Intellia Therapeutics: First-Time Clinical Stage Biotech With 3 Realistic Candidates, 30% Upside

Contra Biotech Review
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Summary

  • Intellia Therapeutics, Inc. (NASDAQ: NTLA) is a preclinical-stage genome editing company focusing on developing novel therapeutics using the genome-editing process known as CRISPR/Cas9.
  • Intellia has a pipeline of four therapies in the post-research phase with three realistically expected to show clinical aspirations before year-end 2021 targeting ATTR, HAE, and AML.
  • Intellia is forecasted for both an EV/Revenue multiple expansion from 15.84x (Sep 2020) to 22.6x (Dec. 2020) and an FYE revenue growth target of $61 million (+41% y/y).
  • Intellia's first proprietary in vivo development candidate (CTA filed Aug 2020) aims to treat ATTR by reducing the level of transthyretin protein production with a single course of treatment with life-long suppression for both hereditary and wild-type with a global patient population as high as 500,000.
  • In summary, with three promising therapeutic candidates taking NTLA clinical by FYE 2021, 2+ years of cash, and advanced synergies within drug-development using CRISPR/Cas9, NTLA is a "buy" at a 2020 FYE price target of $30.55 (+30% upside).

Intellia Therapeutics Corporate Overview August 2020 2 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 its: receiving authorization to initiate clinical studies for NTLA-2001 for the treatment of transthyretin amyloidosis (“ATTR”) pursuant to its clinical trial application (“CTA”) or similar regulatory applications, and plans to dose the first patients with by year end 2020; plans to submit an investigational new drug (“IND”) application or similar clinical trial application for NTLA-5001, its first T cell receptor (“TCR”)-directed engineered cell 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 its hereditary angioedema (“HAE”) program in the second half of 2021; plans to advance and complete preclinical studies, including non-human primate studies for its HAE and other programs, and other animal studies supporting other in vivo and ex vivo programs, including its AML program; development of a proprietary LNP/AAV hybrid delivery system, as well as its modular platform to advance its complex genome editing capabilities, such as gene insertion; further development of its proprietary cell engineering process for multiple sequential editing; presentation of additional data at upcoming scientific conferences, and other preclinical 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 its related 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 in AML in particular, using CRISPR/Cas9 technology; ability to optimize the impact of its collaborations on its development programs, including but not limited to its collaborations with Novartis Institutes for BioMedical Research, Inc. (“Novartis”) or Regeneron Pharmaceuticals, Inc. (“Regeneron”), including its 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 Intellia’s collaboration and co-development agreements with Regeneron and Novartis; and statements regarding the timing of regulatory filings and clinical trial execution, including dosing of patients, regarding its 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 2020; and our ability to fund operations at least through 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 Intellia’s ability to protect and maintain its intellectual property position; risks related to Intellia’s relationship with third parties, including its licensors and licensees; risks related to the ability of its licensors to protect and maintain their intellectual property position; uncertainties related to regulatory agencies’ evaluation of regulatory filings and other information related to its product candidates; uncertainties related to the authorization, initiation and conduct of studies and other development requirements for its product candidates; the risk that any one or more of Intellia’s 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 Intellia’s collaborations with Novartis or Regeneron or its 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. 3 Our Mission Developing curative genome editing treatments that can positively transform the lives of people living with severe and life-threatening diseases 4 Modular Platform Drives Diversified Pipeline Full-Spectrum Genome Editing Company CORPORATE • Experienced management team • Well capitalized to drive pipeline forward PIPELINE • NTLA-2001 for ATTR: Submitted first CTA to initiate Phase 1 study; Intend to dose first patient by YE 2020 • NTLA-5001 for AML: Expect to submit IND in 1H 2021 for WT1-directed TCR T cell therapy • NTLA-2002 for HAE: Expect to submit IND in 2H 2021 PLATFORM • Rapid identification of development candidates • Precise knockout and/or insertion in vivo and ex vivo • Transient Cas9 expression via non-viral delivery ATTR: Transthyretin Amyloidosis AML: Acute Myeloid Leukemia HAE: Hereditary Angioedema 4 IND: Investigational New Drug or IND-equivalent WT1: Wilms’ Tumor 1 TCR: T Cell Receptor 5 Building a Full-Spectrum Genome Editing Company CRISPR creates the therapy CRISPR is the therapy Immuno-oncology Autoimmune diseases Genetic diseases Modular Platform LNP CELL RNA CRISPR/Cas9 In Vivo Ex Vivo LNP: Lipid Nanoparticle 6 CRISPR/Cas9 is an Effective Tool for Modifying the Genome KNOCKOUT Inactivation/deletion of disease-causing DNA sequence Insert new DNA sequence to manufacture therapeutic protein Correction of “misspelled” disease-driving DNA sequence REPAIR INSERT CRISPR/Cas9 7 Development Pipeline Fueled by Robust Research Engine * 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 PROGRAM APPROACH Research Candidate Selection IND-Enabling Early-Stage Clinical PARTNER In Vivo: CRISPR is the therapy NTLA-2001: Transthyretin Amyloidosis Knockout NTLA-2002: Hereditary Angioedema Knockout Hemophilia A and B Insertion Research Programs Knockout, Insertion, Consecutive Edits Research Programs Various Ex Vivo: CRISPR creates the therapy OTQ923 / HIX763: Sickle Cell Disease HSC NTLA-5001: Acute Myeloid Leukemia WT1-TCR Solid Tumors WT1-TCR Undisclosed Programs Undisclosed Other Novartis Programs CAR-T, HSC, OSC UNDISCLOSED *** *** * ** * L E A D L E A D 8 LNP RNA CRISPR is the therapy In Vivo GENETIC DISEASES Strategic Advantages: Systemic non-viral delivery of CRISPR/Cas9 provides transient expression Potentially curative therapy from single course of treatment Permanent gain of function with targeted gene insertion 9 Modular Approach to Unlocking Treatment of Genetic Diseases PROPRIETARY LNP DELIVERY SYSTEM Transient expression Large cargo capacity Redosing capability ENABLES MULTIPLE EDITING STRATEGIES Restore Introduce functional DNA sequence INSERT CONSECUTIVE EDITING Any combination of knockout and insertion strategies + AAV Remove Knockout toxic or compensatory genes KNOCKOUT Remove / Restore + + 10 Modular In Vivo Genome Editing Approach Validated Across Multiple Targets Hem B: Circulating human FIX protein in NHPs at or above normal levels ATTR: >95% reduction of serum TTR sustained for a year in NHPs AATD: >98% reduction of disease-causing protein and sustained restoration of wild type AAT in serum to therapeutic levels in mice Restore Introduce functional DNA sequence INSERT CONSECUTIVE EDITING Any combination of knockout and insertion strategies + AAV Remove Knockout toxic or compensatory genes KNOCKOUT Remove / Restore + + AATD: Alpha-1 Antitrypsin Deficiency FIX: Factor IX Hem B: Hemophilia B NHP: Non-Human Primate 11 Transthyretin Amyloidosis (ATTR) Caused by accumulation of misfolded transthyretin (TTR) protein, which affects nerves, heart, kidneys and eyes NTLA-2001 in development for ATTR • Employs a knockout edit to reduce circulating TTR protein levels • Aims to address hATTR and wtATTR, both polyneuropathy and cardiomyopathy, with a single course of treatment 50,000 hATTR patients worldwide1 ~200-500K wtATTR patients worldwide2 2-15 years typical life expectancy from onset of symptoms1 Only chronic treatment options currently available 1 Ann Med. 2015; 47(8): 625–638. 2 Compiled from various sources hATTR: Hereditary ATTR wtATTR: Wild-Type ATTR 12 Control Lead LNP: Dose Level #1 (n=3) Lead LNP: Dose Level #2 (n=3) Therapeutically relevant serum TTR knockdown Single Dose ATTR: Sustained >95% Serum TTR Protein Reduction After a Single Dose in NHPs 13 ✓ Initiated IND-enabling toxicology studies for NTLA-2001 ✓ Commenced manufacturing for Phase 1 materials ✓ Submitted first CTA for NTLA-2001 to initiate Phase 1 study Dose first patient by YE 2020 ATTR: Advancing NTLA-2001 Toward the Clinic Achievements and Next Steps 14 Hereditary Angioedema (<a href='https://seekingalpha.com/symbol/HAE' title='Haemonetics Corporation'>HAE</a>) Airway obstruction is particularly dangerous because it can cause death by asphyxiation Genetic disease characterized by overproduction of bradykinin, which leads to recurring, severe and unpredictable swelling in various parts of the body Attacks can occur every 7-14 days on average for untreated patients1 NTLA-2002 in development for HAE: • Employs a knockout edit of KLKB1 gene in hepatocytes • Aims to reduce plasma kallikrein activity to prevent excess bradykinin production leading to HAE attacks after a single course of treatment Only chronic treatment options currently available 1 in 50,000 HAE patients1 1 Zuraw BL. Hereditary angioedema. N Engl J Med. 2008;359:1027-1036 15 Reduced angioedema anticipated following knockout of KLKB1 Factor XII Factor XIIa • Kallikrein inhibitors are clinically validated in preventing HAE attacks • KLKB1 knockout is expected to be safe, as human nulls show no associated pathology* Knockout of KLKB1 Aims to Reduce Bradykinin Activity in People with HAE *Girolami B. et. al., Acta Haematol 2010;123:210–214 16 Achieved Sustained Therapeutically Relevant Kallikrein Activity Reduction After a Single Dose in NHPs *Banerji et al., NEJM, 2017 Kallikrein Activity Reduction Single Dose 0 5 10 15 20 25 30 35 40 45 50 0 20 40 60 80 100 120 140 160 180 Kallikrein Activity Reduction Time (Weeks) Plasma Kallikrein Activity (% of Basal) control Dose Level #1 (n=3) Dose Level #2 (n=3) Dose Level #3 (n=3) Control Dose Level #1 (n=3) Dose Level #2 (n=3) Dose Level #3 (n=3) Therapeutically relevant impact on attack rate* 17 LNP Delivery System: gRNA Reprograms Genetic Target Cas9 mRNA AAAA AAAA KLKB1 gRNA AAAA Target-specific gRNA TTR gRNA AAAA HAE: Rapid Path to NTLA-2002 Development Candidate Nomination HAE Program: Builds on ATTR program’s infrastructure, including modular LNP delivery system Applies insights gained from ATTR and other research programs to liver knockout target Platform advances expedite progression to NHP proof-of-concept gRNA: Guide RNA Expect to submit IND or IND-equivalent in 2H 2021 18 CRISPR creates the therapy Ex Vivo IMMUNO-ONCOLOGY / AUTOIMMUNE DISEASES Strategic Advantages: CRISPR/Cas9 enables precise genome engineering for creating cell therapies to treat IO and AI diseases Pursuing modalities, such as TCR, with broad potential in multiple indications Focused on recapitulating natural cell physiology CELL 19 TCR T Cell Modality Broadens Opportunity to Address Most Tumors • TCRs efficiently detect tumor antigens • Physiological signaling minimizes T cell exhaustion and immune toxicity • Healthy donor TCRs avoid reactivity against normal tissues • High-affinity TCRs can activate both cytotoxic and helper T cells Immunol Rev. 2019 Jul;290(1):127-147. Intracellular Tumor Antigens CAR-T: Limited to surface antigens TCRs: Recognizes both surface and intracellular antigens Selecting naturally-occurring, Total Addressable Tumor Targets high-affinity TCRs 20 CRISPR Engineering Overcomes Key Challenges of Traditional Approaches Key Challenges • Mutagenesis risk from random lentiviral insertion • Mixed expression of endogenous and tgTCR • Mispaired TCRs have unpredictable specificities and pose GvHD risk • Lower tgTCR expression per T cell leads to reduced efficacy Our Solution • Precise replacement of endogenous TCR with tgTCR • No insertional mutagenesis risk • Reduced risk of unwanted reactivity against normal tissues • High tgTCR expression per T cell leads to a more efficacious cell product Traditional tgTCR addition CRISPR/Cas9 tgTCR replacement Mixed TCRs tgTCRs only Heterogenous Cell Product Homogenous Cell Product tgTCR: transgenic therapeutic TCR 21 Based on FACs analysis High and Uniform Expression of tgTCR per T cell 100 80 60 40 20 0 Normalized tgTCR Expression (%) TCR A TCR B TCR C TCR D Removal of Endogenous TCR Prevents Mispairing 60 40 20 0 % Cells with mispaired TCRs TCR A TCR B TCR C TCR D ’s Approach (TRAC and TRBC KO + Insertion) TRBC KO only + Insertion Our Approach for TCR Replacement with Elimination of Endogenous TCRs Creates a Homogenous T Cell Product 22 Efficient multiplexed editing Higher T cell expansion Reduced translocations Untreated Standard Process Intel ia Process 0 20 40 60 80 100 %Editing Gene 1 Gene 2 Gene 3 Untreated Standard Process Intel ia Process 0 50 100 150 Fold Expansion Untreated Standard Process Intel ia Process 0 5 10 15 Cumulative Translocat oi n Events per 200 Cells Complex Translocations Reciprocal Translocations Translocations to other chromosomes Standard Process: Cas9/sgRNA RNP electroporation based on manufacturer’s instructions Proprietary Process Enables Multiple Sequential Edits With Minimal Translocations 23 Acute Myeloid Leukemia (AML) >21K new cases in the U.S. in 20191 >40K new cases in the 7MM2 in 20181 Cancer of the blood and bone marrow that is rapidly fatal without immediate treatment, and is the most common type of acute leukemia in adults1 <30% 5-year overall survival1 NTLA-5001 in development for AML • Engineer WT1-directed T cells capable of specifically killing AML blasts 1 NIH SEER Cancer Stat Facts: Leukemia – Acute Myeloid Leukemia (AML) 2 GlobalData EpiCast Report: Acute Myeloid Leukemia July 2017, 7MM: Seven Major Markets (includes U.S.) 24 Wilms’ Tumor 1 (WT1) is an Attractive Tumor Target WT1 is Overexpressed in >90% of AML Blasts • Independent of mutational status • Low normal tissue expression WT1 is Overexpressed in Variety of Solid Tumors • AML program provides foundation for expansion into solid tumors Normalized WT1 expression Normal expression Overexpression Cilloni et al., J Clin Oncol, 2009 Sugiyama et al., Jap J Clin Oncol, 2010 25 Engineered T Cells Capable of Specific and Potent Killing of WT1-Positive AML Blasts Lead WT1-Specific TCR Profile: Proprietary T Cell Engineering Process Yields: • Sourced from healthy donor T cells • HLA-A*02:01 restricted TCR • Displays high avidity for VLD* epitope ‒ VLD epitope is efficiently processed by tumor proteasome, and presented by AML blasts • Consistent high-level editing efficacy • High and homogeneous tgTCR expression • Cytotoxic and helper T cell response • No detectable bone marrow cell toxicity *VLD is the WT1(37-45) epitope VLDFAPPGA In collaboration with IRCCS Ospedale San Raffaele 26 ✓ Engineered WT1-specific T cells capable of specifically killing patient-derived AML blasts ✓ Nominated NTLA-5001 as development candidate Submit IND or IND-equivalent in 1H 2021 AML: Advancing NTLA-5001 Toward the Clinic Achievements and Next Steps 27 Multiple Workstreams to Advance Cell Therapy Efficacy in Solid Tumors Allogeneic Cell Source • Knock out MHC-I and MHC-II complexes • Address multiple surface protein signals • Achieve persistence in presence of natural killer cells Solid Tumor Efficacy • CRISPR screening to unravel targetable key regulators of T cell fitness in the tumor microenvironment Functional Modulation • Knock out and/or knock-in of key receptors, including checkpoint inhibitors, to modulate T cell functionality in multiple microenvironments 28 Upcoming Milestones: Driving Forward In Vivo and Ex Vivo Programs in 2020 o Submitted first CTA for NTLA-2001 to initiate a Phase 1 study ATTR o Dose first patient by YE 2020 AML o Presented preclinical data at scientific conference in 1Q 2020 o Submit IND or IND-equivalent for NTLA-5001 in 1H 2021 o Presented preclinical data at scientific conference in 1Q 2020 o Nominated NTLA-2002 as development candidate in 1H 2020 o Submit IND or IND-equivalent for NTLA-2002 in 2H 2021 In Vivo In Vivo Ex Vivo NTLA-2001 NTLA-5001 R&D Advancements o Present preclinical data at upcoming scientific conferences in 2020 ✓ ✓ HAE ✓ NTLA-2002 ✓Graphic Source: Intellia Therapeutics Inc.

Introduction: What is Intellia Therapeutics?

Intellia Therapeutics, Inc. (NASDAQ: NASDAQ:NTLA) is a preclinical-stage genome editing company focusing on developing novel therapeutics using the genome-editing process known as CRISPR/Cas9, or Clustered, Regularly Interspaced Short Palindromic Repeats. Currently, Intellia is broadly focused on in-vivo, delivering directly to target cells in the body, and ex-vivo, developing a therapy from engineered human cells, with a global clinical focus (three countries in progress).

Founded in 2014, NTLA has since grown to revenues of $43 million (2019) with over 270 employees based in Cambridge, Mass. Although CRISPR/Cas9 genome editing technology is not yet clinically validated for human therapeutic use, the company is making strides in strategic markets to achieve the required approvals and is currently transitioning from pre-clinical to clinical in 2020-2021.

Products: Intellia has a pipeline of four therapies in the post-research phase with three realistically expected to show clinical aspirations before year-end 2021.

1. NTLA-2001 for transthyretin amyloidosis "ATTR": Submitted first CTA to initiate a Phase 1 study; Intend to dose first patient by YE 2020

2. NTLA-5001 for acute myeloid leukemia "AML": Expected to submit IND in 1H 2021 for WT1-directed TCR T-cell therapy

3. NTLA-2002 for hereditary angioedema "HAE": Expected to submit IND in 2H 2021

Customers/market: Currently, Intellia is pre-clinical, but the potential market for patients of each of the above products is as follows. For ATTR alone, the expected patient population is hard to estimate, but rival Akcea has found there to be an estimated 50,000 patients with hereditary ATTR amyloidosis worldwide and 200,000 patients with wild-type ATTR amyloidosis worldwide. Intellia additionally estimates there to be over 120 unique mutations from the traditional ATTR adding a layer of complexity to current therapies, but expanding the patient pool to 250,000-500,000. For AML globally, the expected afflicted population is very

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