1 Revolutionizing Medicine A Breakthrough Scientific Discovery Curative Treatments Targeting the Underlying Genetic Cause of Disease Investor Presentation 2018
Intellia Therapeutics Legal Disclaimers This presentation contains "forward-looking statements" of Intellia Therapeutics, Inc. 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 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 with a single treatment dose; the potential timing and advancement of our preclinical studies, including continuing non-human primate studies, and clinical trials; our ability to replicate results achieved in our preclinical studies in any future studies, including human clinical trials; the potential development of ex vivo cell therapeutics of all types using CRISPR/Cas9 technology; our ability to conduct successful IND-enabling studies of a lead ATTR development candidate and subsequently submitting an IND application by the end of 2019 that will be accepted by the regulatory agencies; our intent to 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; our ability to nominate a development candidate for a second indication by late 2018; the intellectual property position and strategy of Intellia s licensors; actions by government agencies; 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-2020. 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
Intellia Value Drivers Genome Editing Proprietary Delivery System Diversified Pipeline Scalable Application Committed Partnerships First company to demonstrate dose-dependent CRISPR/Cas9 liver editing in non-human primates 3 Based on publicly available information and reports of peer companies
Intellia Recent Accomplishments In non-human primates: First company to demonstrate dose dependent CRISPR/Cas9 editing in non-human primates First company to demonstrate CRISPR/Cas9 editing via lipid nanoparticles First company to demonstrate in vivo CRISPR/Cas9 editing at a disease-causing gene in NHP livers Showed that redosing increased genome editing levels in the liver Demonstrated that CRISPR/Cas9 leads to TTR serum protein reduction Observed a safe and well-tolerated profile following single and repeat dosing In rodents: Demonstrated well-tolerated, year-long editing durability in in vivo mouse studies Demonstrated well-tolerated in vivo liver genome editing in rats Path to clinic: Commenced characterization of human guides in in vivo NHP studies for identification of development candidate 4 Based on publicly available information and reports of peer companies
Genome Editing is Positioned to Revolutionize Medicine Current Standard of Care Mostly palliative Not personalized Requires multiple/chronic dosing regimens Intellia s Approach Potentially curative Personalized genetic approach Single/limited dosing paradigm Small Molecules Biologics Gene Therapy Genome Editing Current therapies do not treat underlying genetic cause of disease 5
Genome Editing Approaches to Address Wide Spectrum of Genetic Diseases Disease-Defined DNA Editing Cas9/RNA Permanent Modifications Non-Permanent Modifications Knockout Inactivation/ deletion of disease-causing DNA sequence Repair Insert CRISPRi (Interference) Correction of misspelled disease-driving DNA sequence Insert new DNA sequence to manufacture therapeutic protein Transient inactivation of targeted DNA expression CRISPRa (Activation) Transient activation of DNA sequence expression e.g. ATTR, HBV, AATD e.g. AATD, IEMs e.g. IEMs 6 Application in monogenic AND polygenic diseases
Diversified Opportunities with in vivo and ex vivo Delivery in vivo ATTR AATD PH-1 HBV Initial focus: liver indications with unmet need Rapid expansion into other liver indications planned ex vivo In vivo franchise expansion into other organs directly, or indirectly, through BD ex vivo Oncology T cell therapy NK cell therapy Auto-Immune Disease Type 1 Diabetes* Crohn s Disease* 7 * Represents potential opportunities, subject to change
8 in vivo Opportunities
in vivo Pipeline in vivo Programs Type of Edit Delivery Stage ATTR (Transthyretin Amyloidosis) Knockout LNP Late Stage Preclinical Development Genetic Disease AATD (Alpha-1 Antitrypsin Deficiency) Knockout Repair Insertion LNP Preclinical Development PH-1 (Primary Hyperoxaluria Type 1) Knockout Repair Insertion LNP Preclinical Development Infectious Disease HBV (Hepatitis B) Knockout LNP Preclinical Development 9
Lipid Nanoparticles: Cornerstone of Intellia s Current Delivery System LNP AAV Transient expression Low immunogenicity Robust expression Efficient local delivery Ideal for systemic and local dosing Chemical system Large cargo capacity Scalable synthetic manufacturing Favorable safety profile Limited cargo capacity Cargo can persist for years Immunogenic potential Developing a toolbox of delivery mechanisms to reach many organs 10
Roadmap to IND Filing Mouse Rat NHP ~70%* editing of TTR gene in liver ~97%* Serum TTR reduction ~66%* editing of TTR gene in liver ~91%* Serum TTR reduction Interim** top-line data show editing achieved in NHPs IND Filing Rapid clearance of LNP 12 months of durable editing LNP delivered to NHP liver Upcoming Milestones Human guide selection IND-enabling activities *Optimized **Prior to optimization LNP Delivery to Liver Durability Optimize Guide Human Guide Selection 11 Edit in Liver Guide Selection Optimize Formulation IND Enabling Activities
Lead in vivo Program: ATTR Caused by accumulation of misfolded TTR protein that can affect nerves, heart, kidneys and eyes ATTR 50,000 Fatal within 2-15 years from onset of symptom ATTR patients worldwide Limited options for treatment 12 J Neurol Sci. 2014 Sep 15;344(1-2):121-8. doi: 10.1016/j.jns.2014.06.041. Epub 2014 Jun 27 Ann Med. 2015 Nov 17; 47(8): 625 638. Published online 2015 Nov 27. doi: 10.3109/07853890.2015.1068949
Roadmap to IND Filing - Mouse Data Mouse Rat NHP IND Filing ~70%* editing of TTR gene in liver ~97%* serum TTR reduction Rapid clearance of LNP 12 months of durable editing 13 *Optimized LNP Delivery to Liver Edit in Liver Durability Guide Selection
Mouse Study: High Knockdown & Edit Efficiency After One Dose First To Show ~97% TTR Knockdown in vivo Using CRISPR/Cas9 70% Editing of TTR Gene in Liver 97% Decrease in Serum TTR Rapid Clearance of Cargo In Liver Traceability Results that motivate future development High liver editing efficiency after one dose Editing almost completely stopped TTR protein production Undetectable Cas9 mrna and sgrna in the liver at 72 hours post-administration 14
Editing Effect Durability in Mouse Study High Durability in vivo After Single Dose; Persistent Effect for Full 12 Months Liver Editing Durable at 12 months Low Serum TTR Levels Persist Edited Edited Liver Liver Cell Cell Population Population Linked To Durability Linked To Durability GS (Glutamine Synthetase) mrna Delivered by LNP Cas9 expression is transient, with durable editing effect Durable and stable liver editing for duration of 12 month study ~97% reduction in serum TTR levels, ~70% liver editing Stem cell editing likely drives durability 15
Roadmap to IND Filing - Rat Data Mouse Rat NHP IND Filing ~66%* editing of TTR gene in liver ~91%* serum TTR reduction 16 *Optimized LNP Delivery to Liver Edit in Liver Durability Guide Selection
Characterization in Higher Species - Rats 66% Liver Editing Achieved 91% Reduction in Serum TTR G531 G533 G534 G531 G533 G534 Sprague Dawley rats Single administration 7 day time point n = 5 in each treatment group Results similar to mouse data High liver editing efficiency after one dose Dose dependent serum reduction Proof of concept achieved without additional optimization of guide 17
Roadmap to IND Filing - Non-Human Primate Data Mouse Rat NHP IND Filing Interim** top-line data show editing achieved in NHPs LNP delivered to NHP liver Upcoming Milestones Human guide selection IND-enabling activities 18 **Prior to optimization LNP Delivery to Liver Edit in Liver Durability Guide Selection
Path to NHP PoC (Efficient Liver Editing) Observed effective delivery of LNP using GFP mrna in NHP studies to date Control 12.5x 25x Multi-species and multi-parameter optimization of cargo and LNP to attain efficient liver editing in NHP grna: Chemical modifications to enhance stability and evade host immune system Cas9 mrna: Format and modifications to enhance translation efficiency and evade host immune system LNP: Composition alterations to enhance efficient delivery to liver Systemic testing of multiple dose levels and scheduled in multiple species 19
Editing Achieved with Single and Repeat Dose of LNP Single Dose Repeat Dose 35 35 Not redosed 30 30 % Liver Editing 25 20 15 10 5 % Liver Editing 25 20 15 10 5 High: High Low: High Low: Low 0 Control Low Dose High Dose 0 1st Dose 2nd Dose 20 Sample set from multivariate analysis, prior to optimization
Higher Editing Resulted in Higher Reduction of Circulating TTR Serum Liver Editing %TTR Knock Down 1 st Dose 2 nd Dose 35 Single dose only 140 30 120 % Liver Editing 25 20 15 10 5 % of basal level TTR 100 80 60 40 20 Single dose only 0 1st Dose 2nd Dose 0 0 10 20 30 40 50 60 70 80 Tim e (d) 21 Sample set from multivariate analysis, prior to optimization
Formulation Improvements Produce Consistent Editing and Reduction of Serum TTR in NHPS Liver Editing %TTR Knock Down 45 150 % Liver Editing 40 35 30 25 20 15 10 5 TTR Protein (% of baseline) 125 100 75 50 25 Vehicle High Dose (Improved) 0 Vehicle Initial Low dose Initial High dose Improved 0 0 10 20 30 40 Tim e (d) 22 Single bolus injection in NHPs Achieved consistent editing (mean 34%) at high dose Achieved consistent reduction (mean 70%) in serum TTR protein
Well Tolerated: No Major Changes to Liver Enzyme and Cytokine Levels Observed Average Liver Enzyme (ALT) Units/liter 200 150 100 50 Pre Bleed 6h 24h Upper Limit of Normal Units/liter 200 150 100 50 Pre Bleed 6h 24h Upper Limit of Normal Units/liter 200 150 100 50 Pre Bleed 6h 24h Upper Limit of Normal 0 Control Low Dose 0 Control High Dose 0 Control Repeat Dose Low Dose High Dose Repeat Dose Average Inflammatory Cytokine (IL-6) Units/liter 200 150 100 50 90min 6h 24h Units/liter 200 150 100 50 90min 6h 24h Units/liter 200 150 100 50 90min 6h 24h 0 0 0 Control Low Dose Control High Dose Control Repeat Dose Low Dose High Dose Repeat Dose 23 Sample set corresponds to data on page 21
Beyond the Liver in vivo in vivo ATTR AATD PH-1 HBV Initial focus: liver indications with unmet need Rapid expansion into other liver indications planned in vivo franchise expansion into other organs directly, or indirectly, through BD ex vivo 24
In vivo Potential in CNS LNP-mediated CNS Delivery and Editing Observed in Mice in Collaboration with Dr. Beverly Davidson LNP Dose Response Observed in CNS 1-28% Editing in Striatal and Cerebellar Tissue 2 mg/ml 1 mg/ml 30.0% 25.0% % Editing 20.0% 15.0% 0.5 mg/ml 0.12 mg/ml 10.0% 5.0% 0.0% LNP1 LNP2 LNP3 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 LNP-mediated CNS delivery led to protein expression and editing in mouse Single, local administration was well-tolerated with no behavioral changes Uptake is seen in the cerebellum and striatum, and results in genome editing Significant opportunities for CNS-specific improvements of LNP formulation and guide selection 25
26 ex vivo Opportunities
ex vivo Pipeline ex vivo Programs Type of Edit Delivery Stage HSC* (Hematopoietic Stem Cells) Knockout Repair Insertion Electroporation Late Stage Preclinical Development CAR-T Cells** (Chimeric Antigen Receptor) Knockout Insertion Electroporation Preclinical Development I-O (Immuno-Oncology) Knockout Insertion Electroporation Preclinical Discovery AIID (Autoimmune and Inflammatory Diseases) Knockout Insertion Electroporation Preclinical Discovery *In collaboration with Novartis **Collaborating with Novartis in pre-development activities 27
Group s Vision To create the world s premier edited cell therapy company by leveraging CRISPR/Cas genome editing to fulfill the potential of living medicines Oncology: To discover and unlock new immune-cell capabilities and options that can dramatically improve therapeutic efficacy and safety in existing and expanded areas of application Beyond Oncology: To open large and untapped therapeutic areas of application that can benefit from genomic engineering Allogeneic Source Autologous Source 28
Maximizing Future Opportunities in Other Indications Pursuing CRISPR s Application in Hemoglobinopathies* >90% CD34+ Gene Editing >20% Increase in Fetal Hemoglobin (HbF) Expressing Cells Data support advancement of programs to treat hemoglobinopathies (in partnership with Novartis) in vivo HSC function maintained following Cas9/CRISPR editing of human CD34+ cells Targeted genomic disruption induced clinically-relevant levels of fetal hemoglobin Investigating additional editing strategies, including gene insertion *In collaboration with Novartis 29
Maximizing Future Opportunities in Other Indications Pursuing CRISPR s Application in HSCs* Hematopoietic Stem Cells (HSCs) Multiple potential therapeutic applications through HSC editing Relatively low quantity of available stem cells for treatment Intellia/Novartis Approach Deliver CRISPR/Cas9 ex vivo ex vivo editing target genes & re-engraftment % Human Engraftment 100 80 60 40 20 CRISPR Editing Does Not Alter HSC Function Peripheral blood BM Control + CRISPR % KO (NGS) >16 Week Maintenance of Editing in vivo 100 80 60 40 20 0 4 8 12 16 18 Weeks post-editing 0 Day 3 Week 16 (PB) Week 18 (BM) Time post-editing *In collaboration with Novartis 30
Maximizing extellia Roadmap ex vivo Platform Portfolio Through extellia 1 st generation products Next-gen products. 2017 Immunoonc Autologous Efficacy in heme tumors Safety/CRS issues Donor-derived autologous Checkpoint knockout Solid tumor efficacy Persistent donor-derived allo Robust to tumor escape Better side-effect profile Off-the-shelf derived allo High function in tumor microenv. Effective against tumor genetic drift Managed cytokine release Autoimmune Autologous CAR retargeting Donor-derived autologous Robust Treg expansion Persistent donor-derived allo Enhanced Treg function Off-the-shelf derived allo Site-specific suppression Enhanced function Effective against epitope spreading Current Optimal 31
Maximizing Platform Potential Through extellia s ex vivo Opportunities Apheresis Transduction ex vivo Opportunities Immuno-oncology Editing allogeneic TILs, CTLs, and NK cells to enhance efficacy, potency, and safety Auto-immune and Inflammation Editing antigen-specific T-regs to suppress autoimmunity Re-Infusion Genome Editing Culture and Expansion 32
33 Partnerships and IP
Differentiated Partnership Strategy 34 ex vivo in vivo Multi-year collaboration Up to 10 in vivo targets Two component deal Liver-centric product development Platform development Multi-year collaboration Product-focused discovery for CAR-Ts and HSCs Draft pick process for HSC targets Deal economics Up to $320M milestones per target High single-digit to low-teen royalties $75M upfront $50M equity investment Co-development and commercialization options Deal economics Up to $230M in milestone payments per product Mid single-digit royalties Up to $50M in committed collaboration funding $18M equity investment Partnership with leading pharmaceutical company ATTR first selected co-co target Intellia access to: Regeneron Genetics Center Animal model development Tools & reagents Leading CAR-T & HSC pharma provides near term access to CAR-T & HSC development Access to: LNP library utilized in in vivo program HSC expansion technology utilized in ex vivo program Regulatory & manufacturing expertise Enhances Intellia s R&D Capabilities and Pipeline Growth
Global IP Portfolio to Capture Greater Market Opportunity Site-Specific Nuclease Technology Structural and Chemical Modifications of grnas LNP and Other Delivery Methods Scale-Up, Purification and Analytics Capabilities Indication- Specific Patents Final Product Composition Commercial Product Preclinical Asset Editing Platform Guide RNA Delivery Manufacturing Indication Commercial 35
36 Pipeline
R&D Programs 37
Upcoming Goals in vivo Nominate first Intellia development candidate Initiate IND-enabling activities for first development candidate Hold pre-ind meeting with regulatory authorities Demonstrate in vivo insertion/repair edit in non-human primates Advance additional in vivo liver target(s) Progress delivery and editing on second organ in non-human primates ex vivo Develop key data on generalized allogeneic engineered cell therapy Generate preclinical data on T cell candidate for immuno-oncology indication Deliver preclinical data for Treg-based candidate in auto-immune related disease Intellia selection of hematopoietic stem cell target in Novartis collaboration 38
Industry Leading Investment Thesis Scalable Application Committed Partnerships Proprietary Delivery System Robust, Global IP Portfolio Diversified Pipeline Strong Balance Sheet Accelerating the development of life-transforming therapies 39
40 NASDAQ: NTLA www.intelliatx.com