Corporate Overview January 2021 - investor relations
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Corporate Overview
January 2021
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 of 1995. These forward-looking statements include, but are not limited to, express or implied statements regarding Intellia’s beliefs and expectations regarding our: being able to enroll and dose the necessary subjects in our clinical studies for NTLA-2001 for the treatment of transthyretin amyloidosis (“ATTR”), provide timing on the first expected data readout, and successfully secure additional clinical studies authorizations, such as clinical trial applications (“CTA”), in other countries; ability to evaluate NTLA-2001 in a broader ATTR population; plans to submit an investigational new drug (“IND”) application or similar clinical trial application for NTLA-5001, our first T cell receptor (“TCR”)- directed engineered cell therapy development candidate in our acute myeloid leukemia (“AML”) program in mid-2021; expectations of evaluating the safety and activity of NTLA-5001 in patients with persistent or recurrent AML who have previously received first-line therapies; plans to submit an IND or similar clinical trial application for its hereditary angioedema (“HAE”) program in the second half of 2021; plans to nominate at least one additional development candidate in 2021; plans to advance and complete preclinical studies for our programs; development of a proprietary LNP/AAV hybrid delivery system, as well as our modular platform to advance our complex genome editing capabilities, such as gene insertion; further development of our proprietary cell engineering process for multiple sequential editing; presentation of additional data at upcoming scientific conferences, and other preclinical data in 2021; advancement and expansion of our CRISPR/Cas9 technology to develop human therapeutic products, as well as our ability to maintain and expand our related intellectual property portfolio; ability to demonstrate our platform’s modularity and replicate or apply results achieved in preclinical studies, including those in our 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 in AML in particular, using CRISPR/Cas9 technology; ability to optimize the impact of our collaborations on our development programs, including but not limited to our collaborations with Novartis Institutes for BioMedical Research, Inc. (“Novartis”) or Regeneron Pharmaceuticals, Inc. (“Regeneron”), including our co-development programs for hemophilia A and hemophilia B; Regeneron’s ability to successfully co-develop products in the hemophilia A and B programs, and the potential timing and receipt of future milestones and royalties, or profits, as applicable, based on our license, collaboration and, if applicable, co-development agreements with Regeneron and Novartis; and statements regarding the timing of regulatory filings and clinical trial execution, including dosing of patients, regarding our development programs; and the potential commercial opportunities, including value and market, for our product candidates; our expectations regarding our use of capital and other financial results during 2021; and our ability to fund operations for at least the next 24 months. 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 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 related to our ability to protect and maintain our intellectual property position; 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; the risk that any one or more of our product candidates, including those that are co-developed, will not be successfully developed and commercialized; the risk that the results of preclinical studies or clinical studies will not be predictive of future results in connection with future studies; and the risk that our collaborations with Novartis or Regeneron or our other ex vivo 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 those contained in the forward-looking statements, 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 other important factors in Intellia’s other filings with the Securities and Exchange Commission (“SEC”). All information in this presentation is as of the date of the presentation, and Intellia undertakes no duty to update this information unless required by law. 2
Intellia’s Investment Summary
Transforming lives of people with severe diseases
by developing curative genome editing treatments
In Vivo
Ex Vivo
Leading Genome Full-Spectrum Broad Portfolio
Editing Platform Strategy Opportunity
Building differentiated Advancing therapies for Driving pipeline expansion
modular solutions diseases with high unmet need with robust R&D engine
3
Building a Full-Spectrum Genome Editing Company
CRISPR/Cas9
In Vivo Ex Vivo
LNP CELL
CRISPR is CRISPR creates
the therapy RNA
Modular Platform the therapy
Genetic diseases Immuno-oncology
Autoimmune diseases
4 LNP: Lipid Nanoparticle
Development Pipeline Fueled by Robust Research Engine
Candidate IND- Early-stage Late-stage
PROGRAM APPROACH Research Selection PARTNER
Enabling Clinical Clinical
In Vivo: CRISPR is the therapy
LEAD
NTLA-2001:
Knockout *
Transthyretin Amyloidosis
NTLA-2002:
Knockout
Hereditary Angioedema
LEAD
Hemophilia A and B Insertion *
Knockout, Insertion,
Research Programs
Consecutive Edits
Research Programs Various **
Ex Vivo: CRISPR creates the therapy
OTQ923 / HIX763:
HSC ***
Sickle Cell Disease
NTLA-5001:
WT1-TCR
Acute Myeloid Leukemia
Solid Tumors WT1-TCR
Undisclosed Programs Undisclosed
Other Novartis Programs CAR-T, HSC, OSC Undisclosed ***
5 * Lead development and commercial party ** Rights to certain in vivo targets *** Milestones & royalties CAR-T: Chimeric Antigen Receptor T cells HSC: Hematopoietic Stem Cells OSC: Ocular Stem Cells
2020 Key Accomplishments:
Significant Execution Across Pipeline and Platform
Dosed first patient with NTLA-2001, first systemically delivered
CRISPR-based therapeutic
Pipeline
Execution Advanced IND-enabling activities for NTLA-5001 and NTLA-2002
Demonstrated preclinical proof-of-concept for NTLA-5001 and NTLA-2002
Broadened genome editing, delivery and cell engineering capabilities
Platform Expanded Regeneron collaboration to apply targeted insertion technology
Innovation for hemophilia A and B
Demonstrated modularity of insertion technology with two transgenes that
durably produce normal levels of protein in NHPs (Factor 9 and SERPINA1)
6 NHP: Non-Human Primate
2021 Upcoming Milestones:
Ushering in a New Era of Curative Medicines with Nobel Prize-Winning Technology
Clinical o NTLA-2001 for Transthyretin Amyloidosis (ATTR): Continue enrolling
Validation patients in global Phase 1 study to establish optimal dose
o NTLA-5001 for Acute Myeloid Leukemia (AML): Submit IND in mid-2021
Pipeline
Advancement o NTLA-2002 for Hereditary Angioedema (HAE): Submit IND in 2H 2021
o Nominate at least 1 new development candidate in 2021
Platform o Present updates on multiple in vivo targets in the liver and other tissues
Innovation and an allogeneic solution for engineered cell therapies
7 IND: Investigational New Drug or IND-equivalent
In Vivo
CRISPR is the therapy
GENETIC DISEASES
LNP
Strategic Advantages:
RNA
Systemic non-viral delivery of CRISPR/Cas9 provides
transient expression
Potential curative therapy from single course of treatment
Permanent gain of function with targeted gene insertion
Delivery to multiple tissue types enabling new therapeutic
applications
8
Modular Approach to Unlocking Treatment of Genetic Diseases
PROPRIETARY LNP DELIVERY SYSTEM
Transient expression Large cargo capacity Redosing capability
ENABLES MULTIPLE EDITING STRATEGIES
Remove Restore Remove / Restore
KNOCKOUT INSERT CONSECUTIVE EDITING
Knockout toxic or Introduce functional Any combination of knockout
compensatory genes DNA sequence and insertion strategies
+ + +
AAV
9
NTLA-2001 for Transthyretin Amyloidosis (ATTR)
OUR APPROACH KEY ADVANTAGES
ATTR
• Caused by accumulation of Knock out TTR gene with a • Potential to halt and
misfolded transthyretin (TTR) single course of treatment reverse disease
protein, which affects nerves,
heart, kidneys and eyes • Reduce wild-type and • Potential “one-and-done”
• Chronic dosing is required
mutant TTR protein treatment
with current treatments • Aims to address
• Expect lifelong, stable TTR
polyneuropathy and
• 50,000 reduction
hATTR patients worldwide1 cardiomyopathy
• ~200-500K
wtATTR patients worldwide2
10 1 Ann Med. 2015; 47(8): 625–638. 2 Compiled from various sources hATTR: Hereditary ATTR wtATTR: Wild-Type ATTRNTLA-2001 Ongoing Global Phase 1 Study
Two-part, open-label, multi-center study in adults with hATTR with polyneuropathy, with plans
to evaluate in a broader ATTR population of both polyneuropathy and cardiomyopathy patients
PART I PART II
Total Enrollment:
Up to 38 patients, Single-Ascending Dose Single Dose Potential to
age 18 to 80 years Expansion Cohort advance toward
N = Up to 30 subjects* a pivotal trial for
Intervention: N = 8 subjects
Administer optimal dose NTLA-2001 based
Single dose Up to 4 selected from Part I on Phase 1 safety
administered via an dose-escalation Administer optimal dose and efficacy
intravenous (IV) cohorts selected from Part I data
infusion
PRIMARY OBJECTIVES SECONDARY OBJECTIVES
Evaluate safety, tolerability, PK and PD Evaluate efficacy on clinical measures of neurologic function
Measure serum TTR levels Neuropathic impairment endpoints include NIS (Part 1 and 2) and
mNIS+7 (Part 2 only)
*Minimum of 3 subjects per cohort Clinicaltrials.gov ID: NCT04601051
11 NIS: Neuropathy Impairment Score mNIS+7: modified NIS+7 PK: Pharmacokinetics PD: PharmacodynamicsNTLA-2001 Phase 1 Follows Successful Preclinical Proof-of-Concept
Sustained >95% Serum TTR Protein Reduction After a Single Dose in NHPs
Control
Lead LNP:
Dose Level #1 (n=3)
Lead LNP:
Dose Level #2 (n=3)
Therapeutically
relevant serum TTR
knockdown
Single Dose
12NTLA-2001 Holds Promise to Transform the Lives of People with ATTR
Achievements Received regulatory authorizations to initiate
and Next Steps global Phase 1 study
Dosed first patient with NTLA-2001 in Q4 2020
Continue enrolling patients in global Phase 1
study to establish optimal dose
13NTLA-2002 for Hereditary Angioedema (HAE)
OUR APPROACH KEY ADVANTAGES
HAE
• Genetic disease Knock out KLKB1 gene with • Potential “one-and-done”
characterized by recurring,
severe and unpredictable
a single course of treatment treatment
swelling in various parts of • Extensive and continuous
• Reduce kallikrein activity
the body
to prevent attacks reduction in kallikrein
• Chronic dosing is required activity
with current treatments
‒ Minimizes the risk of
• Attacks can occur every breakthrough attacks
7-14 days on average for
untreated patients1 • Potential to eliminate
significant treatment burden
• 1 in 50,000
HAE patients worldwide1
14 1 Zuraw BL. Hereditary angioedema. N Engl J Med. 2008;359:1027-1036Modular Delivery Solution Enables Rapid and Reproducible Path
to Clinical Development
LNP Delivery System:
gRNA Reprograms Genetic Target NTLA-2002 for HAE:
AAAA Builds on ATTR program’s infrastructure,
KLKB1
Cas9 gRNA
including modular LNP delivery system
mRNA
TTR Applies insights gained from ATTR and other
gRNA
research programs to liver knockout target
Target-
specific Platform advances expedite progression to
gRNA NHP proof-of-concept and clinical development
15 gRNA: Guide RNAAchieved Sustained Therapeutically Relevant Kallikrein Activity Reduction
After a Single Dose in NHPs
180 Kallikrein Activity Reduction Control
Plasma Kallikrein Activity (% of Basal)
160 Dose Level #1 (n=3)
140 Dose Level #2 (n=3)
120 Dose Level #3 (n=3)
100
80
60
40
Therapeutically
20 relevant impact
0
on attack rate*
0 4 8 12 16 20 24 28 32 36 40 44 48 52
Time (Weeks)
Single Dose
16 *Banerji et al., NEJM, 2017NTLA-2002 for HAE: Advancing Toward the Clinic
Achievements Achieved year-long therapeutically relevant
and Next Steps kallikrein activity reduction after a single dose in NHPs
Initiated GLP toxicology studies
Submit IND or IND-equivalent in 2H 2021
17Beyond Knockout: Insertion Technology Enables Production of High Levels of
Therapeutic Protein
Precisely Create Deliver Insertion Alpha-1 Antitrypsin Deficiency (AATD)
Insertion Site Template Achieved Normal hAAT Protein Levels in NHPs
22,000
000
Circulating hAAT (µg/ml)
11,500
500
Normal
range1
LNP AAV 11,000
000
Therapeutically
relevant1
Promoter 5 500
00
GOI
GOI
Targeted, Stable Gene Insertion 00
00 33 66 99 112
2
Weeks Post Treatment
Potential best-in-class modality Cohort A (n=3) Cohort B (n=3) Buffer Control
for a gain of function
18 1 Stoller & Aboussouan The Lancet, 2005In Vivo Pipeline Expansion Strategy
Unlocking Full Potential
First Wave of Products
Focused On Targets Across
Multiple Tissues
Genetic Diseases Unlock Liver Targets
Address diseases with genetically Enable access to treat
defined targets in the liver diseases across multiple
• Remove a toxic protein via knockout tissue types
• Restore a functional protein via insertion
AATD, ATTR, HAE, Hem A and B, Bone Marrow, CNS,
PH, Undisclosed Indications Other Tissues
19 PH: Primary Hyperoxaluria CNS: Central Nervous SystemEx Vivo
CRISPR creates the therapy
IMMUNO-ONCOLOGY / AUTOIMMUNE DISEASES
CELL
Strategic 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 improved
safety and efficacy
20Proprietary Engineering Platform to Power Next-Generation Engineered Cell Therapies
CELL ENGINEERING PLATFORM
Highly efficient sequential editing Optimal cell performance Scalable manufacturing process
ENABLES VERSATILE SOLUTIONS BY “MIXING AND MATCHING”
Cell Type Targeting Modality Rewiring Instructions
HSCs, T cells TCRs Immune-enhancing edits
21 NK: Natural Killer TCR: T Cell ReceptorProprietary Cell Engineering Technology Optimizes Cell Health and Function
Platform capability can be applied broadly to various cell types and targeting receptors
Enhanced
EnhancedTT
cell
cell Improved Safety Profile vs.
Expansion
expansion Traditional Multiplex Editing
15
Translocations to other chromosomes
Cumulative Translocation
100 Reciprocal Translocations
Events per 200 Cells
Complex Translocations
Fold Expansion
10
50
5
0 0
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es
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In
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In
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22 Standard Process: Cas9/sgRNA RNP electroporation based on manufacturer’s instructionsNTLA-5001 for Acute Myeloid Leukemia (AML)
OUR APPROACH KEY ADVANTAGES
AML
• Most common acute leukemia Engineer Wilms’ Tumor • Potential to address all
in adults1 Type 1 (WT1)-directed mutational subtypes of AML
TCR-T cells capable of
• ~20K • Low WT1 expression in
New cases in the U.S. in 20201 specifically killing
AML blasts normal tissues for improved
• > 40K safety
New cases in the 7 Major
Markets in 20192 • TCR sourced from healthy
donor T cells minimizes
• < 30% immune toxicity
5-year overall survival1
1 NIH SEER Cancer Stat Facts: Leukemia – Acute Myeloid Leukemia (AML)
23 2 GlobalData EpiCast Report: Acute Myeloid Leukemia July 2020, 7MM: Seven Major Markets (includes U.S.)NTLA-5001: Potential Best-in-Class Engineered T Cell Therapy For AML
WT1-
specific
TCR Inserts a natural, high-avidity TCR to replace
native TCR for upgraded safety profile
‒ Activates both cytotoxic and helper T cells
Specifically targets Wilms’ Tumor 1 (WT1),
an antigen overexpressed in >90% of AML blasts1
‒ Recognizes an epitope (VLD2) presented broadly
by AML blasts with the HLA-A*02:01 allele
Modified by proprietary cell engineering
technology for optimized cell health and function
1Cilloni et al., J Clin Oncol, 2009
2VLD is the WT1(37-45) epitope VLDFAPPGA
24 In collaboration with IRCCS Ospedale San RaffaeleNTLA-5001: Robust Anti-Tumor Efficacy Observed Against Patient-Derived
AML Blasts in Mouse Model
500
No Tretament
Treatment(pAML
(pAMLAlone)
Alone)
MART1-TCR (Control)
400 WT1-TCR
pAML Cells/μL of Blood
300
200
100
T cell infusions
**** NTLA-5001’s
0
0 5 10 15 20 25 30 35 40 45 lead TCR-T cells
Days post AML Infusion
25NTLA-5001: Uniform Expression of Therapeutic TCR for Potent Tumor Targeting
Apheresis & T Cell Thaw and
Cryopreservation Re-infusion
Estimated
vein-to-vein
time of
~3 weeks
Rapid Cell Engineering: 10 Days
Sequential KO of TRAC and TRBC
Insert
tgTCR
THAW ACTIVATE REMOVE INSERT EXPAND HARVEST
T cells T cells endogenous TCR WT1 TCR in locus rapidly and FREEZE
26CRISPR Engineering Overcomes Key Challenges of Traditional TCR Approaches
Traditional tgTCR Addition
Removal of Endogenous TCR
Prevents Mispairing
60
% Cells with Mispaired TCRs
40
Mixed TCRs Heterogenous
Cell Product
20
CRISPR/Cas9 tgTCR Replacement
0
TCR A TCR B TCR C TCR D
TRAC KO Only + Insertion
Intellia’s Approach (TRAC and TRBC KO + Insertion)
tgTCRs only Homogenous
Cell Product
27 tgTCR: transgenic therapeutic TCRNTLA-5001 for AML: Advancing Toward the Clinic
Achievements Demonstrated high anti-tumor activity in preclinical
and Next Steps proof-of-concept models
Completed scale-up for clinical process in Q4 2020
Submit IND or IND-equivalent in mid-2021
28Ex Vivo Pipeline Expansion Strategy
Unlocking Full Potential
First Wave of Products
Focused On Novel Cell Rewiring
for Cancers and
Hematological and Solid Tumors Autoimmune Diseases
Immuno-oncology
Address a variety of cancers Advance cell therapy for cancer
• Target new antigens with TCR and autoimmune diseases
identification and cell engineering platform • Novel immune-enhancing edits
• Allogeneic solution
Prioritize diseases with
AML, Undisclosed Indications
significant unmet need
29Upcoming 2021 Milestones
NTLA-2001
o Continue enrolling patients in global Phase 1 study to identify optimal dose
In Vivo ATTR
NTLA-5001
o Submit IND or IND-equivalent for NTLA-5001 in mid-2021
Ex Vivo AML
NTLA-2002
o Submit IND or IND-equivalent for NTLA-2002 in 2H 2021
In Vivo HAE
R&D o Nominate at least one new development candidate
Advancements o Present preclinical data at scientific conferences
30Intellia’s Pipeline Expansion Strategy Unlocks Full Potential of Genome Editing
Unlocking Full
Potential
First Wave of Products
Focused On Targets Across
Multiple Tissues
Unlock Liver Targets
Genetic Diseases
MODULAR
PLATFORM Novel Cell Rewiring
Hematological for Cancers and
Immuno-oncology and Solid Tumors Autoimmune Diseases
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