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Nano Delivery of Cancer Therapeutics & siRNA A smart delivery system – small, safe, simple, and versatile. Improved Efficacy Lower Dosing Fewer Side Effects The Opportunity Employ NanoJackets to create more effective cancer and potentially gene therapeutics at lower dosing with fewer side-effects 2 NanoJackets Are Distinct • • • • • • 3 Small & do not agglomerate (20 – 50nm) Protect Active Pharmaceutical Ingredient Calcium Phosphate based Increased time in circulation Dissolve in the cell Scalable and low-cost manufacturing NanoJacket Structure Active Pharmaceutical Ingredient Calcium Phosphate NanoJacket Surface Treatment (Carboxylic Acid, Amine, or PEG) 4 Keystone Nano Overview • • • • Licensed and internally developed IP In-Vivo Data and Characterization of nanoparticles Focused and expedited path to Market Effective Partnerships with Nalco driving toward product revenues • Ability to “package” compounds and siRNA in nano scale Calcium Phosphate 5 Keystone Nano Summary KN Lead Compound Application Area Label Objective Doxorubicin Breast, Bladder, Stomach, Ovaries, Thyroid Similar efficacy with decreased nausea, vomiting, decrease in white blood cells, hair loss, congestive heart failure, cardiomyopathy Doxorubicin Comparative Drugs KN Additional Docetaxel, siRNA, Etc. Compounds 6 NanoJackets are Molecular Smart Bombs; Encapsulated components are released as a function of pH NanoJackets NJs 7 Doxorubicin NanoJackets Treating Dox Resistant Cancer 1. This is the 1st trial of NanoJacketed Doxorubicin in a Doxorubicin Resistant breast cancer model and dose level or schedule has not yet been optimized. 2. NanoJacketed Doxorubicin is at 10% of concentration of free doxorubicin. 3. Dosing was 3 times weekly, which has not been optimized. 8 Near-Infrared Emitting Fluorophore-Doped Calcium Phosphate Nanoparticles for In Vivo Imaging of Human Breast Cancer ACS NANO Erhan I˙. Altınoǧlu, Timothy J. Russin, James M. Kaiser, Brian M. Barth, Peter C. Eklund, Mark Kester, and James H. Adair 9 PEG Coated NJs 10 Intellectual Property A. Patent Application – Kester / Adair use of NanoJackets in cancer product applications B. Patent Application – Adair / Kester on process to make and “NanoJacket” drugs C. Patent Applications (KN and Nalco) on methods and applications relating to industrial uses D. Patent Application (KN) on alternative methods of manufacturing E. Know-how in creating NanoJackets 11 Development Path Partnering Discussions Co-Development Agreements Testing NanoJackets in Animal Models Studies as Advised by Regulatory Team & FDA New Drug Application 505 (b) (2) Trial 12 Keystone Nano Network Research Group Strategic Advisors Investor Groups Corporate Partners Zetachron (4) Sage I-Networks Silence Therapeutics Nalco (10) Axiom Capital Management White Door Inc. Genentech PSU COM Kester RG (5) Ben Franklin Axiom Led Individuals Nalco Kruse Consulting Ben Franklin PSU MRI Adair RG (5) Partnership with Nalco • Joint venture is - NanoSpecialties LLC • Focus on industrial applications - nonpharmaceutical, non-biotechnology, and nonimaging applications • Nalco provides up front research investment, milestone payments, and profit sharing • First Industrial Product Launch 2009 14 Investment Opportunity • KN is finalizing a multi-million investment in development with Nalco around our joint venture • KN is seeking to complete a $7 million pre-A convertible debt round for the Cancer / siRNA applications of the technology • KN will test its first product in a comparison trial within 18 months of financing • KN will file an NDA within 24 months of financing 15 Thank You! For More Information Contact: Jeff Davidson Keystone Nano, Inc. 1981 Pine Hall Road State College, PA 16801 [email protected] (814) 466-5080 16 505 (b) (2) • Shorter, less expensive regulatory path • Testing CHANGE from approved therapeutic, no need to repeat Phase 1, 2, 3 trials • More than 100 therapeutics approved • Often used for alternative delivery systems • Examples – Abraxane, Doxil, ANX-514 17 Ca binding Free siRNA 18 RNA-NJs siRNA control Boundsi RNA RNA-NJs + EDTA No Ca siRNA is Captured and Protected by NanoJackets NanoJacket payloads are delivered intracellularly 5 Cy3-NanoJackets •Cy3 is a fluorescent, organic molecule which has been encapsulated in NanoJackets Free cy3 + cytochalasin D •Punctuate staining seen when Cy3-NJs are treated with cytochalasin D suggests that late endocytosis is involved in NJ dissolution •Similar staining pattern in endothelial cells treated with free Cy3 and Cy3-NJs suggests NJs have dissolved Competitive Approaches Company (Product) Technology Key Difference J & J (Doxil) Liposome NJ likely to provide improved delivery and fewer lipid associated side effects Abraxis Oncology (Abraxane) Albumin Coupled Taxol NJ should not cause pains in joints and muscles pSividia Silica NJs are soluble and less toxic Tempo Pharmaceuticals Combined Delivery of APIs NJ are simpler to produce and validate with clinical trials Insert Therapeutics Polymeric particles NJ offer pH dependent dissolution and have better biological compatibility Bind Biosciences Polymeric particles NJ pH dependent dissolution and have better biological compatibility 20 NanoJackets (NJs) • 40 nm, non-toxic, stable, calcium phosphate • Targetable, pH dependent dissolution • Provides intracellular release of drugs • Lessens systemic exposure and toxicity • Shown to allow use of potent/insoluble drugs • Simple surface chemistry for targeting moieties 21 Key Team Members • Jeff Davidson, CEO, BS Chemical Engineering, MBA – Developed Partnerships with Nalco & Ben Franklin raising $1.5 million to support KN – Founded PA BIO, Co-Founder of KN • Mark Kester, Chief Medical Officer, Ph.D. – G. Thomas Passananti Professor of Pharmacology Hershey Medical – Scientific Advisor to Several Companies • Jim Adair, Chief Science Officer, Ph.D. – Developed NanoJacket Technology – Professor of Materials Science and Engineering – – • • • • • 22 Robert Cornwall, VP Operations, MS Mylisa Paretter, Technical Lead, Ph.D. Penn State University / Hershey Medical Nalco, Inc. Sage Advisors, Inc. Axiom Capital, Inc. Mostafa Analoui Keystone Nano Summary KN Lead Compound Application Area Label Objective Doxorubicin Breast, Bladder, Stomach, Ovaries, Thyroid Similar efficacy with decreased nausea, vomiting, decrease in white blood cells, hair loss, congestive heart failure, cardiomyopathy Comparative Drugs Doxorubicin (Likely Doxil after NDA) Nano - Differentiation Calcium Phosphate 20 to 40 nm particle with good safety profile – small, simple, non-exotic Evidence of Efficacy Cellular and animal experiments have demonstrated efficacy. Additional animal experiments are planned Targeting We have early supporting evidence supporting longer circulatory residence time and Enhanced Permeability and Retention effects. Targeting Moieties KN views additional targeting moieties on the surface as being opportunities for 2nd generation nanoparticles rather than 1st generation. 23 Summary of NanoJacket Experimentation • Lack of calcium-induced toxicology for amine functionalized NanoJackets in vitro (normal calcium currents in imaged neural stellate ganglia) as well as in vivo (ApoE knock out model of atherosclerosis); • In-vitro efficacy against drug sensitive and drug resistant breast cancer cells with Ceramide NanoJackets; • In-vitro efficacy against melanoma cells with Ceramide NanoJackets; • In-vivo (mice) biodistribution data shows effect of surface functionalization • In-vivo (mice) safety / efficacy for delivery of NanoJacketed Doxorubicin 24 NanoJackets are non-toxic In-Vivo 25 1. NanoJackets do not affect weight gain of ApoE knockout mice, a model of atherosclerosis 1. Dose of 1015 NanoJackets three times per week NanoJacketed Ceramide (as API) kills drug sensitive and drug resistant breast cancer cells 1. At 1/5 of the dosing NanoJackets are approximately 7 times as effective 2. NanoJackets are effective against drug resistant cells (Panel B) 26 Ceramide NanoJackets Image & Treat Melanoma Cells Untreated Melanoma Cells Melanoma Imaged with NanoJackets NanoJacketed Ceramide Eliminates Melanoma Cells Panel 1 – DAPI Stained Melanoma Cells Panel 2 – Demonstrating NanoJackets Image (Target) Melanoma Cells Panel 3 – When treated with NanoJacketed Ceramide the cells quickly die 27 Ceramide NanoJackets reduce melanoma growth In Vivo without toxicology 1. Mice treated with NanoJackets were not harmed. 2. Mice treated had a 40% smaller tumor at the conclusion 28 of the study with suboptimal dose of Ceramide PEG Coated NanoJackets • Image of Mouse with NJ at right showing Small Intestine recirculation of NJs for extended circulation • NJs provide sustained distribution as Duodenum shown in the photo of the NJs at right • Free ICG entirely susceptible to hepatic clearance (Secretion in bile through gastrointestinal track) Pancreas Stomach • Localization in tumors evident with Excised GI Track after 4-hour PEGylated NJs after 24 hours ICG-doped NJ injection 29 Work Underway DEVELOPMENT EXPERIMENTS PLANNED • Dose Response versus free Dox (7 groups of 6 animals) • Surface Treatment Effects (4 groups of 6 animals with dosing) • CRO Toxicology and biodistribution / PK Study (designs being planned) REGULATORY INITIATIVES • Prepare for Pre-IND discussions with FDA (planning underway) 30 Summary Small, simple, safe, versatile delivery technology Large cancer therapy opportunities Expedited / Advantaged Pathway to Market Protected IP Strong in-vivo data 31