

10

0
1 Dose55* Blood. 2017;130(17):1946-1948** Lin-Sca-1+c-Kit+CD34-Flk2- cell population

2 Doses

3 Doses

4 DosesIntellia’s Allogeneic Solution

Return to Appendix Table of Contents

Immune Concerns Unaddressed by Current Allogeneic Solutions
Intellia’s
Approach

Approach

Employ intense
lymphodepletion
regimen

Knockout (KO)HLA-I (B2M)

Avoid rejection of cell therapy
by host CD8 T cells
Avoid rejection of cell therapy
by host CD4 T cells
Avoid rejection of cell therapy
by host NK cells
Avoid profoundimmunosuppression

57

Slide based on preclinical data disclosed by Intellia. Intellia’s cell product to be further explored in additional preclinical and clinical studies.

KO HLA-I & express
NK inhibitor (HLA-E)

KO HLA-II &partial HLAClass I match

Allo TCR-T Cells Resist NK Cell Killing for at Least 90 Days In Vivo
Mice engrafted withhuman NK cells ormock treated

Luciferase+
T cells
Days 0-90
IVIS imaging to detect
Luciferase+ T cell signal

Allo TCR-T Cells>90% B2M KO T cells killed by NKs within 24h

Minimal Allo T cell rejection in the presence of NK cells

Mock mice
NK engrafted mice

10 8

Mock mice
NK engrafted mice

10 8

Total IVISFlux (p/s)

10 7

10 6
0

10

20

30

40

50

60

Days Post T Cell Injection

58

Signal from Live Allo TCR-T Cells

B2M Knockout T cells

Total IVIS Flux (p/s)

Signal from Live B2M KO T Cells

Day -28

70

80

90

10 7

10 6
0

10

20

30

40

50

60

Days Post T Cell Injection

70

80

90

Platform: Identifying Potent
and Highly Specific Guide RNAs

Return to Appendix Table of ContentsComprehensive gRNA Specificity Assessment: An Off-Target Workflow
1: Discovery of Potential
Off-Target Edits

2: Cell-based Validation of True
Off-Target Edits by Deep Sequencing
Aggregate

Computational
prediction+

SITE-Seq
Genomic
DNA digest+

GUIDE-seq
Cell-based
DNA repair

60

ALL

potential
off-target
genomic loci

Multiplex panel for
NGS

Ex Vivo•

Cell drug product

In Vivo
Targeted Amp-Seq
NGS follow-up•

Edit cells in vitro using
drug product formulation•

Therapeutically relevant
human primary cell type(s)(multiple donors)•

Dose range to exceed
projected therapeutic
exposure (>10X)

Limited Overlap in Discovered Off-Target Loci by Three Leading Methods
1: Discovery of Potential
Off-Target Edits

658 non-overlapping potential off-target loci
SITE-Seq

Computational
prediction+

SITE-Seq
Genomic
DNA digest+

GUIDE-seq
Cell-based
DNA repair

61

Data above is a representative example

AggregateALLpotential
off-target
genomic loci

GUIDE-Seq

Cas-OFFinder

Off-Target Workflow In Practice: Representative Example
1: Discovery of Potential
Off-Target Edits

2: Validation of Off-Target
Edits in Cells
In Vivo Programs
Multiplex panel for
NGS

Targeted Amp-Seq
NGS follow-up• Dose responses using
drug product formulation• Therapeutically relevant
human primary cell type(s)(2 donors)• Dose range to exceed
projected therapeutic
exposure (>10X)• Validation: off-target indels
detected in edited cells

62

Data above is a representative example

Validation of Off-Target Editing in Primary Human Hepatocytes at
Supersaturating LNP CRISPR Concentrations to Maximize Sensitivity

658 potential off-target loci
7 validated off-target (OT) loci

SITE-Seq

2 in introns and 5 in intergenic regions

4 validated OT• SITE-Seq discovered
GUIDE-Seq

3 validated OT

63

Data above is a representative example

Cas-OFFinder

100%• GUIDE-Seq and Cas-OFFinder
discovered the same 3 out of 7
validated off-target loci 43%• Eliminate gRNA with validated offtarget indels in regions of the
genome associated with cancer

In Vitro: No Detectable Off-Target Editing with Pharmacologic
Concentration of sgRNA

Editing frequency (%)

100

EC90

80

On target
Sequence 1
Sequence 2
Sequence 3
Sequence 4
Sequence 5
Sequence 6
Sequence 7

60
40
20
2.5
2.0
1.5
1.0
0.5
0

0.007 0.021 0.063 0.191 0.574 1.724 5.172 15.517

sgRNA concentration (nM)64Strategic Collaborations

Return to Appendix Table of Contents

Growing Intellia’s Impact on Patients Through Strategic Collaborations

66

Genetic diseases

IO (Universal CAR-T)

Ophthalmology

Autoimmune diseases(CD19 CAR-T)

Cystic Fibrosis

IO (NK Cells)

Collaborations Helping to Accelerate the Development of CRISPR-Based
Therapies

Collaboration
Overview:• Up to 15 in vivo targets with a mix of co-developed
and licensed programs– Liver-centric product development• ATTR (in vivo knockout): Intellia is lead party;
Regeneron will share 25% of costs and profits• Hemophilia A (in vivo insertion): Regeneron islead party; Regeneron will share 65% of costs and profits• In vivo targets exclusively developed by Regeneron:– Up to $320M in milestones per target– High single to low double-digit royalties• Non-exclusive license to certain platform IP for up to
10 ex vivo CRISPR products in defined cell types• New research collaboration as of September 2023
to develop treatments for neurological and muscular diseases

67

Click below to learn more
about our other collaborations

Abbreviations

Return to Appendix Table of Contents

Abbreviations
AAT: alpha-1 antitrypsin

GvHD: graft-versus-host disease

NASH: nonalcoholic steatohepatitis

AATD: alpha-antitrypsin deficiency

EC90: concentration inducing 90% of maximal effectnex-z: nexiguran ziclumeran

AAV: adeno-associated virus

FEV1: Forced expiratory volume in 1 second

NHP: non-human primate

AE: adverse event

FOD: follow-on dose

NK: natural killer

AESI: adverse event of special interest

Gr: Grade

NT-proBNP: N-terminal-pro-B-type natriuretic peptide

AI: autoimmune diseasegRNA: guide RNA

NYHA: New York Heart Association

AST: aspartate transaminase

HAE: hereditary angioedema

PD: pharmacodynamics

ATTR amyloidosis: transthyretin amyloidosis

Hem A/B: hemophilia A/B

PHx: partial hepatectomy

ATTRv: hereditary ATTR amyloidosis

HLA-I / II: human leukocyte antigen class I / II

PK: pharmacokinetics

ATTRwt: wild-type ATTR amyloidosis

HLA-E: human leukocyte antigen class E

PNS: peripheral nervous system

ATTR-CM: ATTR amyloidosis with cardiomyopathy

HSC: hematopoietic stem cells

Pt: patient

ATTRv-PN: hereditary ATTR amyloidosis with polyneuropathy IO: immuno-oncology

SAE: serious adverse event

B2M: beta-2-microglobulin

IQR: interquartile range

SE: serious event

BLA: biologics license application

IRR: infusion-related reaction

SCD: sickle cell disease

CAR-T: chimeric antigen receptor T cells

KCCQ-OS: Kansas City Cardiomyopathy Questionnaire-Overall SD: standard deviation
SummarysgRNA: single-guide RNAKLKB1: kallikrein B1
TCR: T cell receptor
LNP: lipid nanoparticle
TEAE: treatment-emergent adverse event
MedDRA: Medical Dictionary for Regulatory Authorities
TTR: transthyretinmRNA: messenger RNA

CNS: central nervous system
CTCAE: Common Terminology Criteria for Adverse Events
CV: cardiovascular
ddPCR: digital droplet polymerase chain reaction

69

DSB: double strand break

NAC: National Amyloidosis Centre