Biologics Market: Where Are We Now? Where Are We Going?

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1 Biologics Market: Where Are We Now? Where Are We Going? Rakesh Dixit, Ph.D., DABT Vice President, Research & Development AstraZeneca-Medimmune Biologics R & D

2 Scope of Biologics Medicines Biotechnology Derived Products (e.g., Products made in live cells) Hormones e.g., Growth hormone, insulin Blood products e.g., albumin, clotting factors Cytokines e.g., interferons, interleukins mabs (CDER) e.g., humanized, chimeric, Murine, single chain/bispecific, naked/conjugated Vaccines e.g., recombinant Proteins, DNA plasmid Anti-idiotype Gene Transfer Products e.g., Viral and non-viral vector delivery Cell therapy products (CAR-T cells) Tissue Engineered Products

3 Distribution of Biologics Market 56 Approved

4 Current State of Biologics

5 Non-Mab Biologics Approvals (Future of Biologics)

6 Future of Biologics Drugs

7 Prescription Bio-Pharma Market ~ 6.5 % Increase in Sales/year of prescription Biopharmaceuticals > 1 trillion $ Oncology Biologics Major share by Immunotherapy Biologics (e.g., Immune Checkpoint Antagonists, CAR-T cells) Anti-Diabetic Drugs to grow over 7%/year

8 Non-Mab Current status

9 Future of Biologics Drugs

10 A Perspective on the Future of Biologics Biosimilars and Biobetters/Biosuperors Bispecifics drugs to offset the cost of combination biologics Antibody Drug Conjugates CAR-T cells advances Long-term future is in disrupting biologics model. Personalized in vivo biologics- using your own cells to make your biologics drugs- no need for bioreactors Advancement in delivery technologies Oral delivery of biologics Innovations in injectable biologics Virus to patient Gene to patients Cells to patients

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12 Biosimilar Biologics Where Are We Now and Where Are We Going

13 Global Opportunities for Biosimilars By 2030 > 240 Billion $ Opportunity Cost savings Up to 70 billion $

14 Drivers and Brakes for Biosimilars Opportunities to increase affordability of life-saving biologics Advancement in biosimilars development Bioanalytical-CMC capabilities Nonclinical and clinical evaluation Cost efficiency in manufacturing of biologics Increasing world-wide regulatory approvals, including US FDA Better acceptance of biosimilars by physicians and patients; increasing market absorption world-wide Gaps in knowledge and understanding of biosimilars Highly variable and fragmented biosimilar regulations and approvals world-wide Interchangeability, naming etc. Patent Infringements (the Major Brake in Effective Marketing) Abbvie claims that Amgen violated > 50 patents related to humira biosimilaramjevita (adalimumab-atto)

15 Impact of Patent Protections Example of Humira Potentially no marketing of humira biosimilars until 2019 or this could extend to 2022 Humira will likely become > 20 billion $ drug by 2022

16 Biosimilars versus Biosuperiors Innovator vs. Biosimilars Same MOA/class Highly similar CMC Similar antibody protein quality Similar PK-PD, safety, immunogenicity Similar efficacy Scientific and technological advances Innovator vs. Biosuperior/Biobetter Biobetter/Biosuperior Same or similar MOA Potency improvement Enhanced half-life Enhanced and convenient delivery Better safety and immunogenicity Better and broader efficacy PHC approaches

17 Concepts in Biobetters or Biosuperiors (within the similar MOAs) Second in Class (slight improvement) Increasingly better in class (increasingly differentiated products) Increasing Innovations

18 Opportunities for Biosimilars and Biobetters Biosimilars Lower prices, saving hundreds of billion $ to health care providers No negative impact on safety and efficacy Broader affordability Potential for serving a greater number of patients in both developed and developing world Biobetters Unmet medical needs Current therapies: inadequate to treat refractory patients Highly differentiated and potent biologics within the same general MOA Serving patients not benefited from existing therapies High blockbuster potential

19 BioSuperiors Applying Best Science + Antibody Technologies mab (+YTE) ADC: Ab-drug conjugate Single-chain immunotoxin Ab mimetic Bispecific Ab T cell NK BiTE Antibody* Agonist/ antagonis t mab Internalized Ab Release of cytotoxic drug Blocks protein synthesis Target cell Induction of T Cell Killing Enhanced ADCC 19

20 Major Biosimilars and Biobetters in Development Product Biosimilars Biobetters Humira (adalimunmab) Remicade (infliximab) Epogen (epoetin alfa) Neupogen (filgrastim) Enbrel (etanercept) Rituxan (rituximab) Herceptin (transuzumab) Source: Biotechnology Information Institute

21 Bispecific Biologics

22 Enhanced War on Cancer Targeted Weapon Systems of MedImmune NK Cell ADCC Enhanced Antibody Drug Conjugate Checkpoint Antagonists Oncolytic Viruses TAA binding arm Immunotoxins Bispecific T-Cell Engagers CD-3 binding arm

23 Bispecifics, Combinations and Mixtures of Antibodies Bispecific Mixtures Combinations Single molecular biologic entity Multiple targets Antigens Effector functions Combination of antibodies (single or multiple targets) in mixture May be considered a single entity, if produced as a single product Typically, a constant ratio of antibodies Not a single biologic entity More than one antibody Combinations In a single bag as a mixture Sequenced Simultaneous 23

24 Multi-targeted Oncology Biologics Vs. Combination of Two or More Biologics BiS (multi-targeted) mab Combination of mabs Design flexibility with various formats: able to combine multiple targets in a single molecule Highly specific and effective targeting High avidity/valency like target interactions may allow better efficacy Must provide synergistic benefits > combinations or mixture of two MOAs Toxicity can be reduced by engineering differential potency in one mab Cost of one mab vs. combining two separate expensive mabs could be less and attractive to payers Convenience of dosing and flexibility with dosing schedule (simultaneous, sequential etc.) to reduce toxicities Fixed combinations with enhanced efficacy and reduced toxicities are potentially attainable Business case for combining two expensive antibodies can only be made in terminal cancers or other debilitating diseases with very few options 24

25 Challenges and Opportunities for Oncology Bispecifics Challenge for industry: Costs matter to both payers and providers Are the exceptionally high prices of biologics justified by the health benefits they afford to patients? Do biopharmaceuticals provide good value for money? Opportunity for industry: High efficacy due to synergism with potential for lower toxicity vs. mixtures and combinations Use of a bispecific molecule could substantially reduce costs associated with drug development, production, clinical testing, and regulatory approval compared to single protein-based agents developed in combination therapies Opportunity for payers / patients: Payment for one drug product instead of payment for each of single proteinbased agents in combination PMID , PMID:

26 Oncology Bispecifics: Financial Case Cost-effectiveness of adding bevacizumab to chemotherapy for patients with untreated metastatic colorectal cancer: Adding bevacizumab to Irinotecan+Fluoruacil+Leuvocorin costs approximately 62,857 ($96,258 USD) per Quality ADJUSTED LIFE YEAR QALY gained Adding bevacizumab to 5-FU/LV costs approximately 88,436 ($135,433 USA) per QALY gained. Costs for newest biologics (financial toxicity): Two courses of the newly approved agent blinatumomab, used to treat relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL), cost a staggering $178,000 The cost of using ipilimumab alone is ~ $158,282 (for a median progress-free survival [PFS] of 2.9 months), the cost of nivolumab alone is ~ $103,220 (for a PFS of 6.9 months), and the cost of the combination is ~ $295,566 (PFS of 11.4 months, nearly four times that seen with ipilimumab alone, which is currently the standard of care). PMID , PMID , PMID

27 Can bispecifics strike a balance across fiscal sustainability and innovation, as well as demonstrate substantial benefit to patients? If drug-makers want to retain pricing control and have broad distribution in the world markets, then the drugs in combination must provide substantial benefit over single agent therapies Cost of two drugs cannot be the sum of individual drug price Challenges and Opportunities for Bispecifics in Reducing Financial Toxicity of Combinations and Providing Synergistic Superior Efficacy Identify patient population most likely to respond Demonstrate superior synergistic efficacy as measured by gain in length and quality of life compared to single-target biologics Cost of a bispecific antibody should generally be lower than the cost of combinations in most cases 27

28 Bispecific (BiS) Biologics Landscape 2 Approved BiS Amgen's bispecific antibody Blincyto (blinatumomab) Removab( EpCAM X CD3 trifunctional mab) > 30 BiS In Clinical Development > 60 ADPE BiS Formats 28

29 Flavors of Bispecific (BiS) Biologics with Desired Properties Multiple antigen (s) binding simultaneously Maintaining FcGamma interactions to maximize the benefits of ADCC and CDC Low Immunogenicity FcRn function delivering desirable PK similar to parental antibodies Or use of other methodologies to maintain desirable PK High quality CMC and good yield in manufacturing with consistency 29

30 # of Candidates Bispecific Biologics Landscape 5 Formats in Clinical Trials BiTE TrioMab DNL scfv fusions 2 in 1 Tandab Platform CrossMab Nanobody DVD-Ig/TBTI Other >80% are monovalent bispecific 70% are for oncology Source: Roots Analysis 30

31 Antibody Drug Conjugate

32 payload Our strategies for redirecting the toxicity of potent warheads exclusively to tumors antibody Off-target Target selection Tumor (high) Normal cells (none or very low) warhead Better screening technologies On-target and off-target binding And internalization linker On-Target Non-target mediated Normal Cell Designer antibodies Low off-target binding Differential epitopes (tumors vs. normal cells) Designer warheads Maximal tumor killing Abilities to kill all tumor cells, including cancer stem cells Synthetic lethality cancer cell Metabolically stable linkers Site selective conjugation Differential tumor enzymes cleavable linkers 32

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36 Thank you for attention Questions?? 36