Enhanced tgTCR T Cell

Product Attributes Through

Process Improvement of

CRISPR/Cas9 Engineering

23rd Annual Meeting of the American Society

of Gene and Cell Therapy

Aaron Prodeus, Ph.D. | May 12, 2020

Disclosure: Employee of Intellia Therapeutics, Inc.

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This press release contains “forward-looking statements” of Intellia Therapeutics, Inc. (“Intellia” or the “Company”) within the meaning of the Private Securities Litigation ReformAct of 1995. These forward-looking statements include, but are not limited to, express or implied statements regarding Intellia’s beliefs and expectations regarding its: plannedsubmission of an investigational new drug (“IND”) application or similar clinical trial application for NTLA-2001 for the treatment of transthyretin amyloidosis (“ATTR”) in mid-2020 and its planned dosing of first patients in the second half of 2020; plans to submit an IND application for NTLA-5001, its first T cell receptor (“TCR”)-directed engineeredcell therapy development candidate for its acute myeloid leukemia (“AML”) program in the first half of 2021; plans to submit an IND or similar clinical trial application for itshereditary angioedema (“HAE”) program in the second half of 2021; plans to advance and complete preclinical studies, including non-human primate studies for its ATTRprogram and HAE programs, and other animal studies supporting other in vivo and ex vivo programs; development of a proprietary LNP/AAV hybrid delivery system, as well asits modular platform to advance its complex genome editing capabilities, such as gene insertion; presentation of additional data at upcoming scientific conferences, and otherpreclinical data in 2020; advancement and expansion of its CRISPR/Cas9 technology to develop human therapeutic products, as well as its ability to maintain and expand itsrelated intellectual property portfolio; ability to demonstrate its platform’s modularity and replicate or apply results achieved in preclinical studies, including those in its ATTR,AML, and HAE programs, in any future studies, including human clinical trials; ability to develop other in vivo or ex vivo cell therapeutics of all types, and those targeting WT1 inAML in particular, using CRISPR/Cas9 technology; ability to optimize the impact of its collaborations on its development programs, including but not limited to its collaborationswith Novartis or Regeneron Pharmaceuticals, Inc., and Regeneron’s ability to enter into a co-development and co-promotion agreement for the HAE program; statementsregarding the timing of regulatory filings regarding its development programs.

Any forward-looking statements in this press release 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 anduncertainties include, but are not limited to: risks related to Intellia’s ability to protect and maintain its intellectual property position; risks related to Intellia’s relationship with thirdparties, including its licensors and licensees; risks related to the ability of its licensors to protect and maintain their intellectual property position; uncertainties related to theinitiation and conduct of studies and other development requirements for its product candidates; the risk that any one or more of Intellia’s product candidates will not besuccessfully developed and commercialized; the risk that the results of preclinical studies or clinical studies will not be predictive of future results in connection with futurestudies; and the risk that Intellia’s collaborations with Novartis or Regeneron or its other ex vivo collaborations will not continue or will not be successful. For a discussion ofthese and other risks and uncertainties, and other important factors, any of which could cause Intellia’s actual results to differ from those contained in the forward-lookingstatements, see the section entitled “Risk Factors” in Intellia’s most recent annual report on Form 10-K as well as discussions of potential risks, uncertainties, and otherimportant factors in Intellia’s other filings with the Securities and Exchange Commission. All information in this presentation is as of the date of the release, and Intelliaundertakes no duty to update this information unless required by law.

Intellia Therapeutics’ Legal Disclaimer

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CRISPR/Cas9 Genome Editing Can Power Next-Generation T Cell Therapies

Today’s Presentation

Intellia’s

approach

and goals

Overcoming

limitations of

standard

electroporation

methods

Enabling

sequential edits

for safe and

effective

T cell therapies

1 2 3

Intellia’s

proprietary

process shows

promise to

engineer safe

and potent

CRISPR/Cas9-

based T cell

therapies with

multiple

genome edits

To unlock the

full potential of

T cell therapies,

we need to

enable multiple

edits with high

efficiency and

cell viability

but low

translocations

4

Our Goal: Engineer TCR-T Cell Therapies While Preserving Normal Cell Physiology

NTLA-5001 for the Treatment of AML

• Lead engineered cell therapy development candidate

• WT1 (Wilms’ Tumor 1) targeting TCR-T cell therapy:

- High avidity αβ-TCR

- In locus insertion (TRAC)

- TRBC KO

PRECISE • POTENT • PERSISTENT

GvHD: Graft-Versus-Host Disease

WT1-

specific

TCR

KO: Knockout 1Provasi, Genovese et al., Nature Medicine 20122Mastaglio et al., Blood 2017

CRISPR-Based Gene Engineering

• Overcomes key challenges of traditional TCR approaches

• Enables precise gene KO and insertion

• Replaces endogenous with therapeutic TCR1,2:

- Enhances TCR expression and function

- Reduces mispairing and GvHD risk

- Improves cell drug quality and potency

TCR: T Cell Receptor

AML: Acute Myeloid Leukemia

Proprietary Process Yields High Editing Rates

While Maintaining Normal T Cell Physiology

6

Improved T Cell Expansion and Memory Phenotype with Proprietary Process

Une

dite

d

Sta

ndar

d

Pro

prieta

ry

Sta

ndar

d

0

50

100

150

Fo

ld E

xp

an

sio

n

Day 10 Day 14

p<0.01

Une

dite

d

Sta

ndar

d

Pro

prieta

ry

0

20

40

60

80

% W

T1 T

CR

Insert

ion

(Vb

8+

CD

3+

)

CD8+ tgTCR+

CD4+ tgTCR+

CD

27

CD45RA

Standard Process

Proprietary Process

Proprietary process yields:

• More rapid expansion post-editing

• Favorable CD45RA+CD27+ memory phenotype

• Comparable editing rates

Standard Process: Cas9/sgRNA RNP electroporation based on manufacturer’s instructions

Expansion Post-Editing WT1 tgTCR Insertion Rates

7

WT1 TCR-T Cells Engineered with Proprietary Process Have Enhanced Potency

IL-2 Secretion: WT1-VLD

Peptide Pulsed OCI-AML3

Re-stimulation Stress Test:

OCI-AML3 pulsed cells

0.05 0.5 5 50 500 5000

0

2000

4000

6000

WT1-VLD peptide (nM)

IL-2

(pg

/ml)

Standard

Proprietary

0 1.25 2.5 5

0

2000

4000

6000

Effector/Target

IFN

(pg

/ml)

Proprietary

Standard

IFN-γ Secretion:

K562-HLA-A*02:01+ Cells

WT1 TCR-T cells engineered with proprietary process:

• Secrete more cytokines in response to WT1-presenting tumor cell lines

• Have long-term proliferative capacity in a repeat-stimulation assay with tumor cells

0 5 10 15 20

0

50

100

150

Day

Fold

Expansio

n

OCI-AML3+VLD

Proprietary Process

Standard Process

120 fold expansion

27 fold expansion

-

-

8

WT1 TCR-T Cells Generated Using Proprietary Method Suppress Tumor Growth and Prolong Survival in a Disseminated Leukemia Model

0 3 6 9 12 15 18 21 24105

106

107

108

109

1010

1011

1012

Days

Tota

l Flu

x (

p/s

)

T-cellinfusion

* * * **

WT1 TCR-T cells

GFP ctrl T cells

697 ALL cell line expresses endogenous levels of WT1 and is HLA-A*02:01+

ALL: Acute Lymphocytic Leukemia

0 10 20 30

0

20

40

60

80

100

Days

Perc

ent surv

ival

p<0.01

*p<0.05

NOG-IL2 mice, n=7

Proprietary Process Enables Sequential

Editing to Reduce Translocation Rates

10

Improved Expansion Post-Editing Enables Sequential Editing of TRBC and TRAC

TCR Replacement

0. Thaw T cells

DAY 0

1a. Activate

1b. TRBC KO

Harvest and

quality control• Count

• Cryopreserve

• Characterize

TRBC

DAY 1 DAY 10DAY 3

3a. TRAC insertion

3b. AAV6 WT1 TCR

DAY 4

4. Rapid expansion

TRBC

Exon 1 Exon 2

TRBCExon 1 Exon 2

CRISPR/Cas9 for TRBC1/2 KO

TRACTCRβ TCRα Exon 2

TRACExon 1 Exon 2

AAV

TCRβHA

2A TCRα

HA

Insertion Template

Exon1

ST

OP

In locus insertion

EF

1α

EF

1a

CRISPR/Cas9 for tgTCR insertion in TRAC locus

tgTCR: Transgenic TCR

11

Une

dite

d

Sim

ulta

neou

s

Seq

uent

ial

0

1

2

3

%T

RB

C-T

RA

C t

ranslo

cate

d c

ells

Une

dite

d

Sim

ulta

neou

s

Seq

uent

ial

0.0

0.5

1.0

1.5

2.0

%T

RB

C-T

RA

C t

ranslo

cate

d c

ells

Proprietary Process Enables Sequential Editing Strategies to Reduce Translocations

TRBC locusTRAC locusTRAC locusTRBC locus

Sequential editing of TRAC and TRBC results in:

• High cell expansion

• High endogenous TCR KO (~99%)

• High insertion rates (>50%)

• 4- to 8-fold reduction in TRAC-TRBC translocations

Fold

Expansion

% WT1 TCR

Insertion

ddPCR assay to detect TRAC-TRBC translocations

p<0.05p<0.05

Endogenous

TCR KO

Une

dite

d

Sim

ulta

neou

s

Seq

uent

ial

0

50

100

150

Fold

Expansio

nUne

dite

d

Sim

ulta

neou

s

Seq

uent

ial

0

20

40

60

80

% W

T1

TC

R in

se

rtio

n (

CD

3+

Vb8

+)

Une

dite

d

Sim

ulta

neou

s

Seq

uent

ial

0

1

2

50

100

% e

ngode

nous T

CR

(C

D3

+V

b8-)

99% endogenous

TCR removal

p=0.07

12

Proprietary Process Enables Multiple Sequential Edits With Minimal Translocations

KromaTiD dGHTM Assay Shows

Reduced Translocation Rates With Sequential Editing

Une

dite

d

Stand

ard

Simulta

neou

s

Seque

ntia

l

0

5

10

15

Cum

ula

tive T

ranslo

cation

Events

per

200 C

ells Complex Translocations

Reciprocal Translocations

Translocations to other chromosomes

Efficient sequential editing strategy supports development of:

• TCR-T cell therapies like NTLA-5001 that require multiple edits

• Advanced cell therapies that require even more edits, such as allogeneic T cells

PROPRIETARY

PROCESSPROPRIETARY

PROCESS

>97% Editing Across Three Genes

Une

dite

d

Stand

ard

Simulta

enou

s

Seque

ntia

l

0

25

50

75

100

%E

ditin

g

B2M

CIITA

TRAC

13

Key

Takeaways

13

Proprietary process enables efficient, scalable genome editing

of T cells with high viability

– High KO efficiency of target genes (>98%)

– 50-70% in locus insertion of tgTCRs

– Faster and higher T cell expansion for reduced vein-to-vein times

– Improved T cell memory phenotype and increased T cell functionality

Intellia’s T cell engineering platform powered by proprietary

process unlocks full potential of CRISPR/Cas9

– Supports development of NTLA-5001, with IND or IND-equivalent

planned for 1H 2021

– Potential for safer T cell product developed utilizing sequential editing,

with minimized chromosomal translocations

– Future potential development of allogeneic TCR and CAR-T cells

requiring multiple KOs and insertions

– Lays the groundwork for T cell candidates engineered to

overcome immune suppression in solid tumors

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Acknowledgements

• Chiara Bonini

• Eliana Ruggiero

• Erica Carnevale

• Claudia Politano

• Zulma Magnani

• Lorena Stasi

• Barbara Camisa

• Beatrice Cianciotti

• Alessia Potenza

• Francesco Manfredi

• Paola Vella

• Fabio Ciceri

Intellia’s Cell Therapy Team(AML World Awareness Day 2019)