Teva in BioSimilars Improving access to treatments of serious diseases

Transcription

1 Teva in BioSimilars Improving access to treatments of serious diseases

2 improving access 06 What is a Biotech drug? 07 The picture of today s Biotech drug landscape 11 The future opportunity 14 What is a Biosimilar? 15 How are they developed? 16 The Regulatory Environment 22 Teva s corporate Identity Card 24 Challenges & Critical success Factors 25 Teva s Commitment 28 A Recipe for success Biotech drugs Biosimilars BIOSIMILARS at teva

3 INTRODUCTION TEVA Today TEVA Pharmaceutical Industries Ltd., headquartered in Israel, is a global pharmaceutical company specializing in the development, production and marketing of generic and proprietary branded pharmaceuticals and active pharmaceutical ingredients. TEVA is leader in the generic pharmaceuticals, and among the top 15 pharmaceutical companies in the world. Worldwide, TEVA has over 40,000 employees and production facilities in Israel, North America, Europe and Latin America and reached $18.3 billion net sales in TEVA is ready to meet the biosimilar challenge TEVA has made, and will continue to make, substantial investments in the ability to develop and produce biotech products. A generation of biotech drugs are reaching the end of their patent lives, heralding the market entry for biosimilars. The cost of these biosimilars are expected to be lower than the originator biopharmaceuticals, making medications accessible to patients who might otherwise not be able to afford them. TEVA focuses on products with meaningful differentiation from existing products in terms of clinical attributes, expected economics value and benefit to patients and health insurers.

4 Improving access

5 Biotech drugs

6 Biotech drugs are protein-based medicines Insulin Herceptin Paracetamol Large and complex molecules Produced by biological systems rather than chemical synthesis Biological medicinal products (also referred to as biopharmaceuticals or biotech drugs) are medicinal products containing biotechnology-derived proteins as active substances. Biotech drugs, introduced in the early 1980s, are more specific and therapeutic target-oriented than small molecules and often less toxic. Traditional pharmaceutical drugs, such as paracetamol, are small, simple molecules, manufactured by chemistry and usually work through chemical reactions to achieve the desired result. Biotech drugs, on the other hand, are made from biological material, like proteins and antibodies, produced by living systems and consist of very large, complex heterogeneous molecules that are often folded and twisted in such unique ways that are difficult to duplicate. Given the immunogenic potential of these proteinbased medicines, the human body s immunological response must be tested rigorously and monitored to ensure that patients are receiving the desired benefits of the product in a safe manner. 06

7 Biotech drugs treat serious diseases The emergence of biotech drugs has revolutionized the treatment landscape in a number of therapeutic areas. By developing products based on the human body s own endogenous biological processes, biotech companies have been able to create products with therapeutic potential previously unattainable through treatment with traditional drugs. Worldwide, the lives of over 300 million people have been changed markedly by the availability of a growing number of biotech drugs. Biotech drugs are used to treat a wide range of serious and rare diseases, such as cancer, autoimmune diseases and anemia. For example, the biotech drug Herceptin (trastuzumab, a monoclonal antibody), initially approved in 1998, has earned Dr. Dennis Slamon a number of research awards for a therapy that was the first to target a specific type of breast cancer.* The top 10 biotech drugs today** Indication Molecule type $bn Sales (2011) Humira Autoimmune MAb (anti-tnf) 7,3 Enbrel Autoimmune (RA, Psoriasis, Crohn s) Fusion-protein (anti-tnf) 6,9 Remicade Autoimmune MAb (anti-tnf) 6,9 Rituxan Cancer (hematological) MAb (anti-cd-20) 5,8 Avastin Cancer (solid tumors) MAb (anti-vegf) 5,3 Lantus Diabetes Long-acting insulin 5,3 Herceptin Cancer (solid tumors) MAb (anti-her2) 4,7 Novorapid/Novomix Diabetes Short Acting Insulin 4,4 Neulasta Cancer (supportive) Long-acting GCSF 4,3 Lucentis Wet Age Related Macular Degeneration MAb (VEGF-A inhibitor) 3,9 *Source : Herceptin-Dr. Slamon UCLA Jonsson Comprehensive Cancer Center, Triumph issue fall-winter 2007, available at: (accessed 5 July 2011) **Source : IMS padds 2011 improving access

8 Biotech drugs sales increased 5 fold in the last decade, reaching $155B in 2011 * Global biotech drug sales, $ bn Biotech drugs make up one of the fastest growing segments of the global pharmaceutical market. According to IMS Health, the biopharmaceutical market reached global sales of over $100 billion in Bharat Book Bureau notes that The growing interest in biotechnology development has transitioned the pharmaceutical industry to biopharmaceuticals in less than a decade. *Source : IMS padds

9 Today, the average cost of treatment is high * Schizophrenia Zyprexa 3,200 6,500 Small molecule example Anemia Epo 8,500 7,500 Anemia Aranesp 6,500 7,600 RA RA RA Remicade Enbrel Humira 18,400 13,800 29,200 27,200 29,700 25,900 US Public price, $ EU Public price, $ NHL Rituxan 25,800 36,200 BC Herceptin 43,100 46,300 CRC Avastin 53,500 64,700 0$ 70,000$ Biotech drugs are often used to combat long-term conditions such as cancer, rheumatoid arthritis, diabetes and multiple sclerosis. On average, biotech drugs cost much more per patient than conventional (small-molecule) pharmaceuticals for treatment of chronic conditions (e.g. schizophrenia). Possible explanations are that the manufacturing processes for the development of biotech drugs are more complex and more costly than the production of traditional pharmaceutical drugs and there is currently no competition from copycat drugs. *Source : IMS Padds Q EU : average EU5 improving access

10 The main part of Biotech drug sales is in highly regulated markets * Each market has different dynamics with pricing and reimbursement policies going hand in hand with the regulatory requirements. Due to inherent molecular complexity, cost, and development risks, biotech drug production and commercialization in developed markets is concentrated in the Western world. By far, the US is the most mature market for biotech drugs with the largest number of products available. Europe 32% Japan 9% Row 9% US 50% % of world market *Source : IMS Padds MAT 2011 EU : average EU5 10

11 Biotech Drugs will increasingly be perceived by payers as the main cost driver $300 $250 Biotech Drugs outlook What savings from generics? Only a few core small molecules to potentially yield savings in the future (Diovan, Lipitor, Seretide, Spiriva, Seroquel) $200 Billion dollars $150 $100 $50 $ % CAGR ,8% CAGR Continuous price reduction of existing generics Savings from small molecules to decline after 2015 Total pharma growth % Total branded growth % Conservative estimates Source: IMS MIDAS, MAT 12/2010 improving access

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13 BIOSIMILARS

14 What is a BioSimilar - The Teva definition A biosimilar is a biopharmaceutical that is physically, chemically, biologically, and clinically similar to an approved biological reference product, whereas generics of chemistry-based medicines are identical copies of the original product. Biosimilars are similar but not identical to the originator biological medicine due to the complexity of the active substance and the nature of the manufacturing process, which makes it impossible to produce an exact copy of a biologic molecule in the same way as a traditional chemical molecule (generally a single molecular entity) can be copied. As a result, manufactured drugs may vary slightly (in drug structure and physico-chemical profile) from the drug that was originally approved. But, even for any innovator s drug, batch to batch variation is often observed. Slight variations do not affect efficacy and safety as long as they are within well-defined product specifications and the manufacturing process is well controlled. Biosimilars are intended to have the same mechanism of action and are designed to treat the same diseases as the reference product. In this regard, key challenges lie in demonstrating therapeutic equivalence and interchangeability of biosimilars. Insulin Herceptin Paracetamol Large and complex molecules Produced by biological systems rather than chemical synthesis 14

15 Biosimilars are developed through a step wise process Heterogeneity is inherent to the nature of biological products and their manufacturing process, which is also highly susceptible to changes (or differences) in production conditions (e.g. purification). Since the product and process development of biosimilars is such a complex issue, a step-by-step process is considered to be the most effective approach. In the first step, it is critical to select a reference (branded-market-approved) drug and to establish a robust manufacturing process via quality studies to ascertain that the physico-chemical properties and biological characteristics of the biosimilar and the biological reference product are completely consistent. When considered to be sufficiently comparable in terms of quality, preclinical and clinical studies are conducted to confirm the comparability of safety and efficacy between the biosimilar and the reference drug in a second step. These studies should demonstrate that there are no meaningful differences with respect to the pharmacokinetic, pharmacodynamic, safety (with emphasis on immunogenicity testing) and efficacy (equivalent therapeutic efficiency) profile. The demonstration of an acceptable level of similarity between the biosimilar and the reference drug is the rationale for a reduced non-clinical and clinical data submission package. First step Establish a production process that yields a product that is completely consistent with - physical - chemical - biological product specifications of the reference drug Second step Confirm comparability: - Pre-clinical studies - Clinical studies (PK / PD / efficacy) The development of a biosimilar occurs through a stepwise process. In a first step, comparability to the reference product by evaluation of physico-chemical properties and biological characteristics, and, in a second step, appropriately designed preclinical and clinical studies to confirm similar efficacy and safety are required. For conventional small-molecule generic drugs, it is sufficient to show pharmaceutical equivalence and bioequivalence in a small study of volunteers via an abridged procedure to obtain market approval. However, the amount of data for biosimilars will be more than for a typical generic drug application since toxicological and other non-clinical and clinical data is needed in addition to the pharmaceutical, chemical and biological data normally required for generic drug applications. Source : Federal Agency for Medicines and Health Products, Biosimilars, available at: Medicines/MA_procedures/types/Biosimilars/ (accessed 6 July 2011) World Health Organization, Guidelines on Evaluation of Similar Biotherapeutic Products (SBPs), available at: of%20similarity%22&source=web&cd=1&ved=0cbsqfjaa&url=http%3a%2f%2fwww.who.int%2fbiologicals%2fareas%2fbiological_ therapeutics%2fbiotherapeutics_for_web_22april2010.pdf&ei=jkc3tvsygcue-wbz6ptsdw&usg=afqjcnflbbeayjbocpgh8ecatlq1ozz _0A (Accessed 6July 2011) Schellekens H. Biosimilar therapeutics what do we need to consider? NDT Plus (2009) 2 [Suppl 1]: i27 i36. improving access

16 Regulation for Biosimilars is in place in Europe* and FDA released its guidance document in February 2012 The history of regulation for biosimilars is an exceptionally short one due to the fact that the issue did not exist before expiry of patent protection for many of the first-generation biotech drugs on the market, which mainly occurred in The European legislation provides 10 years of market exclusivity for innovator drugs. In the US model, the market exclusivity provision for biologic products is 12 years. Many of the first-generation biotech drugs now at the end of their patent lives were developed originally as orphan drugs in the US or through new Biologics License Application. These first biotech products were introduced in Europe mostly through National or Deconcertation or Mutual Recognition approval procedures prior to the establishment of the European Medicines Agency (EMA). EMA has established regulatory pathways specific for biosimilars since 2004, while the counterpart legislation in the US came out in February *Source : EMA available at: listing_ jsp&murl=menus/special_topics/special_topics.sp&mid=wc0b01ac bf0 (accessed 07 July 2011)

17 Regulatory framework - EU* The regulatory framework for biosimilars has been established in the EU and is in place since Biosimilars can only be authorized for use once the period of data exclusivity on the original reference biological medicine has expired. The first biosimilars were approved by the European Commission in 2006 based on the positive scientific opinion issued by the EMA. The EMA s Committee for Proprietary Medicinal Products (CPMP) and the Committee for Human Medicinal Products (CHMP) have issued a number of guidance documents for the development and the market approval procedures of biosimilars. The overarching guideline introduced the concept of biosimilars, outlined the basic principles to be applied and served as a user guide to applicants on where to find relevant scientific information in the various CHMP guidelines. Other general guidelines can be categorized according to their focus on quality, pre-clinical and clinical issues. In addition, a number of product-specific guidelines (e.g. for G-CSF) and concept papers have been released. Finally, there are other guidelines also relevant for biosimilars such as the immunogenicity assessment of biotech derived therapeutic proteins. Post marketing surveillance to monitor immunogenicity and potential rare adverse events is required. Tracking product & patient safety is a key concern of the company. Thanks to its size and its diversity, Teva has a large and professional Pharmaco-vigilance system in place. Pathway for approving products as Biosimilars has been established Small proteins mab Specific regulatory requirements defined for most: GCSF EPO hgh Interferon Insulin General guidelines exist, Specific regulatory requirements currently being established To date, > 10 products approved following the Biosimilar approval pathway The regulatory pathway is applied to small proteins and to more complex biologicals such as mabs. The EMA released draft guidelines on biosimilar medicines containing mabs and on immunogenicity assessment of mabs intended for in vivo clinical use for public consultation between November 2010 and May The formal guidelines are expected to be issued in the second half of 2011 and put into effect soon afterwards. *Source : European Medicines Agency website, Multidisciplinary: Biosimilars, available at: eu/ema/index.jsp?curl=pages/regulation/general/general_content_ jsp&murl=menus/regulations/regulations. jsp&mid=wc0b01ac c (accessed at 11 July 2011) improving access

18 Example: Tevagrastim TM * Tevagrastim, a biosimilar medicine containing the active substance filgrastim, stimulates the production of white blood cells and is primarily used to reduce the risk of infections in oncology patients receiving chemotherapy. filgrastim is very similar to the human protein, namely granulocyte colony stimulating factor (G-CSF). In September 2008, Tevagrastim, which was jointly developed by TEVA and Ratiopharm, became the first biosimilar G-CSF to be approved in the EU. Since Tevagrastim showed a comparable quality, safety and efficacy profile to the reference product Neupogen (Amgen), the benefits were expected to be same. Therefore, the product was approved by the EMA and granted the entire scope of therapeutic indications of Amgen s Neupogen. The bridging principle refers to the request for approval of a biosimilar for use in another indication (without evidence from clinical studies in the submission package ) based on the indications of the reference product. These indications can be granted by EMA through extrapolation of clinical-trial data from one indication to another provided the physico-chemical, biological and clinical similarity to the reference product is demonstrated. EMA approved in September 2008 Tevagrastim as the first BioSimilar to Amgen s Neupogen in Europe EMA granted Tevagrastim the full scope of indications of Neupogen Bridging Principle Submitted comparability data package with EMA Indications granted by EMA Physical similarity + Chemical + Biological + similarity similarity Clinical similarity (in relevant setting) Chemotherapy induced neutropenia extrapolation Chemotherapy Induced neutropenia Bone marrow transplantation Severe chronic neutropenia Neutropenia in HIV patients Stem cell mobilization *Source : 18

19 Regulatory framework - US* A guidance document on biosimilars has been released by the FDA (February 2012) The FDA has issued the following 3 draft guidance documents pertaining to Biosimilar product development: Scientific Considerations in Demonstrating Biosimilarity to a Reference Product: The draft guidance is intended to assist companies in demonstrating that a proposed therapeutic protein product is biosimilar to a reference product for the purpose of submitting an application, called a 351(k) application, to the FDA. This draft guidance describes a risk-based totalityof-the-evidence approach that the FDA intends to use to evaluate the data and information submitted in support of a determination of biosimilarity of the proposed product to the reference product. As outlined in the draft guidance, FDA recommends a stepwise approach in the development of biosimilar products Quality Considerations in Demonstrating Biosimilarity to a Reference Protein Product: The draft guidance provides an overview of analytical factors to consider when assessing biosimilarity between a proposed therapeutic protein product and a reference product for the purpose of submitting a 351(k) application. This includes the importance of extensive analytical, physico-chemical and biological characterization in demonstrating that the proposed biosimilar product is highly similar to the reference product notwithstanding minor differences in clinically inactive components. Biosimilars: Questions and Answers Regarding Implementation of the Biologics Price Competition and Innovation Act of 2009: The draft guidance provides answers to common questions from people interested in developing biosimilar products. The question and answer format addresses questions that may arise in the early stages of product development, such as how to request meetings with the FDA, addressing differences in formulation from the reference product, how to request exclusivity, and other topics. *Source : improving access

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21 Biosimilars at teva

22 Teva Today TEVA Pharmaceutical Industries Ltd. - incorporated in Israel in is the successor to a number of Israeli corporations, the oldest of which was established in It is the no. 1 generic pharmaceutical company and ranks among the top 15 pharmaceutical companies. The company s global presence covers North America, Europe, Latin America, Asia and Africa. It currently has direct operations in more than 60 countries, including 40 finished dosage pharmaceutical manufacturing sites in 19 countries, 28 pharmaceutical R&D centers, and 21 API manufacturing sites around the world. TEVA manufactures and sells generic pharmaceutical products in a variety of dosage forms, including tablets, capsules, ointments, creams, liquids, injectable drugs and inhalants with distribution channels to over 100 markets. Headquartered in Israel, above 80% of TEVA s sales, which totaled US$18,3 billion net sales in 2011, are in North America and Europe. TEVA has a global product portfolio of more than 1,480 molecules and totals over 40,000 employees worldwide. No. 1 generic pharmaceutical company Top 15 global pharmaceutical company Operations in 60 countries Distribution of products to over 100 markets Global product portfolio of about 1,480 molecules Approximately 40,000 employees $18,3 billion net sales in

23 Teva worldwide presence With more than a century of experience in the healthcare industry, the company enjoys a firmly established international presence, operating through a carefully tailored network of worldwide subsidiaries. TEVA has a significant presence in about 60 countries, including marketing offices & distribution centers, finished dosage pharmaceutical plants, R&D centers, API manufacturing sites, and biosimilar activities plants. The majority of the subsidiaries are located in Europe, followed by North and Latin America, Asia and Africa. In the 1980s, TEVA established leadership on the Israeli market through a series of acquisitions and joint ventures. Also during this decade, TEVA entered the US market. Through the 90s, TEVA continued to expand and became a major player in the global generic market, driven by an aggressive Merger and Acquisition strategy both in North America and Europe. In the 21st century, global leadership is assured by constant search for strategic partnerships and successful acquisitions. 60 Locations Worldwide improving access

24 The Biosimilar market has high barriers of entry There is a higher barrier to entry for the biosimilar market than for small-molecule generics. Development costs for Biosimilars can be $100 to $200 million taking 8 to 10 years for completion. Biotech product manufacturing, in general, is highly complex, implying the need for investments comparable to original biologics. Both the complexity of the clinical development and manufacturing of biosimilars request for specialized know-how and expertise. TEVA s commitment to establish the necessary operational capabilities are three-way: increase the manufacturing capabilities, obtain specialized clinical development experience and regulatory know-how, and setup a customized sales & marketing team. The company defined a clear long-term biosimilar strategy and made (and will continue to make) significant upfront capital investments to enter the biosimilars market successfully. BioSimilar characteristics Up to $150m per molecule Up to 8 years development cycle Capital-intensive manufacturing Highly complex manufacturing and development process Minimum requirement to play Financial scale, long-term commitment Access to manufacturing capacity Specialized know-how and expertise 24

25 teva in Biosimilars A decade of commitment & vision It is the vision of TEVA that winning in biosimilars requires a full set of skills. Shortest time to market requires excellent execution of CMC development, accurate IP navigation, and appropriate speed of action and sense of urgency. Control of the manufacturing cost can be achieved by establishing solid production processes at the right scale. Finally, customer value proposition is assured with a broad product portfolio, and a strong focus on affordability and availability. Already the undisputed leader in generics for small molecule drugs, TEVA invested heavily in biosimilars over the last decade. During these last 10 years TEVA put tremendous effort in establishing a development ( First to market ) culture for biosimilars lead by innovation, expertise and mindset. Manufacturing is consolidated through in-house quality standards. Since 2000, TEVA has entered into several acquisition and CMO agreements, and alliances, providing for strong internal development, manufacturing, and R&D capabilities. Sicor Lithuania Hualida Biotech Co-Genesys EMA approves Ratiopharm Eporatio First Teva BioSimilar activities Israel BioSimilar R&D FDA approves Tev-Tropin EMA approves Tevagrastim Lonza JV improving access

26 A Global Biosimilars operation with: strong R&D capabilities strong development and manufacturing capabilities strong technology Teva Israel Biotechnology R&D (Israel) Development of BioSimilar mab s. (product characterization / cell line construction / process development) Sicor Biotech (Lithuania) Development / production of BioSimilars in microbial systems (e.g. GCSF, Interferon) / formulation development The leader of the biotech pharmacy in Lithuania, SICOR Biotech, has been working in the field of advanced biotechnology for over 20 years now and is the only company in Central and Eastern Europe developing and producing high-tech recombinant biopharmaceuticals. In 2004, the company joined the TEVA group. Through the SICOR acquisition, TEVA now has plants in Mexico, China and Latvia that develop, manufacture, and market biosimilar materials, e.g. G-CSF, interferon alpha 2B and human growth hormone. Teva Biopharmaceuticals (USA) A unique half-life extension technology : Recombinant Albumin Fusion The acquisition of COGENESYS in 2008 further expanded TEVA s biopharmaceutical pipeline and provided access to the recombinant albumin fusion technology. This technology enables the development of Long Acting biotech drugs and additional protein-based medicines across broad therapeutic categories. The clinically validated albumin-fusion technology offers a number of advantages, including the ability to improve the bioavailability of existing biotech drugs and increased feasibility of developing pharmaceutically relevant peptides. 26

27 strong alliances extended development and manufacturing capabilities JV with Lonza (Switzerland) TL Biopharmaceuticals Access to the world s largest commercial scale mab manufacturing infrastructure Headquartered in Basel, Switzerland LONZA Group Ltd. is one of the world leaders in exclusive contract manufacturing of monoclonal antibodies and recombinant proteins using mammalian cell culture. Combined with TEVA s global leadership and expertise in clinical development and marketing of generics, the joint venture generates significant opportunities and benefits for both companies. Ratiopharm group (Germany) Development / production of BioSimilars in mammalian systems (e.g. EPO, FSH) / glycpegylation technology In 2010, TEVA has completed its acquisition of Germany s RATIOPHARM, strengthening its position in Europe s growing generics market. The internationally oriented generic business, the development and sales of biotech preparations, combined with highly efficient, modern production, are the main pillars of the RATIOPHARM group. improving access

28 A recipe for success The core elements of TEVA s strategy are three-ways: development culture, manufacturing infrastructure and customer value proposition. The company s development culture focuses on improving generic R&D capabilities and production capacity, high value first-to-market opportunities as well as leveraging the broad product portfolio to enhance the global market position. Developing innovative drugs involves different processes and expertise than ever relied upon in the development of generic drugs. TEVA believes that continuing to invest, either directly or in partnership with others, in the technologies, infrastructure and capabilities is necessary to develop and produce affordable biopharmaceuticals, including biosimilars. Because of the amounts required to be invested in augmenting the innovative pipeline, TEVA is increasingly reliant on partnerships and joint ventures with third parties. Finally, customer value is achieved by broadening the product portfolio and executing more new product launches, optimizing the global supply chain, helping customers more efficiently manage their inventory and customizing shipping methods based on specific customer needs. TevaBioSimilars Development Culture Fully integrated Development System Innovative + Generic expertise IP navigation capabilities First to market Culture TevaBioSimilars Manufacturing In-house Quality Manufacturing Broad CMO agreements Lonza JV TevaBioSimilars Customer Value Proposition Making better Health Care accessible around the World Wide range of Biosimilars and Follow-on Biologics in development 28

29 Notes improving access

30 Notes

31 Improving access to life saving treatments

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