Building a Full-Spectrum Genome Editing Company

Transcription

1 Building a Full-Spectrum Genome Editing Company

2 Intellia Therapeutics Legal Disclaimers This presentation contains forward-looking statements of Intellia Therapeutics, Inc. ( Intellia ) within the meaning of the Private Securities Litigation Reform Act of These forward-looking statements include, but are not limited to, express or implied statements regarding Intellia s ability to advance and expand the CRISPR/Cas9 technology to develop into human therapeutic products, as well as our CRISPR/Cas9 intellectual property portfolio; our ability to achieve stable or effective genome editing; our ability to administer multiple doses of our CRISPR/Cas9 product candidates; the potential timing and advancement of our preclinical studies, including continuing non-human primate studies for our Transthyretin Amyloidosis ( ATTR ) program and other programs (such as, alpha-1 antitrypsin deficiency ( AATD )), and clinical trials; the timing and potential achievement of milestones to advance our pipeline including filing INDs; our ability to replicate results achieved in our preclinical studies, including those in our ATTR, AATD and Wilms Tumor 1 ( WT1") programs, as well as central nervous system-related efforts, in any future studies, including human clinical trials; our ability to generate data and replicate results relating to enhancements to our proprietary lipid nanoparticle ( LNP ) technology, including its formulation and components, in preclinical or clinical studies, or that any enhancements will result in animproved product candidate profile; the potential development of our proprietary LNP- adeno-associated virus ( AAV ) hybrid delivery system to advance our complex genome editing capabilities; the potential development of other in vivo or ex vivo cell therapeutics of all types, and those targeting WT1 inparticular, using CRISPR/Cas9 technology; our ability to conduct successful Investigational New Drug ( IND )-enabling studies of a lead ATTR development candidate and subsequently submitting an IND application that will be accepted by the regulatory agencies; our intent to generate and present additional data for organs beyond the liver, additional insertion/repair data, and preclinical data in support of our first ex vivo programs on immuno-oncology and autoimmune/inflammation indications during 2018 or thereafter; our ability to advance a development candidate for anin vivo second indication by late 2018 or thereafter; the intellectual property position and strategy of Intellia s licensors or other parties from which it derives rights, as well as third-parties and competitors; actions by government agencies; our growth as a company and the anticipated contribution of the members of our board of directors and our executives to our operations and progress; the impact of our collaborations on our development programs; the potential timing of regulatory filings regarding our development programs; the potential commercialization opportunities, including value and market, for product candidates; our expectations regarding our uses of capital, expenses, future accumulated deficit and other 2018 financial results; and our ability to fund operations through mid 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 our intellectual property position; risks related to the ability of our licensors to protect and maintain their intellectual property position; uncertainties related to the initiation and conduct of studies and other development requirements for our product candidates; the risk that any one or more of Intellia s product candidates will not be successfully developed and commercialized; the risk that the results of preclinical 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 and quarterly reports on Form 10-Q filed with the Securities and Exchange Commission, 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 this presentation is as of the date of the release, and Intellia Therapeutics undertakes no duty to update this information unless required by law. 2

3 Intellia is Building a Full-Spectrum in vivo and ex vivo Genome Editing Company Focused on developing breakthrough CRISPR-based therapies Balanced and synergistic efforts across in vivo and ex vivo applications Modular in vivo and ex vivo strategies Enabled by a comprehensive genome editing platform 3

4 in vivo CRISPR-Based Therapies

5 Basic Edit Types Complex Our in vivo Strategy: Liver Knockout Platform Expands Stepwise Into Complex Edits and Other Tissues Insertion Repair CNS Eye Lung Muscle Skin Knockout Liver Other Tissues Delivery Targets 5

6 Lipid Nanoparticles are the Cornerstone of Intellia s in vivo Delivery Approach Lipid Nanoparticle (LNP) Adeno-Associated Virus (AAV) Large cargo capacity for CRISPR/Cas9 Efficient template delivery for insertion and repair Biodegradable Wide range of tissue tropism Redosing capability Broadly used in clinical studies Transient expression 80 nm Low immunogenicity Adjustable range of tissue tropism Scalable synthetic manufacturing 20 nm Challenges for Cas9 delivery: Potentially immunogenic Limited cargo capacity Persistent gene expression 6

7 Edit Types Our in vivo Strategy: Liver Knockout Platform Expands Stepwise Into Complex Edits and Other Tissues 1. Liver Knockout Programs Transthyretin Amyloidosis (ATTR) Primary Hyperoxaluria Type 1 (PH-1) 2. Advancing to Complex Edits Alpha-1 Antitrypsin Deficiency (AATD) 3. Other Tissues Complex Basic ATTR Insertion Repair Knockout PH-1 CNS Eye Lung Muscle Skin Liver Other Tissues Delivery Targets 7

8 ATTR: First Liver Knockout Program Advancing Toward the Clinic Transthyretin Amyloidosis (ATTR) Caused by accumulation of misfolded TTR protein, which affects nerves, heart, kidneys and eyes 50,000 ATTR patients worldwide 1 Typically fatal within 2-15 years from onset of symptoms 1 Only chronic treatment options ATTR Program Achievements First to demonstrate CRISPR/Cas9 editing via LNPs First to show dose-dependent CRISPR/Cas9 editing in Non-Human Primate (NHP) Achieved incremental editing in NHP through repeat dosing Achieved therapeutically relevant reduction of serum TTR protein in NHP in a single dose 1 Ann Med. 2015; 47(8):

9 % L iv e r E d itin g Achieved Unprecedented Liver Editing Levels in NHPs After a Single Dose for ATTR with Improved in vivo Delivery Formulations Liver Editing in NHP Recent NHP studies incorporating certain LNP cargo modifications demonstrated up to 78% liver editing that resulted in up to 96% reduction in circulating levels of TTR protein following a single dose V e h ic le O c to b e r M a y O c to b e r Chart above includes single administration within a range of dose levels 9

10 Data from Enhancements to in vivo Delivery Formulations Suggest Potential for Substantially Improved Efficacy at a Lower Dose LNP component modifications yielded near-complete reduction of circulating TTR protein Range of dose levels portrayed from lead candidate and recent in vivo delivery formulations administered in a single dose Liver editing of 35-40% is sufficient to achieve a reduction of >60% of TTR protein Intellia will pursue a period of confirmatory research activities to further investigate LNP component improvements Therapeutically Relevant Range: >60% TTR Knockdown Single dose from lead candidate (previously reported data only) Single dose from recent in vivo delivery formulations (selected modifications) 10

11 ATTR: Performing NHP Studies to Confirm Enhanced Formulation Results That Could Result in Materially Improved Product Profile Preclinical Studies NHP Perform confirmatory studies with goal of integrating enhanced LNP cargo components into lead candidate 59% liver editing with corresponding TTR protein reduction of 78% after a single dose Safety data indicate potential for both single and repeat dosing Submit IND application: 2020 Rat 66% liver editing with corresponding TTR protein reduction of 91% after a single dose Well-tolerated in vivo liver genome editing in rats Mouse 70% liver editing with corresponding TTR protein reduction of 97% Well-tolerated, year-long editing durability in in vivo mouse studies Figures above include average results from previously reported data only 11

12 Modularity of LNP Delivery System Enables Rapid Progression of Follow-On Liver Knockout Programs Critical Liver Knockout Milestones Achieved Identify high efficiency guides Create modified guides to enhance activity Develop highly active Cas9 mrna Create LNP with high performance characteristics Achieve high level editing on single IV application Variable Portion Limited to 20mer of grna ATTR grna AATD grna PH1 grna Demonstrate successful redosing Achieve sustained editing effect Achieve favorable safety profile LNP and mrna Remain Constant Within a Tissue 12

13 ~45% Urinary Oxalate Reduction Achieved in PH-1 Mouse Model Primary Hyperoxaluria Type 1 (PH-1) Rare inborn error of metabolism leading to renal damage and dysfunction Prevalence of ~1-3 per million 1 Potentially ~1,000 patients in U.S.* Majority of patients progress to ESRD** by the age of 40 2 Liver transplant is only curative option 1 PH-1 Program Achievements ~80% editing of HAO1 achieved in mouse model, leading to a ~45% urinary oxalate reduction after a single dose 1 N Engl J Med. 2013; 369: J Am Soc Nephrol. 2015; 26: *Assumes prevalence numbers in U.S. are similar to Europe ** ESRD: End-stage renal disease 13

14 Edit Types Our in vivo Strategy: Liver Knockout Platform Expands Stepwise Into Complex Edits and Other Tissues 1. Liver Knockout Programs Transthyretin Amyloidosis (ATTR) Primary Hyperoxaluria Type 1 (PH-1) 2. Advancing to Complex Edits Alpha-1 Antitrypsin Deficiency (AATD) 3. Other Tissues Complex Basic Insertion Repair Knockout AATD CNS Eye Lung Muscle Skin Liver Other Tissues Delivery Targets 14

15 Intellia s CRISPR-Mediated Insertion Combines the Advantages of LNP and AAV to Create a Hybrid Delivery System for Targeted, Stable Gene Insertion LNP AAV Combines advantages of: LNP for transient Cas9 delivery AAV as effective template delivery system To achieve targeted, stable gene insertion CRISPR/Cas9 mrna and grna Insertion template Cas9 mrna Gene of Interest Gene of Interest 15 grna

16 HALO-processed image First Robust Demonstration of CRISPR-Mediated, Targeted Insertion of Transgenes in the Liver Quantification of Factor IX (FIX)-Expressing Hepatocytes with BaseScope TM Method Hybrid malb-f9 Transcripts Detected in >50% of Hepatocytes in Adult Mice AAV alone sgrna 6 AAV alone 16

17 Progressing Insertion and Knockout Edits to Address Alpha-1 Antitrypsin Deficiency Alpha-1 Antitrypsin Deficiency (AATD) Caused by mutations in the SERPINA1 gene, commonly leading to lung dysfunction and liver disease ~6,000 diagnosed patients in the U.S. 1 ~250,000 at risk* globally 2 Diagnosed patients associated with >3X higher risk of death vs. general population 3 Limited options for treatment AATD Program Achievements Insertion approach: Achieved therapeutic levels of gene expression in adult mice with in vivo insertion of SERPINA1 Knockout approach: 85% editing of SERPINA1 achieved in mouse model of disease, leading to a ~95% protein reduction 1 Clin Chem. 2006; 52: Int J Chron Obstruct Pulmon Dis. 2017;12: Eur Respir J. 2017; *Based on estimated global frequency of Pi*ZZ genotype 17

18 serum haat µg/ml Intellia s Insertion Approach Works for Multiple Transgenes: in vivo Insertion of SERPINA1 Also Results in Therapeutic Levels of Protein Expression in Adult Mice in vivo Insertion of SERPINA1 Therapeutic Levels of Protein Expression Promoter Alb Exon 1 Exon 2 Promoter Alb Human Exon 1 SERPINA1 Exon 2 Human SERPINA1 Human AAT (haat) Protein 18

19 Evidence of a Modular Platform: Insertion Site Performance in Adult Mice is Independent of Transgene Relative ranking of insertion sites is consistent across transgenes Each point corresponds to protein expression of FIX and AAT inserted at the same site haat protein (µg/ml) 19

20 Edit Types Our in vivo Strategy: Liver Knockout Platform Expands Stepwise Into Complex Edits and Other Tissues 1. Liver Knockout Programs Transthyretin Amyloidosis (ATTR) Primary Hyperoxaluria Type 1 (PH-1) 2. Advancing to Complex Edits Alpha-1 Antitrypsin Deficiency (AATD) 3. Other Tissues Complex Basic Insertion Repair Knockout CNS Eye Lung Muscle Skin Liver Other Tissues Delivery Targets 20

21 % Editing LNP Delivery to Central Nervous System (CNS) Successfully Achieved LNP-Mediated Mouse CNS Delivery Mouse CNS Editing NHP CNS Delivery 2 mg/ml 1 mg/ml 30.0% 25.0% IHC for GFP 20.0% 0.5 mg/ml 0.12 mg/ml 15.0% 10.0% 5.0% 0.0% LNP4 LNP5 LNP6 LNP Formulations 0.1 mg/ml Left Striatum 0.1 mg/ml Right Striatum 1.0 mg/ml Left Striatum 1.0 mg/ml Right Striatum Uptake is seen in cerebellum and striatum, and results in genome editing Editing in mouse up to 28% LNP-mediated CNS delivery Successful delivery of GFP to the striatum In collaboration with Dr. Beverly Davidson, Children s Hospital of Philadelphia 21

22 Genetic Diseases Growing the in vivo Pipeline Across Multiple Indications in vivo Programs Edit Type Stage ATTR* (Transthyretin Amyloidosis) Knockout Late Stage Preclinical AATD (Alpha-1 Antitrypsin Deficiency) Knockout Insertion Preclinical PH-1 (Primary Hyperoxaluria Type 1) Knockout Preclinical *In collaboration with Regeneron 22

23 ex vivo CRISPR-Based Therapies

24 Autologous Cell Source Allogeneic Our ex vivo Strategy: T Cell Receptor Approach Serves as the Basis for Next-Generation Therapies AML WT1 AML WT1 Breast Brain Colon Lung Ovarian Sarcoma Stomach Thyroid Hematological malignancies Cancer Type Solid tumors 24

25 Current Challenges with Autologous Solutions Need to be Addressed Current State Key Challenges: Re-infuse Culture & Expand Autologous cells / apheresis Transduce CAR / TCR Efficacy: Limited to blood cancers Limited to surface-expressed proteins Limited to antigens shared between tumor and normal tissue Safety: Life-threatening side-effects (e.g. CRS, neurotoxicity) Few qualified treatment centers for patients Cost and Consistency: High all-in cost for personalized treatment Complex manufacturing process and variable product CRS: Cytokine Release Syndrome 25

26 Intellia Aims to Create a Truly Allogeneic Solution Future State Preliminary editing Intellia s Vision: Efficacy: Expanded efficacy to solid tumors Extended efficacy to internal antigens Personalized neoantigen targets Final customization Safety: Naturally occurring T cell receptors (TCRs) Reduced toxicity Cost and Consistency: Renewable allogeneic source of T cells Standardized via master cell bank Administer to patient 26

27 Intellia s CRISPR/Cas9 Editing of Transgenic T Cell Receptors (TCRs) Aims to Engineer T Cells Against Specific Cancer Antigens Current State: Random Insertion of TCRs Without Complete Knockout of Endogenous TCR Future State: Targeted Insertion of TCR With Complete Knockout of Endogenous TCR Endogenous TCR Tumor-Specific TCR Genes Mixed TCRs Knockout of Both Protein Chains of Endogenous TCR Full TCR Replacement Vector Delivery TCR DNA Cut and Gene Disrupted by CRISPR/Cas9 TCR Gene Addition Tumor-Specific TCR Genes Viral Vector TCR Gene Addition Key Challenges: Random insertion of new TCRs potentially mix with endogenous TCR proteins Mixed TCRs potentially bind to unexpected targets and cause graft vs. host reactions TCR transgene expression drops or is eliminated completely over time Intellia s Objective: Knock out both protein chains of the endogenous TCR Insert tumor-specific TCR in locus ( cut and replace ) Achieve physiological expression without potential graft vs. host reaction 27

28 Wilms Tumor 1 (WT1) is an Attractive Target for TCR-Based Therapies WT1 is Highest Rated Amongst 75 Cancer Antigen Targets Across 9 Criteria by NCI WT1 Epitope is Over-Expressed on >90% of Tumors Cheever M. A., Hum Canc Bio, 2009 Sugiyama et al., Jap J Clin Oncol, 2010 WT1 is Intellia s first cell therapy target for the treatment of acute myeloid leukemia In collaboration with Ospedale San Raffaele 28

29 T R AC K O T R B C K O T R AC /T R B C K O C o n tr o l R N P TRAC KO TRBC KO TRAC/TRBC KO Control T C R E d itin g [% ] %WT1 TCR Positive Multiplex Knockout and Insertion of Genes in T Cells Can Be Accomplished with High Efficiency Engineered T Cells Show >98% Knockout of the Endogenous TCR Engineered T Cells Express WT1-Specific TCR Insertion TRAC KO TRBC KO TRAC/TRBC KO Mock In collaboration with Ospedale San Raffaele 29

30 First Wholly Owned ex vivo Program Targets AML Acute Myeloid Leukemia (AML) Cancer of the blood and bone marrow that is rapidly fatal without immediate treatment Most common type of acute leukemia in adults 1 ~20,000 new cases in U.S. 1 and >40,000 new cases in the 7MM 2 in year overall survival <30% 1 AML Program Achievements Identified epitope-specific TCRs sourced from healthy donors Observed selective elimination of AML blasts upon co-culture with WT1-specific T cells 1 NIH SEER Cancer Stat Facts: Leukemia Acute Myeloid Leukemia (AML) 2 GlobalData EpiCast Report: Acute Myeloid Leukemia July MM: Seven Major Markets 30

31 Intellia Progressing Toward Next-Generation Engineered Cell Therapy Necessary Elements for Antigen-Specific TCRs for All Tumor Types Knockout MHC1 and MHC2 Modulate checkpoint genes Edit immune response genes Knockout endogenous TCR Insert antigen-specific TCR Achieve high levels of multiplex editing Achieve NK-resistant MHC1-negative T cells Achieve favorable safety profile 31

32 Advancing Genome Editing in HSCs as a Novel Cell Therapy for Sickle Cell Disease* CRISPR/Cas9 editing of the erythroid-specific enhancer region of BCL11A in human HSCs led to significant increase in the number of F-cell and fetal hemoglobin (HbF) expression *In collaboration with Novartis Yu, Vionnie et al. (2017).CRISPR/Cas9 Gene-Edited Hematopoietic Stem Cell Therapy for Sickle Cell Disease. Blood, 130(Suppl 1), 535. HSC: Hematopoietic Stem Cells 32

33 Autoimmune Diseases Hematology Immuno-oncology Progressing an ex vivo Pipeline Across Multiple Therapeutic Areas ex vivo Engineered Cells Initial Programs Cell Source Stage Transgenic TCR-T Cells AML (Acute Myeloid Leukemia) Autologous Allogeneic Preclinical CAR-T Cells* (Chimeric Antigen Receptor) Undisclosed** Autologous Allogeneic Preclinical HSCs* (Hematopoietic Stem Cells) SCD** (Sickle Cell Disease) Autologous Late Stage Preclinical T-reg Cells Undisclosed Autologous Allogeneic Preclinical *In collaboration with Novartis ** Novartis developing/commercializing under an exclusive license from Intellia 33

34 2018 Accomplishments and Recent Events in vivo ex vivo Platform Developments Began IND-enabling activities for lead ATTR development candidate Identified additional LNP cargo modifications for improved liver editing and protein reduction Presented in vivo delivery and editing in CNS of NHPs Presented insertion editing data for F9 and SERPINA1 Presented preclinical data on first proprietary immuno-oncology program (AML) Progressed multiplexing efforts to achieve triple knockout edits and insertion with simultaneous double knockout edits Increased throughput capacity of next-generation sequencing platform Strengthened intellectual property (IP) position with foundational CRISPR/Cas9 patents issued in key jurisdictions, including the U.S. and Europe Organizational Developments Elected Dr. Jesse Goodman to Board of Directors Appointed Glenn Goddard as Chief Financial Officer 34

35 Strong Partnerships and Foundational IP

36 ex vivo in vivo Partnerships Provide R&D Capabilities to Enhance Pipeline Growth Multi-year collaboration Up to 10 in vivo targets Two component deal Liver-centric product development Platform development Deal economics Up to $320M milestones per target High single-digit to low-teen royalties $75M upfront $50M equity investment Co-development and cocommercialization options Partnership with leading pharmaceutical company ATTR first selected co-co target Access to: Regeneron Genetics Center Animal model development Tools and reagents Multi-year collaboration Product-focused discovery for CAR-Ts and HSCs Draft pick process for HSC targets Deal economics Up to $230M in milestone payments per product Mid single-digit royalties Up to $50M in committed collaboration funding $18M equity investment Leading CAR-T and HSC pharmaceutical company provides near term insights into engineered cell therapy development Access to: LNP library utilized in in vivo program HSC expansion technology utilized in ex vivo program Regulatory and manufacturing expertise 36

37 Global IP Portfolio Underpins Genome Editing Platform GENOME EDITING PLATFORM Site-Specific Nuclease Technology Insertion and Repair Templates Structural and Chemical Modifications of grnas LNP and Other Delivery Methods Scale-Up, Purification and Analytics Capabilities Manufacturing Process Development Indication- Specific Patents Final Product Composition 37

38 Autoimmune Diseases ex vivo Hematology Immuno-oncology in vivo Genetic Diseases R&D Pipeline Poised to Move in vivo and ex vivo Products to the Clinic Programs Program Lead Stage Transthyretin Amyloidosis Late Stage Preclinical Alpha-1 Antitrypsin Deficiency Primary Hyperoxaluria Type 1 Preclinical Preclinical Acute Myeloid Leukemia Preclinical Undisclosed Preclinical Sickle Cell Disease Late Stage Preclinical Undisclosed Preclinical 38

39 Experienced Management Team Driving Intellia to Deliver Innovative Therapies John Leonard, M.D. President and Chief Executive Officer Glenn Goddard Executive Vice President, Chief Financial Officer José Rivera Executive Vice President and General Counsel Andrew D. Schiermeier, Ph.D. Executive Vice President, Corporate Strategy Thomas Barnes, Ph.D. Senior Vice President, Innovation Sciences Nishla Keiser, Ph.D. Senior Vice President, Deputy General Counsel Jennifer King, Ph.D. Senior Vice President, Business Development Jennifer Mound Smoter Senior Vice President, External Affairs and Communications Lindsey Trickett Vice President, Investor Relations 39

40 Intellia Primed to Deliver Life-Transforming CRISPR-Based Therapies for Patients 7 Full-Spectrum Genome Editing Platform 2 Partnerships with Industry Leading Pharmaceutical Companies PRECLINICAL PROGRAMS Strong in vivo and ex vivo Pipeline Strong Balance Sheet Robust, Global IP Portfolio 40

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