NSE Grantees Meeting December 2015

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1 NSE Grantees Meeting December 2015

2 The Spherical Nucleic Acid (SNA) Nanoparticle Changes the Paradigm for Oligo Therapeutics Linear DNA SNA Each company limited by chemistry, modality, and tissue of interest Antisense (Science, 2006), sirna (JACS, 2009), mirna (Genes and Dev., 2015) or immuno-modulatory (PNAS, 2015) 2

3 Nanotechnology solves the Grand Challenge of Linear Nucleic Acids Linear DNA SNA High Cell Uptake SNA architecture enables efficient entry into cells vs. linear nucleic acids SNA facilitates cell uptake via natural scavenger receptors without need for encapsulation or complexation PNAS, 2013, 110, p7625 Overcomes Delivery of a Biologic beyond Hepatic Portal Circulation SNA concentrates oligos to a hollow core, with passage through skin PNAS, 2012, 109, p11975 Increased Half-life of Oligonucleotides Structure protects oligonucleotides from nuclease degradation, extending therapeutic half-life Science, 2006, 312, p1027 Ability to Target Specific Tissue Oligo + antigen design achieves both targeting / immunotherapy option, which is ideal for producing a powerful immune response against tumors PNAS, 2015, p3892 3

4 SNA Technology Enables Nucleic Acid Therapies in Multiple Organs Linear DNA SNA Eye: Distribution to cornea, retina Multiple liver indications (~$20B in market cap) Oncology: AST checkpoint inhibitor AST antigen Lungs: Nebulized SNA remain active Dermatology: AST-005 IL17, IL4 GI Tract: Efficacy data in IBD models 4

5 Practical Considerations lead to Spherical SNA Evolution 1 st Generation 2 nd Generation 3 rd Generation Antigen Gold core Direct covalent attachment of oligos Organic, lipid core Conjugated oligos partition into core Co-presentation of antigens Current immuno-oncology programs 5

6 Gene Regulatory SNAs

7 AST-005 Reverses Psoriasis in Mouse Model of the Disease No SNA TNF SNAs 7

8 AST-005 Preclinical Data Proven uptake into viable human skin Demonstrated target engagement and mechanism of action in human psoriatic skin tissue Derm programs allow optimization of drugs in human tissue prior to entering first in man studies SNAs Enter Human Psoriatic Skin After Topical Application Epidermis (SNA in red) SNA Target Knockdown (Psoriatic Human Skin) Negative Control 0% AST ± 14% 8

9 AST-005 First in Human Study Evaluates Safety, Efficacy, and Biomarkers in Patients Quickly and Efficiently Objectives Doses Safety, efficacy, biomarkers AST-005 gel (at three strengths), positive and negative controls Endpoints Safety and tolerability Efficacy as measured by inflammatory infiltrate thickness Biomarker knockdown (TNF) Timing Initiation to report 6 months 9

10 Clinical Proof of Concept Leads to Rapid Follow on Applications Disease Current Targets Atopic Dermatitis Interleukin 4 Receptor Actinic Keratosis Prostaglandin-Endoperoxide Synthase Epidermolytic Ichthyosis (Orphan) Keratin 10 10

11 Nanotechnology Expands Local Delivery Eye Potential for SNA eye drops Biodistribution to cornea and retina observed AST-005 (ng/g tissue) cornea retina AST-005 (Formulation 1) AST-005 (Formulation 2) choroid aqueous Rabbit Eye Tissue vitreous Lung Nebulized formulation of SNA Nebulized compound active in vitro GI tract Oral formulation of SNA Active in IBD models Abs [Oligonucleotide] ( M) Gross Pathology Score AST Nebulized AST

12 Immuno-oncology SNAs

13 AST-008 Increases Efficacy of Checkpoint Inhibitors in a Number of Mouse Cancer Models Checkpoint inhibitors remove immune suppressive cancer signals, allowing for latent immune response to clear the tumor ( brake off ) 70-80% of tumors are non-inflamed and have little to no latent immune response AST-008 increases the magnitude and intensity of the latent immune response ( gas on ) 13

14 Potentiating Activity of Anti-PD-1 and Conferring Adaptive Immunity in Model of EMT-6 Breast Cancer Over 90% reduction in tumor volume in combination group compared to PD-1 antibody alone AST-008 resulted in an 88% average decrease in tumor volume compared to linear oligonucleotides Re-Challenge EMT-6 7 out of 8 mice in the combination group were tumor free AST-008 Anti-PD-1 **p < 0.01 vs. Vehicle Mice treated with AST-008 and anti-pd-1 developed antitumor immunity and rejected the same (EMT-6), but not a different (4T1 or CT26), tumor challenge without further treatment AST-008: 0.8 mg/kg/dose; Anti-PD-1: 10 mg/kg/dose n=8 14

15 AST-008 Phase I Objectives Safety, efficacy Treatment Arms AST-008, AST-008 plus checkpoint inhibitor Indications Endpoints One or more of: Melanoma Bladder cancer Breast Colorectal Other solid and hematological cancers Primary: Safety Secondary: Efficacy, Maximum tolerated dose, Phase II dose verification 15

16 Unlocking the Potential of Nucleic Acid Therapeutics using Nanotechnology Spherical Nucleic Acid (SNA) Technology 3-D design of SNAs overcomes limitations of existing nucleic acid therapies Broad application across multiple disease areas and organ types Strong patent coverage with expiry beyond 2026 Lead Therapeutic Candidates Address Validated Targets AST-005: SNA targeting TNF, topical administration for mild to moderate psoriasis AST-008: SNA of TLR9 agonist, for immuno-oncology applications, in combination with checkpoints and as monotherapy Opportunities to Expand Pipeline and Partner the Technology Going beyond the liver, with opportunities in brain, eye, GI tract, lung and skin Ability to incorporate different types of nucleic acid chemistries In oncology, potential to link SNAs with antigens of interest and work in combination with other immunotherapies Leading Expertise of Scientific Team and its Advisors Proven team with deep expertise in oligonucleotide therapeutics Guided by an accomplished SAB and Board Over $42M of equity raised 16

17 Management Team and Board of Directors Management Team David Giljohann, PhD Chief Executive Officer Board of Directors Chad Mirkin, PhD Founder David Snyder, MBA Chief Financial Officer C. Shad Thaxton, MD, PhD Founder David Walt, PhD Ekambar Kandimalla, PhD Chief Scientific Officer Gordon Beck, PhD VP, Business Development Jay Venkatesan, MD, MBA Helen Kim, MBA Ayer Capital 17

18 Contact David Giljohann, PhD, CEO 18

19 Lead Development Programs Development Stage Therapeutic Candidate Indication Research In Vivo Optimization Preclinical Development Phase 1 Milestones Gene Regulation AST-005 Targeting TNF SNA Targeting IL17RA SNA Targeting IL4RA Mild to moderate psoriasis Inflammatory disorders Inflammatory disorders CTA submission 2H 2015 Phase 1 readout 2H 2016 Immuno-Oncology AST-008 with Checkpoint Inhibitor AST-008 with Antigen AST-008 Monotherapy Solid tumors Solid tumors Solid tumors For one or more of these approaches: IND submission 2H 2016 Phase 1 initiation 1H