AstraZeneca Biologics Day Presentation 7 December 2007

Cautionary Statement Regarding Forward-Looking Statements In order to utilise the ‘Safe Harbor’ provisions of the United States Private Securities Litigation Reform Act of 1995, AstraZeneca is providing the following cautionary statement. These presentations contain forward-looking statements with respect to the financial condition, results of operations and businesses of AstraZeneca. By their nature, forward-looking statements and forecasts involve risk and uncertainty because they relate to events and depend on circumstances that will occur in the future. There are a number of factors that could cause actual results and developments to differ materially from that expressed or implied by these forward-looking statements. These factors include, among other things, the loss or expiration of patents, marketing exclusivity or trade marks; exchange rate fluctuations; the risk that R&D will not yield new products that achieve commercial success; the impact of competition, price controls and price reductions; taxation risks; the risk of substantial product liability claims; the impact of any failure by third parties to supply materials or services; the risk of delay to new product launches; the difficulties of obtaining and maintaining governmental approvals for products; the risk of failure to observe ongoing regulatory oversight; the risk that new products do not perform as we expect; and the risk of environmental liabilities. Biologics Day 7 December 2007 David Brennan, CEO Biologics Day 7 December 2007 AstraZeneca strategic priorities “MAKING THE MOST MEANINGFUL DIFFERENCE TO PATIENT HEALTH THROUGH GREAT MEDICINES” Strengthen the pipeline Grow the business Reshape the business Change our behaviour and our culture OUR VALUES Biologics Day 7 December 2007 Pipeline strengthened Faster, leaner, better R&D Phase III up from 5 to 10 projects Combined Phase I & II up by 50% Externalisation 13 major licensing deals in ’05-’07 Strategic move into biologics Strengthen the pipeline Biologics Day 7 December 2007 Biologics today and in the future 100 Best Selling Drugs 2007 USD (consensus estimates) Bioengineered vaccines 2% Biologics 24% Biologics 37% 2012 USD (consensus estimates) Bioengineered vaccines 5% Small molecules 74% Small molecules 58% Source: EvaluatePharma Biologics Day 7 December 2007 AstraZeneca and New MedImmune Fully leverage AZ investment and expertise in key disease areas CAT discovery combined with MEDI development, manufacturing, regulatory and commercial Global network of clinical investigators Commercialisation on a truly global scale Biologics Day 7 December 2007 Agenda AstraZeneca R&D: Faster, Leaner, Better The New MedImmune MedImmune R&D Overview Antibody and Protein Therapeutics Vaccine Discovery Process Development Infectious Disease & Pediatric Vaccines Oncology Q&A Respiratory & Inflammatory Diseases Commercial Overview: RSV & Vaccines Q&A Closing Remarks David Brennan Biologics Day 7 December 2007 John Patterson David Mott James Young Peter Kiener George Kemble Gail Wasserman Genevieve Losonsky Dirk Reitsma Barbara White Peter Greenleaf AstraZeneca R&D Faster, Leaner, Better John Patterson, Executive Director, Development Biologics Day 7 December 2007 “Quality on Time” Quality Better Pipeline PERFORMANCE Leaner Organisation Faster Cycle-times Cost Speed Biologics Day 7 December 2007 Better Pipeline … since the FY 2006 Results Progressions and additions since FY 2006 results Projects 180 160 140 120 100 80 60 40 20 0 FY 2004 MedI Pre-clinical FY 2005 Pre-clinical Phase I FY 2006 Phase II Dec. 2007 Phase III LCM 156 22 120 106 91 25 5 13 17 31 45 49 25 6 13 17 25 5 18 23 10 20 Crestor™/Fenofibric acid, Dapagliflozin, ZD4054, Motavizumab, PN400 & Recentin GBM additions to Phase III MEDI-524, MEDI-561, MEDI-528, EBV vaccine added to Phase II, AZD6765, AZD4121, AZD2836, AZD0530, AZD5672 & AZD2281 progress to Phase II 14 additions and 18 progressions into Phase I 42 projects enter the pipeline in Pre-clinical 42 43 19 Biologics Day 7 December 2007 Better Pipeline Phase III PreClinical Phase I Phase II Phase III portfolio PN400 Saxagliptin LCM PN400 Jul – successful FDA interaction Jul/Aug – development accelerated by 6 months 7 Sep – passed TG3 19 Sep – First patient in within 8 working days CRESTOR™/ Fenofibric Acid ZACTIMA™ RECENTINTM CRESTOR™/ Fenofibric Acid Sep – TG3 agreed and announced Study exploring lower efficacy moving forward NDA scheduled for 2009 filing RECENTINTM AZD6140 Dapagliflozin ZD4054 Motavizumab Biologics Day 7 December 2007 Faster cycle times 2010 <8 years 2007 8.9 years 2003 - 05 10.6 years Preclinical Phase I Phase II Phase III and launch Quality Processes Quality Programmes Quality CDs Behaviours Biologics Day 7 December 2007 Faster cycle times Pre-clinical target cycle times 2007 Objective AZD2184 AZD2066 AZD2624 AZD3199 AZD1283 AZD9668 AZD4121 AZD1386 AZD3241 AZD8330 AZD1305 AZD1744 AZD1236 AZD7762 AZD1940 AZD0328 AZD6370 0 10 Months Biologics Day 7 December 2007 20 30 Leaner organisation Increasing R&D budget – but improving cost effectiveness Programmes delivering 5% productivity improvements per annum between 2008 and 2011 Approx 1,000 FTEs impacted overall Further Disease Area strategy review conducted Streamlining Clinical data management delivering $30m per year PAR&D re-organisation showing 30% less resource required per project by end of 2007 Centralising Regulatory delivering an 18% headcount reduction by June 2008 Biologics Day 7 December 2007 AZ R&D/MedImmune Strategically aligned, operationally independent R&D Board Market Market Biologics Product Development Aligned TA strategy Small Molecules Product Development CDs Biologicals CDs Small Molecules Combined small & large molecule target identification & Discovery collaboration Biologics Day 7 December 2007 R&D Board Governance with a focus on delivery Jan Lundberg Discovery John Patterson Development Jim Young MedImmune Delivering key targets earlier: 10 projects in Phase III in 2007 vs 2010 John Kennerley Dev. Projects John Goddard SPBD Julie Brown Finance Tony Zook Global Marketing & North America Biologics Day 7 December 2007 AstraZeneca R&D Faster, Leaner, Better February 2006 December 2007 • Faster cycle-times • Early evidence of improving speed and quality • • Moving from a cycle time of 10.6 years towards target of 8 years • Leaner organisation Embarking on a change drive • All major R&D functions ‘re-shaping’ • Better pipeline 12 First Time in Man projects 5 Phase III projects 120 projects in pipeline Implementing long-term biologics strategy with CAT • • 23 First Time in Man projects • 10 Phase III projects • 156 projects in pipeline World-class biologics capability with ‘new’ MedImmune Biologics Day 7 December 2007 The New MedImmune David M. Mott CEO and President Biologics Day 7 December 2007 The New MedImmune Responsible for all global biologics-related activities Combines MedImmune, Cambridge Antibody Technology and AstraZeneca biologics (minus financial synergies) Operationally independent, strategically aligned – Maintain agility and entrepreneurialism – Benefit from expertise and capabilities of broader organization AZ is clear leader in biologics among pharma peers – – – – Antibodies and beyond; vaccine technologies Process development and manufacturing Commercial infrastructure and capabilities MedImmune has approximately 100 biologics in R&D Biologics Day 7 December 2007 Achievements 1996-2006 Revenues: 36% CAGR (in millions) $1,400 $1,200 $1,000 $800 $600 $400 $200 $0 Headcount: 26% CAGR 2,500 2,250 2,000 1,750 1,500 1,250 1,000 750 500 250 0 $500 $450 $400 $350 $300 $250 $200 $150 $100 $50 $0 R&D: 30% CAGR (in millions) 96 97 98 99 00 01 02 03 04 05 06 96 97 98 99 00 01 02 03 04 05 06 96 97 98 99 00 01 02 03 04 05 06 – Launched RespiGam 1/96 – HPV vaccine FTIM 2/97 – Launched Synagis 9/98 (3.5 years FTIM to approval) – – – – Acquired US Bioscience 11/99 Acquired Aviron 1/02 Launched venture fund ‘02 36 BD deals ’04-’07 Biologics Day 7 December 2007 MedImmune Business Profile Fully built-out, vertically integrated biotechnology company – – – – U.S. sales and marketing organization R&D centers: Md., U.K., Calif. Cell culture and vaccine manufacturing Business development, acquisition and venture initiatives Proven entity; end-to-end capabilities; record of success – Developed and commercialized: CytoGam®, RespiGam®, Ethyol®, Synagis® and FluMist® Biologics Day 7 December 2007 Company of Firsts Synagis®, first MAb approved for infectious disease ($1.3B WW sales; >1M babies protected) VLP technology for HPV vaccines (>$6B peak sales) Discovered Humira® (>$2B in 2006 WW sales) First advance in flu technology in 60+ yrs (55% better vs. TIV) Biologics Day 7 December 2007 MedImmune Operations Philadelphia, PA FluMist Blend/Fill/Pack Santa Clara, CA Vaccines R&D & Pilot Plant Bensalem, PA FluMist Warehouse Nijmegen, Netherlands Ethyol Mfg, Clinical Fills Mountain View, CA Vaccine R&D Hayward, CA MAb R&D site Frederick, MD MAb Manufacturing Cambridge, England Antibody R&D Louisville, KY FluMist Distribution Gaithersburg, MD Headquarters and R&D Speke, England FluMist Mfg Rockville, MD Cell culture FluMist Mfg Biologics Day 7 December 2007 Major Changes From Dec 2006 to Dec 2007 Capabilities – Discovery research; Ab screening and technology – Global marketing and sales reach People – Approx 300 CAT personnel (~250 R&D) – Two new research sites Expanded pipeline – New targets and new therapeutic areas Accelerated pipeline momentum Biologics Day 7 December 2007 MedImmune Research Portfolio Excluding CAT and AZ biologics Target Validation Lead Development & Profiling Pre-clinical Development Phase I Phase II Phase III VM 11 Vaccine 3 Rheum 2 Rheum 3 Rheum 4 Rheum 5 Resp 1 IMK 1 Rheum 1 GFSS 2 GFSS 3 GFSS 4 IMK 2 IMK 3 GFSS 5 GFSS 6 Vaccine 1 Vaccine 2 MAb 1 MAb 2 MAb 3 MAb 4 MAb 5 motavizumab topical anti-IFNaR Hsp90 oral IPI 504 Hsp90 oral IPI 493 RSV vaccine Extended half-life MAb Cell culture flu anti-IL-5R anti-IFNa anti-CD19 Bite RSV drug PIV3/RSV vaccine PIV-3 vaccine Pandemic flu vaccine S. pneumo vaccine anti-IL-9 Hsp90 iv Motavizumab (treatment) EBV vaccine motavizumab VM = Vascular Modulator GFSS = Growth Fact Survival Signaling IMK = Immune Mediated Killing Oncology Infectious Disease R,I&A Biologics Day 7 December 2007 Combined “New” MedImmune Research Portfolio Target Validation Lead Development & Profiling Pre-clinical Development Phase I Phase II Phase III VM 11 Resp 10 Resp 11 Resp 12 Resp 13 Resp 14 Rheum 9 OA 2 IMK 5 IMK 6 IMK 7 IMK 8 IMK 9 IMK 10 IMK 11 IMK 12 Vaccine 3 VM 9 VM 10 GFSS 7 GFSS 8 GFSS 9 GFSS 10 GFSS 11 GFSS 12 GFSS 13 SC 1 CV/GI 2 CNS 1 CNS 2 CNS 3 Rheum 2 Rheum 3 Rheum 4 Rheum 5 Resp 1 Rheum 6 Rheum 7 Rheum 8 Resp 2 Resp 3 Resp 4 Resp 5 Resp 6 Resp 7 Resp 8 Resp 9 OA 1 IMK 1 Rheum 1 GFSS 2 GFSS 3 GFSS 4 IMK 2 IMK 3 GFSS 5 GFSS 6 IMK 4 VM 1 VM 2 VM 3 VM 4 VM 5 VM 6 VM 7 VM 8 Vaccine 1 Vaccine 2 MAb 1 MAb 2 MAb 3 MAb 4 MAb 5 motavizumab topical GFSS 1 CAT-412/NGF ALZ anti-IFNaR Hsp90 oral IPI 504 Hsp90 oral IPI 493 RSV vaccine Extended half-life MAb Cell culture flu anti-IL-17 anti-IGF anti-IL-5R anti-IFNa anti-CD19 Bite RSV drug PIV3/RSV vaccine PIV-3 vaccine Pandemic flu vaccine S. pneumo vaccine anti-IL-13 anti-CD22-PE anti-GM-CSFR anti-IL-9 Hsp90 iv Motavizumab (treatment) EBV vaccine motavizumab CTD CV/GI 1 VM = Vascular Modulator GFSS = Growth Fact Survival Signaling IMK = Immune Mediated Killing CNS/Pain CV/GI Oncology Infectious Disease R,I&A Biologics Day 7 December 2007 MedImmune Staffing ~3,000 Employees Administrative 16% Sales and Marketing 20% Clinical/Regulatory 15% 47% Clinical / R&D Manufacturing/QA/QC 18% Research & Development 32% Biologics Day 7 December 2007 Biologics Business Characteristics Rapidly growing markets – 13% CAGR 2007-20101 Longer product life cycles – Lower exposure to generic competition; high unmet need Higher probabilities of success – Higher success rates in clinical development2 Higher/more complex COGS Lower/more targeted sales and marketing 1 2 Source: Datamonitor (MAbs and vaccines) Source: Managerial and Decision Economics Biologics Day 7 December 2007 Strategic Priorities for Biologics 6 INDs (8 CDs) per annum – At least 3 new projects in pivotal trials by 2010; 1 BLA/year steady state Drive value from CAT and Abgenix investments Bring biologics commercial expertise to AstraZeneca Expand external strategic opportunities Fully exploit targets from prior AZ research investment Fully exploit revenues from MEDI products Biologics Day 7 December 2007 Recent Progress and Successes Approval for refrigerated formulation of FluMist® with label expansion to include children down to 2 – CDC advisory committee recommendations for children under 5 and VFC inclusion Filed IND for 3rd generation RSV MAb FTIM – RSV/PIV-3 and PIV-3 vaccines – Anti-GM-CSFR MAb – CAT-8015 (anti-CD22 immunotoxin fusion protein) Additional reverse genetics licenses to Novartis and GSK Efficacy results for motavizumab Phase III leading to early trial halt (BLA 1Q 2008) Biologics Day 7 December 2007 The New MedImmune Delivers biologics ambition faster Positions AstraZeneca as leader in biologics among pharma peers Enhances AstraZeneca pipeline Clear synergies for both parties Above all Provides new strategic, product development opportunities Biologics Day 7 December 2007 MedImmune R&D Overview James Young, Ph.D. President, Research and Development Biologics Day 7 December 2007 Building a World Class Sustainable Biologics Pipeline What is covered under biologics? – Current emerging and novel product classes within MEDI Naked MAbs MAbs with altered effector function MAb conjugates or fusion proteins Bi functional MAb derivatives (BiTE®, dAb etc) Polyspecific MAbs (target 2 or more Ags); oligoclonal Abs Ab mimetics Peptides/peptide derivatives siRNA Live attenuated vaccines Subunit/VP-like vaccines Cancer vaccines (subunit, cells, viral) Biologics Day 7 December 2007 Therapeutic Areas of Focus Respiratory and Inflammatory Disease Infectious Disease Oncology Cardiovascular Gastrointestinal Neuroscience – CNS & Pain Control Biologics Day 7 December 2007 Therapeutic Area Focus Respiratory and Inflammatory Diseases Specialty care products for chronic use in diseases that cause significant morbidity and mortality Significant opportunities exist in asthma, COPD, RA, SLE and OA Target patients will have severe and uncontrolled disease Biologics will be used as add-on therapies Biologics Day 7 December 2007 Therapeutic Area Focus Infectious Disease Focus on antivirals and antibacterials for unmet medical needs and product improvement with novel approaches Vaccines Monoclonal antibodies – – – – Extended half-lives Optimized Fc functionality Heteropolymer technology to bypass need for complement Turn antibody therapy into vaccination approach e.g., heteropolymers as vaccine platform for Staph Biologics Day 7 December 2007 Therapeutic Area Focus Oncology Strong growth expected – – – – New treatments New biology on previously untreated populations Earlier diagnosis Incidence growth Emerging new biological approaches – Enhanced mediated killing – Toxin/drug conjugates – Personalized medicine Biologics Day 7 December 2007 Therapeutic Area Focus Cardiovascular and Gastrointestinal Area of significant size and growth – CV and GI disease remains a leading cause of morbidity and mortality on a global basis Expect biologics to become increasing share of treatment market Core disease expertise in AstraZeneca Biologics Day 7 December 2007 Therapeutic Area Focus Neuroscience – CNS & Pain Control 2nd largest and 2nd fastest growing segment of world-wide pharmaceutical market Size and growth rate sustained by – – – – Aging and demanding population Negative impact of lifestyle (stress) Low remission rates of today´s therapies Huge burden for caregivers and society Potential for a paradigm shift with disease modifying approaches Core disease expertise in AstraZeneca Biologics Day 7 December 2007 Building a World Class Sustainable Biologics Pipeline Ability to achieve ~8 CDs per year steady state @~80% success rate, this gives 6 FTIM Per annum – – – – 3-4 CDs from Cancer 3-4 from Respiratory & Inflammatory Diseases 0-1 from Infectious Disease 0-1 from CV/GI/NS Leverage drugs across therapeutic areas; get more opportunities per CD Biologics Day 7 December 2007 Combined “New” MedImmune Research Portfolio Target Validation Lead Development & Profiling Pre-clinical Development Phase I Phase II Phase III VM 11 Resp 10 Resp 11 Resp 12 Resp 13 Resp 14 Rheum 9 OA 2 IMK 5 IMK 6 IMK 7 IMK 8 IMK 9 IMK 10 IMK 11 IMK 12 Vaccine 3 VM 9 VM 10 GFSS 7 GFSS 8 GFSS 9 GFSS 10 GFSS 11 GFSS 12 GFSS 13 SC 1 CV/GI 2 CNS 1 CNS 2 CNS 3 Rheum 2 Rheum 3 Rheum 4 Rheum 5 Resp 1 Rheum 6 Rheum 7 Rheum 8 Resp 2 Resp 3 Resp 4 Resp 5 Resp 6 Resp 7 Resp 8 Resp 9 OA 1 IMK 1 Rheum 1 GFSS 2 GFSS 3 GFSS 4 IMK 2 IMK 3 GFSS 5 GFSS 6 IMK 4 VM 1 VM 2 VM 3 VM 4 VM 5 VM 6 VM 7 VM 8 Vaccine 1 Vaccine 2 MAb 1 MAb 2 MAb 3 MAb 4 MAb 5 motavizumab topical GFSS 1 CAT-412/NGF ALZ anti-IFNaR Hsp90 oral IPI 504 Hsp90 oral IPI 493 RSV vaccine Extended half-life MAb Cell culture flu anti-IL-17 anti-IGF anti-IL-5R anti-IFNa anti-CD19 Bite RSV drug PIV3/RSV vaccine PIV-3 vaccine Pandemic flu vaccine S. pneumo vaccine anti-IL-13 anti-CD22-PE anti-GM-CSFR anti-IL-9 Hsp90 iv Motavizumab (treatment) EBV vaccine motavizumab CTD CV/GI 1 VM = Vascular Modulator GFSS = Growth Fact Survival Signaling IMK = Immune Mediated Killing CNS/Pain CV/GI Oncology Infectious Disease R,I&A Biologics Day 7 December 2007 Development Goals Through 2010 Seven potential pivotal trial go/no-go decisions* 2008 – Hsp90 (Phase II/III - GIST) 2009 – Anti-IFNα (lupus); anti-IL9 (asthma); CAT-8015 (HCL) 2010 – MEDI-538/MT103 (CLL); anti-IL13 (asthma); anti-IL5R (asthma) *Estimate at least three will progress to pivotal trials Biologics Day 7 December 2007 Building a World Class Sustainable Biologics Pipeline What do we need to support this – We have considerable internal expertise Biologics unit collaborates with Therapy Area Teams at all stages – Leverage capabilities across the whole business – MEDI supplants planned growth of CAT, AZ Biologics Day 7 December 2007 Strategic Alignment Biologics Delivery MedImmune Board Product Development Committee Product Development Team Therapy Area Team AZ Board SET R&D Board Joint Therapy Area Strategy Team Joint Research Area Management Teams Joint Target Selection Committee Research Review Committee Research Team Biologics Day 7 December 2007 1+1+1>3 AZ/MEDI/CAT has created – – – – Bigger and broader portfolio with less risk Larger tool kit Shared clinical, regulatory and development expertise Target ID/validation knowledge Biologics Day 7 December 2007 Potential News and Data Flow Submit motavizumab BLA by 1Q08 Initiate pivotal trial Hsp90 (Phase II/III - GIST) 1H08 FluMist® EU submission 1H08 Phase II efficacy data IL-9 2008 Anticipate 5 FTIM 2008 7 potential pivotal trial go/no-go decisions ’08 – ’10 Biologics Day 7 December 2007 Biologics R&D Summary Leader in antibody and vaccine technology Pipeline contains promising programs across all phases of development and in all target therapeutic areas R&D speed and quality Combine strengths of AZ and MedImmune externalization Biologics Day 7 December 2007 Antibody and Protein Therapeutics Peter Kiener, D.Phil. Senior Vice President, Research Biologics Day 7 December 2007 Building a World Class Biologics Pipeline What are antibody/protein-based biologics? –Current, emerging and novel technologies within MEDI Naked MAbs MAbs with altered effector function MAbs with altered half-lives MAb conjugates or fusion proteins Bifunctional MAb derivatives (BiTE®, dAb etc) Polyspecific MAbs (target 2 or more Ags); oligoclonal Abs Ab mimetics Peptides/polypeptides Biologics Day 7 December 2007 Lead Discovery Variety of Approaches to Ab Development Hybridoma technology – Murine, rat, and hamster MAbs – Transgenic mice for human MAbs (velocimmune technology) Recombinant human Ab or protein discovery – Phage display (besides Ab display, also protein/peptide display) Very large naïve antibody libraries (Medi’s libraries)(CAT) Very large semi-synthetic antibody libraries (Dyax libraries) Phage expression/HTS Ribosome display – – Highly automated (HTS functional screening) – Allow isolation of antibodies with a variety of properties (blocker, neutralizer, internalization, agonist, antagonist, anti-idiotypes, etc.) Biologics Day 7 December 2007 Antibody Generation VelocImmune® mice Phage Display Ribosome Display High Throughput Screening Complementary tools providing HT access to different regions of molecular diversity Biologics Day 7 December 2007 Display Technologies The Core of Our Lead Generation Phage display Naïve libraries totalling 1x1011 diversity Routinely used for affinity maturation (1x109 diversity) Increasingly used for cell-based selections Ribosome display Large variant libraries (>1x1012) Introduce mutations between selections Rapid library construction and selection Biologics Day 7 December 2007 Antibody Structure Fab Fc Biologics Day 7 December 2007 Optimization of Leads through Antibody Engineering Affinity maturation (kon and koff manipulation) Humanization (framework shuffling or rational design approach) and germlining Half-life extension (FcRn YTE technology) Effector function engineering (Fc mutation, afucosylation, and hinge engineering) – Can enhance ADCC >50-fold – Can enhance CDC significantly – Can reduce ADCC/CDC to almost undetectable level Ribosome display pI (isolelectric point) manipulation Biologics Day 7 December 2007 Beyond Traditional Ab Technologies BiTE® (with Micromet) – Bifunctional MAb derivatives; Antibody-drug conjugates (with Seattle Genetics) – Deliver cytotoxic drugs into tumour cells using MAbs Heteropolymer technology (with EluSys) – Target pathogens to RES for clearance Poly-/tri-/bi-specific MAbs – Multispecific MAbs ( targets sets of antigens) Protein mimetics (Tn3Fn3) – Small human protein domains with MAb like specificities Biologics Day 7 December 2007 Summary Building world class biologics pipeline Applying display technologies to drug discovery and optimization – HTS drug discovery Adapt MAbs/proteins to have the desired specificity, affinity, “effector” mechanisms – Optimization of drug biological properties Rationally design properties of MAb – Solubility, stability, PK, route of administration Develop MAb/protein mimetics – Size, stability, IP, multispecificities Biologics Day 7 December 2007 Vaccine Discovery George Kemble, Ph.D. Vice President, Vaccine Research and Development Biologics Day 7 December 2007 Vaccine Technologies Many technologies exist for producing vaccines – Weakened virus: Live, attenuated vaccine (FluMist®) – Vectored vaccine: Live, attenuated vaccine expressing a – – – – protein from another virus Killed virus: Inactivated vaccine (inactivated polio) Virus mimic: Virus-like particle (Gardasil®, Cervarix™) Portion of virus: Subunit vaccine (flu shot, hepatitis B) Others: DNA, peptides, more MedImmune has the expertise to address target diseases with many different vaccine technologies – Key patents for VLPs – Active R&D programs with live, attenuated vaccines; vectored vaccines; and subunits Biologics Day 7 December 2007 Pandemic Vaccines Delivering immense numbers of doses in a short time is a key aspect to protecting the population from an oncoming influenza pandemic LAIV has several advantages compared to conventional inactivated vaccines – Over 180 times more doses of LAIV per egg Doses / Person LAIV TIV 1 2 Total Doses Required 300 M 600 M Doses / Egg 180 1 Flocks Needed to Respond <2 >500 – Protects vaccinated people from influenza that is matched – – to the vaccine as well as influenza that has changed One dose may be sufficient to protect Nasal delivery is easier and relieves the burden of having to source and dispense of billions of needles Biologics Day 7 December 2007 Reverse Genetics Reverse genetics: the ability to produce a specific, engineered influenza virus using recombinant DNA technologies – Dramatic refinement in our toolbox for making the vaccine strains – – on an annual basis Key to pandemic vaccine production Specific pathogenic traits of the pandemic virus can be changed before producing the vaccine This technology has enabled our scientists to understand the basis of attenuation at the molecular level Related technologies are in use to produce vaccine candidates for other important respiratory pathogens like RSV PB2 PB1 PA HA NP M NS NA Plasmid DNAs Vaccine Virus Biologics Day 7 December 2007 Cell Culture Production Flu Vaccine Cell culture production enables modern, controlled manufacturing – Industry standard methods – Significant MedImmune experience Vaccine grown in eggs and in cells has the same genetic composition, therefore, the same properties Clinical trials are expected to start in 2008 Biologics Day 7 December 2007 Vaccine Toolbox Live attenuated intranasal vaccines – – – – – Seasonal flu vaccines Pandemic influenza vaccines Reverse genetics Cell culture production Vectored vaccines Virus-like particles technology Subunits Biologics Day 7 December 2007 Process Development Gail Wasserman Senior Vice President, Development Biologics Day 7 December 2007 Development’s Space Clinical Optimizes the Label SYNAGIS® (PALIVIZUMAB) Development Optimizes the Product for Intramuscular Administration DESCRIPTION: Synagis® (palivizumab) is a humanized monoclonal antibody (IgG1 k) produced by recombinant DNA technology, directed to an epitope in the A antigenic site of the F protein of respiratory syncytial virus (RSV). Synagis® is a composite of human (95%) and murine (5%) antibody sequences. The human heavy chain sequence was derived from the constant domains of human IgG1 and the variable framework regions of the V H genes Cor (1) and Cess (2). The human light chain sequence was derived from the constant domain of C k and the variable framework regions of the V L gene K104 with J k -4 (3). The murine sequences were derived from a murine monoclonal antibody, Mab 1129 (4), in a process that involved the grafting of the murine complementarity determining regions into the human antibody frameworks. Synagis® is composed of two heavy chains and two light chains and has a molecular weight of approximately 148,000 Daltons. Synagis® is available in two formulations: a lyophilized powder and a liquid solution. Lyophilized Powder: Synagis® is supplied as a sterile lyophilized product for reconstitution with sterile water for injection. Reconstituted Synagis® (100 mg/mL) is to be administered by intramuscular injection (IM)only. The reconstituted solution should appear clear or slightly opalescent with a pH of 6.0. Each 100 mg single-use vial of Synagis® lyophilized powder is formulated in 67.5 mg of mannitol, 8.7 mg histidine and 0.3 mg of glycine and is designed to deliver 100 mg of Synagis® in 1.0 mL when reconstituted with 1.0 mL of sterile water for injection. Each 50 mg single-use vial of Synagis® lyophilized powder is formulated in 40.5 mg mannitol, 5.2 mg of histidine and 0.2 mg of glycine and is designed to deliver 50 mg of Synagis® in 0.5 mL when reconstituted with 0.6 mL of sterile water for injection. Liquid Solution: Synagis® (100 mg/mL) is supplied as a sterile, preservative-free solution to be administered by intramuscular injection (IM)only. The solution should appear clear or slightly opalescent with a pH of 6.0. Each 100 mg single-use vial of Synagis® liquid solution is formulated in 4.7 mg of histidine and 0.1 mg of glycine in a volume of 1.2 mL and is designed to deliver 100 mg of Synagis® in 1.0 mL. Each 50 mg single-use vial of Synagis® liquid solution is formulated in 2.7 mg of histidine and 0.08 mg of glycine in a volume of 0.7 mL and is designed to deliver 50 mg of Synagis ® in 0.5 mL. Biologics Day 7 December 2007 Bridge from Research to Commercialization Manufacturing Preclinical supply Clinical supply Product testing Research Support Targets and Clinical candidates Product Life-time Support Analytical and Process Development Assays Cell line selection Manufacturing process Formulation Process Scale Up Fit to Plant Tech Transfer Biologics Day 7 December 2007 Facilities and Experienced Staff Gaithersburg, MD Analytical and process development Cambridge, UK Analytical and process development Gaithersburg, MD Process scale up (500 L) Gaithersburg, MD Clinical manufacturing (500 L and 2000 L) Nijmegen, Netherlands Clinical fills Biologics Day 7 December 2007 Selection Get it Right the First Time Product attributes – Fit the process platform (manufacturability) – Meet formulation goals for intended use (stable, high concentration) Cell line attributes – Meet performance needs (stability, high cell density, – high productivity, bioreactor compatible) Meet product quality needs (low aggregation & fragmentation, suitable glycosylation) Biologics Day 7 December 2007 Bioprocess Highlights Established high titer production platforms for monoclonal antibodies (NS/0 and CHO) – In-house culture media – Animal protein-free including cell cloning (minimize risk to – safety and product/process variability) Same bioreactor technology from development (5 L) through to commercial manufacturing (12,500 L) Scale down predictive models Experience with a range of biologics – VLP technology commercialized for HPV vaccine – Single chain antibodies (BiTE® molecules) – Drug/antibody conjugates Biologics Day 7 December 2007 Abegrin™ Produces 5 g/L at All Scales 6000 3L Average (n=10) 50L Average (n=2) 06XX01 (500L, LMA) 5000 4000 Titer (mg/L) 3000 2000 1000 0 0 5 10 15 20 25 Time (Days) Biologics Day 7 December 2007 Benefits of High Titers 1200 1000 Cost ($/g) 800 Majority 600OTHERS 400 200 MEDI 0 Reduced cost of manufacturing product – Patient benefit – Increased profitability 1 2 3 Titer (g/L) 4 5 6 0 Titer (g/L) # of Batches to make 100Kg Improved plant capacity – Fewer batches to meet – market demand More products in plant 0.5 1 2 5 143 72 35 14 Biologics Day 7 December 2007 Maximize Cell Process Performance and Minimize Facility Changes Enhanced Yield Original 5.0E+06 Xv (cells/mL) 4.0E+06 titer (mg/L) 3.0E+06 2.0E+06 1.0E+06 0.0E+00 0 5 10 15 20 25 time (days) 3000 2500 2000 1500 1000 500 0 0 5 10 15 20 25 time (days) Biologics Day 7 December 2007 Plants Needed to Mfg Synagis® for U.S. 6 5 Number of Plants 4 3 Today 2 1 Actual Plant Requirement With Enhanced Yield Process 0 Year 1 Year 2 Year 3 Year 4 Forecast Plant Requirement With Original Production Process Biologics Day 7 December 2007 Purification, Formulation and Drug Delivery Established purification process platform for monoclonal antibodies – Delivers high product yield and purity – Scalable and fit to commercial plant – Predictive small scale models Flexible formulation capabilities – Design for route of administration MEDI experience for IV, IM, SC and IN (live vaccines) • Liquid (HCLF) and solid dosage form experience AZ experience in pulmonary delivery Experience with devices for drug delivery Commercialized sprayers for IN delivery of flu vaccine Pre-filled syringes and autoinjectors for clinical products Biologics Day 7 December 2007 MEDI Ranks With First in Class Among the highest cell growth and product titers in the industry – Leaders: 2 – 5 g/L vs. Majority: 0.5 – 1 g/L Consistent high titers across antibody products and NS/0 & CHO platforms Among the highest purification yields in the industry – Leaders: >70% vs. Majority: 50-60% Among the leaders in high protein concentration formulations – MEDI: 100-150 g/L vs. Majority: 5-50 g/L – Critical enabling technology for antibody delivery Biologics Day 7 December 2007 Analytical Sciences Advanced product and process characterization tool box facilitates development – Understand relationship between product attributes and – – safety & efficacy Understand relationship between process parameters and product attributes Ability to demonstrate product comparability without additional clinical studies High throughput technologies to meet the needs of the biologics portfolio – Automation and robotics Biologics Day 7 December 2007 New Pilot Facility Meets Capacity for Clinical Manufacturing Biologics Day 7 December 2007 Clinical Manufacturing Capacity and Capability Multi-product concurrent operations Multiple scales (500 L and 2,000 L) Mammalian cell culture and microbial fermentation areas Matched to needs of the biologics portfolio; no further capital investment needed Biologics Day 7 December 2007 Industry Leader in Commercial Cell-Culture Mfg Commercial production since 1999 World leader in high-yield cell culture process Excellent reputation with FDA – Quality practices; regulatory processes Current capacity at FMC: two 2,500 liter bioreactors – Target expansion: four 15,000 L bioreactors (2011) Used for cell-culture flu starting in 2011 Frederick Manufacturing Center Potential Annual Pandemic Cell-Culture Capacity 2 x 2500 liter bioreactors by 2011 – 560M doses Biologics Day 7 December 2007 Key Messages Rich body of knowledge in biologics process and analytical development Mature work force with experience through product commercialization Established NS/0 and CHO high productivity antibody platforms coupled with high yield purification processes Designed predictability into process development and scale up Clinical production and analytical capacity matched to biologics portfolio Integrated and closely coordinated development activities Manufacturing and development geographically close Proven track record of delivering products Biologics Day 7 December 2007 Infectious Disease and Pediatric Vaccines Genevieve Losonsky, M.D. Vice President, Clinical Development Biologics Day 7 December 2007 Strategic Approach ID and Pediatric Vaccines Deliver on RSV disease prevention and treatment – Core strategic area for pipeline development – Multi-prong approach (vaccines, antibodies, small molecules) – Employ novel technologies Apply expertise across therapeutic areas and to other relevant viral targets – Asthmatics, COPD, geriatrics, transplantation – hMPV, PIV-3, rhinoviruses Build current discovery pipeline – Prevent significant hospital acquired neonatal bacterial infections Biologics Day 7 December 2007 RSV History Discovered in 1956 Chanock isolates the virus from children 1957 Epidemiology, transmission, and natural history described over next several decades – 100% of all infants infected before the age of 3 – High risk populations identified with 5 fold higher rates of – Formalin-inactivated vaccine in the 1960s: failed Ribavirin treatment in 1980s RespiGam® iv immunoglobulin: use limited hospitalization and death Reinfections common Biologics Day 7 December 2007 Synagis® (palivizumab) Improvement in RSV Prevention % Relative Reduction in RSV Hospitalization IgG1 humanized MAb Binds to conserved RSV F protein 10 times the activity of RespiGam® 90 80 70 60 50 40 30 20 10 0 IMpact-RSV Trial 78 Overall Reduction 55% p < 0.001 Cardiac Trial 58 Overall Reduction 45% p < 0.003 – Blocks RSV replication in vitro and in lungs of cotton rats 39 29 Preterm <36 weeks CLD Acyanotic Cyanotic CHD CHD Biologics Day 7 December 2007 RSV: A Large Unmet Medical Need High risk infants: ~15% birth cohort – ~60% do not get immunoprophylaxis Infects 50% infants in first year of life – Deaths: 230K globally*; 17,000 U.S.** – Hospitalizations: 3M globally – ~30% with LRI: 30M globally, 1.6M U.S. Childhood – ~50% of childhood “asthma” before the age of 5 years: 8M globally, 250K U.S. At risk adults – >5% of hospitalizations of COPD, asthma, cardiac, elderly *WHO; **Thompson 2003 Biologics Day 7 December 2007 Strategic Goals RSV Prevention Increase the clinical benefit of RSV immunoprophylaxis and expand the target population to FT infants born during RSV season – Motavizumab – affinity enhanced MAb – Provide evidence of additional value with prevention of – wheezing sequelae in 32-35 week preterm infants Explore the possibility of serious RSV prevention via reduced dosing immunoprophylaxis High risk infants and extension of use to term infants Develop live attenuated RSV vaccines – For use in all FT term infants Biologics Day 7 December 2007 Motavizumab Immunoprophylaxis Indication Clinical Trials Study CP101 CP104 CP106 CP118 Population Healthy Adults High-risk Children (Premature & CLD) Hospitalized Children with RSV High-risk Children (Premature& CLD) High-risk Children (Premature & CLD) High-risk Children (Premature& CLD) High-risk Children (CHD) Native American (FT) Objective Safety, IM, PK, Safety, IM, PK Safety, IM, PK, Nasal RSV titer Safety, IM, PK 2nd season CP104 Safety, IM, PK Design Open-label Open-label Placebo Control Synagis® Control Mixed dosing Synagis/Motaviz Synagis Control Synagis Control Placebo Control Enrollment 30 217 30 136 Status Completed Completed Completed Completed CP127 CP110 CP124 CP117 240 6635 621 1410 Completed Completed Ongoing Interim Completed RSV hosp/MALRI Safety, IM, PK RSV hosp/MALRI Wheezing Biologics Day 7 December 2007 Motavizumab: Reduces the Incidence of Serious RSV Disease Relative Reductions in Serious RSV Disease 90 80 70 60 50 40 30 20 10 0 pi ta l % Reduction CP110: Motavizumab vs Synagis® in preterm p<0.01* 83** 71** CP117: Motavizumab vs placebo in Native American infants p<0.001 50** 26* LR I tie nt O ut pa pi ta l H H O ut pa Biologics Day 7 December 2007 os os tie nt iz iz * Non-inferiority ** Superiority at at LR I n io io n Next Steps U.S. BLA for premature and CLD 1Q08 Complete 2nd season of CHD study 3Q08 File in EMEA for all high risk infants 1H09 Continue 4th year enrollment of CP117 – Collecting data on persistent wheezing prevention Biologics Day 7 December 2007 Value Added for High-Risk Infants Prevention of Early Childhood Wheezing? Preventing serious RSV may reduce recurrent early childhood wheezing (Simoes/Groothuis 2007) 30 IIT Journal of Pediatrics, 2007 50% Reduction in Recurrent Wheezing events with palivizumab untreated 25 frequency (%) 20 15 10 5 0 all events all events nonhosp children MD events MD events nonhosp children Placebo controlled trial in 32-35 week preterm infants followed 3-5 y for reduction in persistent wheezing – 4Q08 Follow-up of Native American infants (CP117) ongoing Synagis® Biologics Day 7 December 2007 RSV Prevention Third-Generation RSV MAb (YTE) Potential targets – High risk infants – Full term infants <6 months born in season (2M U.S./~60M WW) Predicted YTE Concentrations after 3 mg/kg IV 1 00 Numax 3 mg/kg IV- Observed Mean Serum Conc (mcg/ml) YTE Simulated Concentration Challenges – Low COG and impeccable safety profile essential 1 0 Status – Phase I iv dose escalation safety/POC trial CP144 in adults initiate Dec 2007 1 0 25 50 75 1 00 1 25 1 50 1 75 200 225 250 275 Time (days) Biologics Day 7 December 2007 Strategic Goals RSV Prevention: Live Attenuated Vaccines Targets: <6 m old, universal vaccination (4M US/120 M WW) Status: 2 constructs in Phase I – MEDI-534 (PIV-3 RSV F) Acceptable safety profile seen in seropositive children Phase I dose escalation safety trial in seronegative older children ongoing Phase I safety trial in seronegative infants 2008 MEDI-559 (NIH CRADA, DSH construct) IND to be filed 1H08 Phase I seronegative children trial planned 2Q08 – POC efficacy trial targeted in 2010 Biologics Day 7 December 2007 Strategic Goals RSV Treatment Develop treatment modalities aimed at patients with early and late RSV disease Targets: pediatrics and adults – Successful modalities in pediatrics will be applied to adults As with prevention, multiple shots on goal is the approach – Motavizumab – Small molecules Biologics Day 7 December 2007 RSV Treatment Motavizumab Phase I single iv dose (3, 15, 30 mg/kg) treatment trial in children – Significant reduction in replicating RSV within 24 hours – Dose effect in eradication of viral RNA In-patient: POC Phase II – iv – iv motavizumab treatment indication – Randomized (1:1:1), blinded, placebo controlled, single iv dose (30, 100 mg/kg) in term infants Out-patient: POC Phase II – IM (intranasal target) – IN treatment indication – Randomized (1:1) blinded, placebo controlled single IM dose (30 mg/kg) in term infants Next milestone DBL 2H09 – Data 1H10 Biologics Day 7 December 2007 RSV Treatment Biota Small Molecule Target: pediatric patients with early disease – Application across patient populations Advantages – Oral dosing – Low COG Phase I dose escalation safety trial in healthy adults ongoing Challenge trial anticipated 2009 Biologics Day 7 December 2007 Addressing the Burden of RSV Beyond Synagis® Prevention – High risk preterm infant (acute/wheezing) Technology Antibodies MEDI Program Synagis® Motavizumab YTE – High risk term infants – Patients with transplants – All infants in 1st year of life – Elderly Vaccines RSV Vaccines MEDI-534, MEDI-560 Treatment – Term infants – Elderly, COPD, asthmatics, transplants Antibodies Small Molecules Motavizumab Oral anti-RSV compound Biologics Day 7 December 2007 Oncology Dirk Reitsma, M.D. Vice President, Clinical Development Biologics Day 7 December 2007 AstraZeneca and MedImmune Jointly a Large and Competitive Oncology Portfolio Powerful instrument for new drug delivery Access to large and small molecules – Multiple shots on target – Potential to select best compound in class – for full development Potential for combined development strategies Strategic resource Biologics Day 7 December 2007 Expanded Development Capabilities and Expertise Target identification/validation – Translational science, biomarkers External partnerships Key alliances Multi-regional development strategies Global commercial infrastructure Biologics Day 7 December 2007 MEDI-538/MT103 First BiTE® in Clinical Development Unique mode of action (new class of drug) MEDI-538 triggers natural mechanism of T-cell activation CD3 MT103 CD19 Cytotoxic synapse is formed High potency Collaborative program with Micromet – 2 EU trials ongoing – 2 U.S. trials planned ’08 Biologics Day 7 December 2007 Cancer Statistics 2007 Incidence and Prevalence – NHL 63,190 people will be diagnosed with NHL 18,660 people will die of NHL 381,129 people are alive with a history of NHL (as of 2004) Source: NCI SEER Database Biologics Day 7 December 2007 Frequency of NHL subtypes DLBC 1.2% 1.8% 2.5% 2.4% 2.4% Mantle cell 6.0% CLL 6.7% ALCL 7.6% 7.6% Burkitt's Follicular 22.1% Nodal marginal zone Lymphoplasmacytic Other WHO classification of tumours, 2001 Biologics Day 7 December 2007 Follicular MALT Peripheral T-cell 9.1% DLBC 30.6% CLL/SLL Mantle cell Primary mediastinal MEDI-538 Lymphoma Cells Eliminated in Bone Marrow Baseline MT103 (Day 17) Patient #1 at dose level 4 (15 µg/m²/24 hrs) Previous treatments included CHOP, Chlorambucil, Fludarabine, Dexa-BEAM, Endoxan and repeated Rituxan Biologics Day 7 December 2007 Objective Responses MEDI-538 Dose Levels from 15 to 30µg Follicular lymphoma – One complete response – One partial response – One minor response Mantle cell lymphoma – One complete response ongoing for 7 months Chronic lymphocytic leukemia – One partial response – One minor response In total 4 responders (plus 2 minor responses) among 17 heavily pretreated patients – Data on next cohort ASH – Dec 9 Biologics Day 7 December 2007 CAT-8015 The Target: CD22, a B-cell Antigen Involved in Adhesion and Signaling V L -S-S- V H II Ib III -Anti-CD22Pastan 10/04 -Toxin- Therapeutic Indications: – Non-Hodgkin’s lymphoma – Chronic lymphocytic leukemia – Acute lymphoblastic leukemia – Hairy cell leukemia Biologics Day 7 December 2007 CAT-3888 Results of Initial in Chemotherapy-resistant HCL Hairy Cell Leukemia (n= 31) – 19 complete responses – 6 partial responses 15 non–HCL patients (11 CLL, 4 NHL) treated with CAT-3888 – One partial response (CLL) – CLL and NHL patients did not progress while on CAT-3888 Positive results support decision to move forward with CAT-8015 Partly reported in: N Engl J Med 345:(4) p 241-7 Biologics Day 7 December 2007 CAT-8015 Phase 1/2 Dose Escalation Studies Hairy cell leukemia Chronic lymphocytic leukemia CD22+ non-Hodgkin’s lymphoma Pediatric acute lymphoblastic leukemia Biologics Day 7 December 2007 IPI-504 (MEDI-561) Biologics Day 7 December 2007 Heat Shock Protein 90 Emerging Cancer Target Two roles for Hsp90 in cancer General chaperone function essential for protein homeostasis Specific chaperone function stabilizes oncogene products in key cell signaling pathways Cancer cell Hsp90 different from normal cell Hsp90 Preferential targeting to cancer Biologics Day 7 December 2007 Pathway Validation by Targeted Cancer Therapies Hsp90 Client Protein Hematologic Bcr-Abl Imatinib / Dasatinib CML Targeted therapy Indication Solid tumor c-Kit HER2 EGFR VEGFR / HIF-1a ER AR Imatinib / Sunitinib Trastuzumab / Lapatinib Erlotinib / Cetuximab Sorafenib / Sunitinib Tamoxifen Goserelin / Bicalutamide GIST Breast (HER2+) NSCLC Renal cell Breast (ER+) Prostate Biologics Day 7 December 2007 GIST Incidence and Prevalence US incidence estimates vary from 3,000 - 6,000 new cases per year (10 -20 cases / million) Estimated prevalence of GIST in U.S. ranges from 9,400 patients (high risk or overtly malignant disease only) to 39,000 patients (all patients) EU incidence is estimated at 5,000-10,000 cases per year (again assuming 10-20 cases per million) Estimated prevalence in EU is 64,400 patients. Incidence and prevalence likely to continue to increase due to: – Greater awareness and improved pathologic detection – Survival improvements with new therapies (e.g., Imatinib and Sunitinib) Source: Nilsson, et al Cancer 2005 (Swedish prevalence report). Biologics Day 7 December 2007 IPI-504 Rationale for Treatment of GIST Kit is the oncogene that drives GIST (>90% driven by activated Kit) < 2 year survival from time of metastasis Gleevec & Sutent inhibit Kit, and are approved treatments for GIST, but all patients eventually progress Kit mutations that render GIST refractory to TKIs are “hyper” sensitive to Hsp90 inhibition Biologics Day 7 December 2007 PET response to IPI-504 (150 mg/m2) (following failure of imatinib, sunitinib, and AMN-107) Baseline Cycle 1, Day 11 72 hours post rd dose of IPI-504 3 Cycle 1, Day 21 After 10 days off treatment Cycle 3, Day 12 After treatment re-initiated Dana-Farber Cancer Institute Harvard Medical School Biologics Day 7 December 2007 CT for patient following failure of Imatinib and Sunitinib – Pt received 400 mg/m2 (Schedule A) of IPI-504 Screening End of Cycle 3 December 2007 Biologics Day 7 Diversification in IPI-504 Strategy Pursue fast path to registration of IPI-504 iv –Capitalize on signal in GIST –Current phase I/II study in NSCLC –Phase II study in melanoma Conduct exploratory Phase II studies in multiple tumor types –“Expand early/Fail early” – Phase IIs include early stop points based on clinical activity Phase II HRPC ongoing Lay groundwork for PO formulation –Positive iv signal would accelerate future development and prioritization of these indication Develop oral product (IPI-504 or IPI-493) –Improved probability of commercial success Biologics Day 7 December 2007 Next Milestones IPI-504 MEDI-538 CAT-8015 Initiate pivotal trial, 2008 U.S. phase I, 1Q08 Go/no-go phase II, 2009 Biologics Day 7 December 2007 Anticipated INDs Next Two Years Insulin-like growth factor (IGF) – AZD4253 Platelet-derived growth factor receptor, alpha (PDGFRα) EphA2 conjugate Anti-CD19 CEA BiTE® Biologics Day 7 December 2007 Enhanced Development Potential for MedImmune Responses to three novel biological approaches in ongoing clinical trials – BiTE®, immunotoxin and Hsp90 inhibitor – Phase I trials upcoming with several new targeted MAbs Speed and scope expanded in global clinical trial capabilities – Access to experience with innovative trial designs – Faster start ups even at same sites – Greater geographical opportunities for early development Greater business development scope Biologics Day 7 December 2007 Respiratory & Inflammatory Diseases Barbara White, M.D. Vice President, Clinical Development Biologics Day 7 December 2007 Targeting Diseases with Major Burden of Illness Respiratory Diseases Rheumatology Rheumatoid Arthritis Scleroderma Asthma COPD Lupus Biologics to achieve disease control in moderate to severely active disease Biologics Day 7 December 2007 Targeting Asthma Control disease, reduce exacerbations, reduce use of oral corticosteroids In human testing – Anti-IL-9 (MEDI-528): Phase II (blocks mast cells) – Anti-IL-13 (CAT-354): Phase I (relaxes airway smooth muscle) – Anti-IL-5R (MEDI-563): Phase I (kills eosinophils) Next – OX40L: candidate Ab ’08 – Anti-IL-4R: candidate Ab ’08 – IgE: candidate Ab ’08 Potential cross-over from rheumatology – GM-CSFR (CAM3001): Phase I – Anti-IL-17: FTIM ’08 – ICOS: candidate Ab Dec ’07 Biologics Day 7 December 2007 MEDI-528 (Anti-IL-9) in Asthma Phase II Go/no-go for large phase II 4Q08 IL-9 blockade reduces mast cells in the lung following allergen challenge * 3500 3000 Total MCp /Lung Both allergic and non-allergic asthma Convenience – SC q 2-4 weeks 2500 2000 1500 1000 500 0 Control IgG Control IgG Anti IL-9 Sham OVA * Statistically significant, p<0.05 Biologics Day 7 December 2007 MEDI-528 (Anti-IL-9) in Asthma Studies To Date Study CP105 CP109 CP138 Short Title SAD IV, HV SAD SC, HV SD IV, whole lung inhaled allergen, LAR SD IV, segmental allergen challenge, POBA MAD SC, safety MAD SC, POC in exercise-induced asthma Status Complete Complete Data analysis Ongoing FPFV Aug ’04 June ’05 Nov ’06 LPLV Dec ’04 April ’06 Aug ’07 CP139 July ’07 3Q08 CP131 CP143 Ongoing Planned July ’07 4Q07 3Q08 1Q09 Biologics Day 7 December 2007 CAT-354 (Anti-IL-13) in Asthma Phase I Phase IIa 4Q07 Go/no-go for large phase IIb/III 2H09 Allergic asthma>non-allergic asthma Relax airway smooth muscle Convenience – SC q 2-4 weeks 0401: Proof of Biologic Activity of CAT-354 Biologics Day 7 December 2007 CAT-354 (Anti-IL-13) In Asthma Studies To Date Study 0401 0602 Short Title SAD, safety MD, parallel group, 3 dose levels, safety 3 dose levels, POC SC vs iv bioavailability Status Complete Dosing complete, follow-up ongoing Planned Planned FPFV n/a Aug ’06 LPLV n/a Sept ’07 0603 0703 Dec ’07 1Q08 4Q08 3Q08 Biologics Day 7 December 2007 MEDI-563 (Anti-IL-5R) in Asthma Phase I Go/no-go for phase II 4Q08 500 400 Eosinophils/mm3 300 200 100 0 1 Eosinophilic asthma Convenience – SC q4 weeks CP158: Proof of Biologic Activity of MEDI-563 -14 0 0.03 mg/kg IV 14 Days28 56 Biologics Day 7 December 2007 MEDI-563 (Anti-IL-5R) In Asthma Studies To Date Study Short Title Status FPFV LPLV CP158 SAD, safety Ongoing Jan ’07 2Q08 CP166 SD and MAD depletion of eosinophils in airways Planned Jan ’08 4Q08 Biologics Day 7 December 2007 Targeting COPD First targets Reduce exacerbations – PAI-1: candidate Ab ’08 – – (remove small clots) IL-1R: candidate Ab ’08 (reduce inflammation) C5a: lead optimization (reduce inflammation, block smooth muscle constriction) Potential cross-over from asthma or rheumatology – IL-5R: Phase I – GM-CSFR: Phase I Biologics Day 7 December 2007 Targeting RA In human testing Control signs and symptoms, induce clinical responses and remissions, improve patient-reported outcomes, halt progressive joint damage TNF failure > biologic naïve patients – GM-CSFR (CAM3001): Phase I (reduce inflammation) Next – – – – – IL-17: FTIM ‘08 IL-6: candidate Ab ’08 CXCL-13: candidate Ab ’08 IL-15: candidate Ab ’08 CD22: lead optimization Potential cross-over – IFNα (MEDI-545): Phase I – ICOS: candidate Ab Dec ’07 – CD19: candidate Ab ’07 Biologics Day 7 December 2007 CAM3001 (Anti-GM-CSFR) in RA Phase I Go/no-go for phase II 1Q09 SC q 2-4 weeks Potential diagnostic to identify responding patient subset Anti-GM-CSF inhibits joint inflammation and damage in CIA Vehicle Control CSF Receptor antagonist Synovium Synovial Hyperplasia & inflammation Cartilage erosion Intact cartilage Biologics Day 7 December 2007 CAM3001 (Anti-GM-CSFR) in RA Studies To Date Study Short Title Status FPFV LPLV 0702 SAD IV, RA Ongoing Oct ’07 1Q09 Biologics Day 7 December 2007 Targeting SLE In human testing Control disease activity, reduce flares, reduce immunosuppressive drugs – IFNα (MEDI-545): Phase I (stop innate inflammatory processes) Coming – – – – Diffuse proliferative lupus glomerulonephritis with epithelial crescent (arrow) ICOS: candidate Ab Dec ’07 CD22: lead optimization HMGB1: lead optimization RAGE: lead optimization Potential cross-over – – – – IFNαR: FTIM ’08 IL-17: FTIM ‘08 IL-6: candidate Ab ‘08 CD19: candidate Ab ’07 Biologics Day 7 December 2007 MEDI-545 (Anti-IFNα) in SLE Phase I Go/no-go for large phase II 1H09 Efficacy SC q 2-4 weeks Potential diagnostic to identify responding patient subset Placebo 0.3 mg/kg 1 mg/kg 3 mg/kg 10 mg/kg 30 mg/kg CP126: Proof of Biologic Activity of MEDI-545 1-Fraction of neutralization 1.5 1.0 0.5 0.0 0 10 20 30 40 50 60 70 80 90 Days post treatment Biologics Day 7 December 2007 MEDI-545 Reduces Type I IFN Gene Signature and Type I IFN–Induced Proteins in Skin Blood, Day 0–28 Skin, Day 0,14 Type I IFN–Induced Proteins in Skin Skin, Day 0–28 Day 0 Day 14 Reduction in protein expression Reduction in gene expression Biologics Day 7 December 2007 MEDI-545 Shows Clinical Activity in Lupus SLEDAI = 0 SLEDAI Flares New Systemic Corticosteroids P=0.0947 % patients P=0.0136 P=0.0138 Biologics Day 7 December 2007 Commercial Overview RSV & Vaccines Peter Greenleaf Senior Vice President, Marketing & Sales Biologics Day 7 December 2007 Commitment to RSV Biologics Day 7 December 2007 RSV Burden of Disease Dangerous, unpredictable, and highly variable virus that attacks almost all infants by age 2 Can have devastating effects in high-risk infants ranging from: – Medically attended out-patient lower respiratory track infections – Acute hospitalizations – Long-term consequences such as recurrent wheezing – and/or asthma Death Biologics Day 7 December 2007 RSV Burden of Disease Leading cause of infant hospitalization – >300,000 hospital admittances each year in U.S. Causes substantial economic burden on the U.S. healthcare system – 1.7 million physician office visits in 2000 – >400,000 emergency room visits – >230,000 hospital outpatient emergency room visits Biologics Day 7 December 2007 Synagis® (palivizumab) Technological advancement over polyclonal antibody – Respigam® Standard of care in prevention of serious RSV lower respiratory tract infections in high risk infants Major Launches: U.S. ’98, EU ’00, JP ’02 Liquid formulation intro in U.S. ’05 Marketed by MedImmune in U.S. Distributed by Abbott Intl. ex-U.S. Approved in over 60 countries Biologics Day 7 December 2007 The Future with Motavizumab Near term – Next evolution in RSV prevention – – Increased potency; improved efficacy Improvement in secondary outcomes Significant protection from RSV disease More data to support effectiveness of MAbs in RSV prevention Mid to long-term – Provides competitive “high bar” for efficacy – Patent protection beyond basic Synagis® patents – Greater potential for future development areas Biologics Day 7 December 2007 MedImmune Reported WW Sales RSV Seasonal Basis ($million) $1,400 $1,123 $1,200 $885 12% $992 12% $1,056 5% 7% $1,000 $788 30% $800 $482 34% $606 26% $600 $400 00/01A 01/02A 02/03A 03/04A 04/05A 05/06A 06/07A Reported U.S. sales Reported ex-U.S. sales Biologics Day 7 December 2007 Synagis® U.S. Patient Segment Penetration Second Season estimated 90% CLD & CHD 70% 32-35 Wk GA 85% 22% <32 Wk GA Segment 32-35 Wk GA 32<32 Wk GA CHD & CLD 2nd season >36 Wk GA (TERM) Est. Total Size 06/07 ~248,000 ~85,000 21,000 – 30,000 ~18,000 ~3,900,000 333k Patient portion penetrated Biologics Day 7 December 2007 Evolution of the COID Guidelines Group <32s 1998 During their first RSV season 2003 … 2006 … 32-35s <6 months of age and any risk factors including: school age siblings; crowding in the home; day-care attendance; exposure to tobacco smoke in the home; multiple births <6 months of age and two of the following RFs: child care attendance, school-aged siblings, exposure to environmental air pollutants, congenital abnormalities of the airways, or severe neuromuscular disease. Tobacco “controllable” Same, but tobacco “has not been associated with an increased risk of RSV hospitalization on a consistent basis.” CHD [No indication] Children <12 months of age with hemodynamically significant CHD Children <24 months of age with hemodynamically significant CHD CLD Dosing / Season Children <24 months of age who “have required medical therapy…for CLD within 6 months before the start of the RSV season.” … … No discussion of this issue Physicians should use local virology to determine season; during season infants should get first dose before discharge from hospital National Nov-Mar season, recommend 5 doses. No mention of first dose before discharge from hospital Biologics Day 7 December 2007 Ex-U.S. Strategy Business continues to see robust growth Work closely with Abbott International to expand global reach Future plans to expand MEDI presence as a global biologics business Biologics Day 7 December 2007 Synagis® ROW Patient Segment Penetration Second Season estimated 90% CLD & CHD 33-35 Wk GA 60%* 6% 70% <33 Wk GA Segment 33-35 Wk GA 33<33 Wk GA CHD & CLD 2nd season Total “G7” 06/07 G7” ~139,000 ~77,000 ~41,000 ~5,000 216k Patient portion penetrated Biologics Day 7 December 2007 Key Growth Drivers RSV Franchise Continue to optimize our base business Further develop our value proposition for Synagis® Increased investment in data generation & display – – – – Prove long-term consequences Expand risk factors and COID guidelines Provide for appropriate seasonality Develop expanded populations Develop and execute payor strategy Maximize the ex-U.S. opportunity for growth Drive the future pipeline and innovation in RSV Biologics Day 7 December 2007 RSV Franchise Strategy Franchise Growth Optimize Optimize • Drive efficiencies in • Drive efficiencies in Synagis® business Synagis® business • Launch motavizumab • Launch motavizumab and reset “efficacy bar” and reset “efficacy bar” • Invest in research to • Invest in research to support franchise support franchise expansion expansion ― Maintain base ― Maintain base business business ― Expand COID ― Expand COID risk factors risk factors ― Expand into new ― Expand into new infant populations infant populations Advance Advance • Expand high-risk • Expand high-risk prophylaxis in infants prophylaxis in infants via link to LTC via link to LTC • Advance the science • Advance the science through 1st to market through 1st to market treatments for RSV treatments for RSV ― Motavizumab ― Motavizumab ― Small molecules ― Small molecules • Launch motavizumab • Launch motavizumab ex-U.S. ex-U.S. Expand Expand • Invest in international • Invest in international expansion expansion • Launch mass-market • Launch mass-market prophylaxis // vaccine prophylaxis vaccine in infants in infants ― YTE and/or ― YTE and/or vaccine vaccine ― Continue ― Continue prophylaxis in prophylaxis in high-risk infants high-risk infants as appropriate as appropriate • Pipeline: combination • Pipeline: combination therapies and other therapies and other infectious diseases infectious diseases Infants protected 163k 216k on Px 216k 355k on Px 0 125k on Tx 355k 4.2m on Px / Vx 125k 80k on Tx Time *Discussed in June-Aug presentations Biologics Day 7 December 2007 Vaccine Franchise Biologics Day 7 December 2007 Leadership Will Be Built and Maintained Continued vaccine development – Human metapneumovirus, Epstein Barr virus, Streptococcus pneumoniae and respiratory syncytial virus/parainfluenza virus (RSV/PIV-3) targets NIH pandemic CRADA – Preparing library of prototype pandemic LAIV strains (H2, H4-H16) Cell culture development – Seasonal and pandemic influenza vaccines LAIV technology as platform for FluMist® HPV technology now commercialized – Merck (Gardasil®) and GSK (Cervarix™) Biologics Day 7 December 2007 FluMist® Platform for Commercial Entry Into Vaccines First Nasal Mist Flu Vaccine in the U.S. Biologics Day 7 December 2007 FluMist® First advance in flu vaccines in 60+ years – Highly effective, needle free seasonal flu vaccine – For healthy people 2-49 years of age Proven efficacy against matched and mismatched strains Multiple studies versus “the shot” have demonstrated superior efficacy – CP111: 52.5% and 54.2% better efficacy against matched and mismatched strains Value in pandemic preparedness Biologics Day 7 December 2007 FluMist® Improved product profile for the 2007/2008 season – Expanded indication down to 2 years of age – New refrigerated formulation – 50% volume reduction Favorable reimbursement coverage October 2007: ACIP recommends FluMist® for use in children down to 2 years of age, including VFC Biologics Day 7 December 2007 Vaccine-Preventable Disease/Deaths U.S. Influenza is Leading Vaccine-Preventable Disease for Mortality Diseases Influenza Pneumococcal disease, invasive (bacteremia & meningitis) HPV (cervical cancer) Hepatitis B Meningococcal disease Hepatitis A Varicella Pertussis Annual Cases (Year) 31,000,000 40,000 (’02) 10,520 (’04) 6,741 (’04) 2,500/year (’70-’04) 20,000 (’04) 20,948 (’03) 25,827(’04) Annual Deaths (Year) 36,000/year (’90 - ’99) 5,500 (’02) 3,900 (’04) 685 (’03) 125 (’04) 54 (’03) 16 (’03) 11 (’03) Biologics Day 7 December 2007 Influenza Infection Rates Children have the highest infection rates and are most likely to spread the disease to others 45 40 35 30 25 20 15 10 5 0 0-4 5-9 41 38 31 24 Infection rate (%) 9 11 9 12 7 10-14 15-19 20-29 30-39 40-49 50-59 Age (years) 60+ Biologics Day 7 December 2007 Influenza Market Projections Market growth for 18 and under segment will outpace overall market CAGR 160 140 Total 5.1% 0.7% 6.0% 3.5% 121 126 131 134 136 138 Military HCW 65+ Number of Doses 120 107 100 100 112 93 84 50-64 19-49 3.4% 2.9% 80 60 40 20 23 27 36 39 41 42 43 43 All peds 13-18 9-12 5-8 2-4 10.8% 12.1% 12.9% 13.3% 13.1% 5.5% 30 20 0 15 2005E 2006F 2007F 2008F 2009F 2010F 2011F 2012F 2013F 2014F 2015F 6-23 months Note: 2-4 age group recommended in 2006, 5-8 in 2008, universal peds recommendation in 2010 25Source: Dept of Health and Human Services, FluMist® LROP, CDC, L.E.K. analysis Biologics Day 7 December 2007 FluMist® Coverage Can be used for the majority of children aged ≥2 Years Children aged 2 – 17 years Children with no exclusionary respiratory conditions 80% Approx 80% of children aged 2-17 years - more than 50M children - do not have exclusionary respiratory conditions and may therefore be candidates for FluMist if no other preexisting conditions prevent use 20% Children with exclusionary respiratory conditions Exclusionary respiratory conditions include: • Children aged 2-17 years with asthma • Children aged 24-59 months with recurrent wheezing Biologics Day 7 December 2007 Expansion of Commercial Vaccine Business Global commercialization of FluMist® Continued improvement of FluMist label/profile – Currently excluded populations/additional B strain Continued business progression and pipeline developments Biologics Day 7 December 2007 Vaccines Summary Large worldwide influenza market Newly differentiated superior product profile Significant growth in pediatric segment Strong launch plan and selling resources Pandemic possibility leverages product and company strengths Opportunity to expand focus on adults and ex-U.S. markets Future vaccine candidates represent expansion of commercial opportunity Biologics Day 7 December 2007 An Exciting Future! We have the ability to make a meaningful difference in patient health – Foster a broad spectrum of high-quality science Biologics Vaccines Continued innovation Commercial execution excellence Expanding our global reach – – – Biologics Day 7 December 2007