Nanotechnology: A Brief History and Its Convergence with Medicine. Weston Daniel, PhD Director of Program Management

Nanotechnology: A Brief History and Its Convergence with Medicine Weston Daniel, PhD Director of Program Management

Outline Introduction The Nanoscale Applications Realization of a Vision

There s Plenty of Room at the Bottom I am not afraid to consider the final question as to whether, ultimately in the great future we can arrange the atoms the way we want; the very atoms, all the way down! -- Richard Feynman December 29, 1959 California Institute of Technology

Historical Significance of Nanomaterials 300 1500 1857 1947 1974 1985 1990s 2000s Observation of Nanoscale Phenomena Early Understanding of the Nanoscale/ Era of Miniaturization Rational Design and Manipulation of Nanoscale Objects

How Small is a Nanometer? 50 nm DNA (width) ~2 nm Gold Nanoparticles 2-80 nm Silver Nanoprism 5-75 nm Flu Virus 100 nm

Tools for Studying Nanoparticles Scanning Electron Microscope (SEM) Transmission Electron Microscope (TEM) Scanning Tunneling Microscope (STM) Au (100) Surface

Nanotechnology: An Ambiguous Term 1. Developing tools for making, characterizing, and manipulating materials on the nanometer (nm) length scale 2. Determining the chemical and physical consequences of miniaturization.

On the Nanoscale, Size, Shape, as Well as Composition Matter Rayleigh Light Scattering of Nanoparticles Ag Nanoprisms ~100 nm Au Spheres ~100 nm Au Spheres ~50 nm Ag Spheres ~100 nm Ag Spheres ~80 nm Ag Spheres ~40 nm 200 nm 200nm (the same for all the images)

Nanotechnology: An Ambiguous Term 1. Developing tools for making, characterizing, and manipulating materials on the nanometer (nm) length scale 2. Determining the chemical and physical consequences of miniaturization. 3. Exploiting the ability to miniaturize and its consequences in the development of new technology.

Nanotechnology: Areas of Impact Electronics Security and Defense Nanotechnology Medicine Clean Water and the Environment Energy

Where is Nanotechnology Now? Sunscreens Sporting Goods Sunscreen chalky (war-paint) zinc creams replaced by clear creams with nano-sized zinc oxide particles Home Appliances High-strength carbon composite materials Fabrics Protection from bacteria using thin film coatings and silver particle embedded plastics Stain protection & spill protection - by Nano-Tex

Where is Nanotechnology Now? Disease Detection Bone Replacement Integrated Circuits FDA-cleared Verigene System for detection of blood stream infections Nanocrystalline bone graft scaffold provides high surface area for cell growth Wafer-scale production of transistors at Intel

Where is Nanotechnology Now? ~100 nm

Nanotechnology: Areas of Impact Electronics Security and Defense Nanotechnology Medicine Clean Water and the Environment Energy

Nanotechnology: Areas of Impact Electronics Security and Defense Nanotechnology Medicine Clean Water and the Environment Energy

The Convergence of Nanoscience and Nanotechnology with Medicine Diagnostics Imaging Therapeutics FDA-Cleared Verigene System Animals Cells AuroLase Therapy (Nanoshells) High sensitivity and selectivity molecular diagnostics In vivo imaging materials (better contrast, theranostic capabilities) Tools for genetically manipulating cells and making intracellular measurements New and potentially better approaches to drug delivery and gene therapy

SNA Technology: A Powerful Platform for Nucleic Acid Therapeutics Proprietary, 3D SNAs treat diseases at genetic origins Unlock the potential of nucleic acid therapeutics in large, new therapeutic areas Address targets inaccessible to small molecules and antibodies Potential applications in eye, skin, lung, GI tract, brain, and hematological and solid cancers Cross biological barriers (e.g. skin) when administered locally Produce powerful anti-tumor immune response in mouse models Well protected with IP; sit well outside alternate approaches AST-005, topical anti-tnf for psoriasis (Phase 1 trial expected in 1H 2016) Preclinical data demonstrate TNF knockdown in human psoriatic skin Safety, efficacy and biomarker readouts expected in 2H 2016 Large unmet medical need in mild / moderate psoriasis AST-008 for immuno-oncology (Regulatory filing expected in 2H 2016) Enhanced efficacy against variety of cancers in mouse models in combination with certain checkpoint inhibitors 18

The Spherical Nucleic Acid (SNA) Linear DNA Oligonucleotides can be antisense (Science, 2006), sirna (JACS, 2009), mirna (Genes and Dev., 2015) or immuno-modulatory (PNAS, 2015), Amenable to a variety of attachment chemistries and oligonucleotide modifications SNA 19

SNA Platform Represents the Next Generation of Nucleic Acid Therapeutics Important Biological Properties Existing Technology SNAs Amenable to multiple gene regulation approaches Effective against intracellular targets Entry via receptors found primarily on liver cells Entry via receptors found ubiquitously, including liver Can readily enter cells and organs outside the liver No need for encapsulation No need for complexation Effective for immuno-oncology applications Novel IP 20

Gene Regulatory SNAs

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 2017 22

AST-005 Preclinical Data Demonstrated target engagement and mechanism of action in viable psoriatic human skin Demonstrated uptake into viable human skin Demonstrated efficacy in mouse models of the disease SNA SNAs Enter Human Psoriatic Skin After Topical Application Epidermis (SNA in red) Negative Control 0% Knockdown in Psoriatic Human Skin AST-005 69 ± 14% 23

AST-005 Reverses Psoriasis in Mouse Model of the Disease No SNA TNF SNAs 24

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 25

Mild to Moderate Psoriasis is an Unmet Medical Need Parameters Competitive Advantage Development Advantage Prevalence Topical Psoriasis Market Key Information SNAs penetrate into skin when applied topically and reduce TNF mrna level Rapid clinical trials Up to 7.5 MM Americans have psoriasis $850 MM worldwide (2008) Distribution of Psoriasis Severity Moderate to Severe Mild to Moderate 80% 20% Market size: Nat. Rev. Drug Discov. 8, 767-768 26

Immuno-oncology SNAs

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 ) 28

AST-008 Potentiates Activity of anti-pd-1 Antibodies in PD-1 Resistant Tumors and Confers Adaptive Immunity (Mouse Breast Cancer Model) Tumor Volume (mm 3 ) 2000 1500 1000 500 AST-008 Anti-PD-1 Vehicle Anti-PD -1 Anti-PD-1 + Linear Oligo Anti-PD-1 + AST-008 Naive Mice ** 0 0 10 20 30 40 50 60 Days Re-challenge * = p < 0.05; ** = p < 0.01 * 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 7 out of 8 mice in the combination group were tumor free Mice treated with AST-008 and checkpoint inhibitors resist second tumor challenge without additional therapy AST-008: 0.8 mg/kg/dose; Anti-PD-1: 10 mg/kg/dose n=8 29

AST-008 Synergizes with anti-ctla4 Antibody (Mouse Colorectal Cancer Model) Tumor Volume Survival AST-008 Anti-CTLA4 Over 75% reduction in tumor volume in combination group versus anti-ctla4 Over 42% increase in median survival in combination group versus anti-ctla4 (52.5 days vs 37 days) AST-008: 0.3 mg/kg/dose; Anti-CTLA4: 10 mg/kg/dose; n=10 30

AST-008 Reduces Tumor Growth and Increases Survival in Orthotopic Mouse Bladder Cancer Model AST-008 As a Monotherapy in Sub-Q model AST-008 With Checkpoint Inhibitor in Orthotopic model AST-008 BCG AST-008 decreases tumor volume versus vehicle and a standard of care, BCG AST-008: 2 mg/kg/dose BCG: 1.35 mg/dose n=8 AST-008 Anti-PD-1 Increased in overall survival in combination group versus anti-pd-1 antibody alone AST-008: 2 mg/kg/dose Anti-PD-1: 10 mg/kg/dose n=13 *** p < 0.001 31

AST-008 and a-pd-1 Combination Groups Reduces Tumor Growth in B16F10 Melanoma Model Mean Tumor Vol. (mm 3 ) 3000 2000 1000 AST-008 Anti-PD-1 V eh icle Anti-PD -1 AS T-008 AST-008 + Anti-PD-1 0 0 10 20 30 40 Days ** ** = p < 0.01 100 % reduction in tumor volume in AST-008 and combination groups compared to PD-1 antibody alone At day 39, 10 out of 10 mice in the AST-008 and a-pd-1 combination group alive; 8 out 10 for AST-008 alone; 3 mice alive in anti-pd-1 alone AST-008: 0.8 mg/kg/dose; Anti-PD-1: 10 mg/kg/dose n=10 32

SNA Technology: A Powerful Platform for Nucleic Acid Therapeutics Proprietary, 3D SNAs treat diseases at genetic origins Unlock the potential of nucleic acid therapeutics in large, new therapeutic areas Address targets inaccessible to small molecules and antibodies Potential applications in eye, skin, lung, GI tract, brain, and hematological and solid cancers Cross biological barriers (e.g. skin) when administered locally Produce powerful anti-tumor immune response in mouse models Well protected with IP; sit well outside alternate approaches AST-005, topical anti-tnf for psoriasis (Phase 1 trial expected in 1H 2016) Preclinical data demonstrate TNF knockdown in human psoriatic skin Safety, efficacy and biomarker readouts expected in 2H 2016 Large unmet medical need in mild / moderate psoriasis AST-008 for immuno-oncology (Regulatory filing expected in 2H 2016) Enhanced efficacy against variety of cancers in mouse models in combination with certain checkpoint inhibitors 33

Realization of a Vision Image courtesy of the Mirkin lab, Northwestern University