Biosimilars and Biobetters: Positioning for a New Market

Biosimilars and Biobetters: Positioning for a New Market published by Biophoenix Limited in July, 2009. This report consists of 275 pages and the price starts from US $ 1000.

Introduction

Abstract

This new and timely report analyzes the emerging market for first- and second-generation biosimilars. The market can best be understood in the context of the established $110 billion biologics business, which is therefore comprehensively reviewed. Currently, biologics worth about $59 billion are susceptible to biosimilar competition because of expired (or near-to-expiration) patents, but actual sales of biosimilars are only around $75 million worldwide. By 2013, biologics sales will have almost doubled to $202 billion, of which $80 billion will be susceptible to biosimilar competition, and biosimilars could generate a global market of $5.6 billion. This is one-third of the potential market, assuming that biosimilars are priced at 70% of the innovator products and achieve a 30% share of units sold.

The imminent expiries of several key biologics patents create not-to-be-missed opportunities for biosimilar development and a chance for new companies to establish themselves as suppliers. Initially companies will need to compete on price with first-generation biosimilars. But longer-term success will require the ability to create products that are differentiated from competing biosimilars.

Next-generation innovator products will increasingly confront first-generation products on the market. These newer products (biobetters) offer benefits over the first-generation products that current biosimilars simply attempt to imitate. Biosimilar companies also now need to formulate strategies to develop biobetters, as these are likely to be accepted more readily by end-users, and could match - or even exceed - originator products in terms of revenue-earning potential.

Biosimilars and Biobetters: Positioning for a New Market thoroughly reviews innovator biologics and biosimilars on the market and in development, the regulatory pathway in the EU and developments in the US, and profiles 40 companies developing biosimilars worldwide. Scientific and sales data on almost 90 biologics (peptides, proteins, monoclonal antibodies and other products) on the market are used to derive country-specific forecasts for biosimilars.

Top-selling biological agents in 2008 facing generic competition during the forecast period (2009-2013) were (ranked in descending order):

• erythropoietins
• insulins
• etanercept
• interferon-beta
• G-CSFs
• coagulation factors
• enoxaparin
• human growth hormone
• interferon-alpha
• imiglucerase
• goserelin
• somatostatin
• cyclosporine
• dornase alfa
• tenecteplase
• calcitonin
• rHepB vaccine
• desmopressin
• botulinum toxin type A
• GM-CSF
• IL-2

Current sales of biosimilars are constrained by the lack of a streamlined regulatory pathway for biosimilars in the US, which is the world' s largest market for biologics, and conservatism among prescribers. If readily available, and supported by adequate clinical trial data, biosimilars should appeal to third-party payers because of their lower cost, but even then might be less attractive to prescribers and patients used to the innovator drugs, e.g. because of concerns over bioequivalence. Hence the freedom of prescribers may need to be circumscribed, e.g. by biosimilar quotas or formularies. Germany is a case in point, and is developing various schemes to incentivize biosimilar usage.

At least half of the North American and European companies surveyed in this report have developed or acquired technologies for producing improved protein and antibody therapeutics and some have began to develop biobetter biosimilar products. Proprietary technologies for producing improved biologics include half-life extension methods, glycoengineering, cell production systems, and drug delivery systems. The first wave of proprietary improved biosimilars in commercial development include long-lasting versions of erythropoietins, human growth hormone, G-CSF, insulins, and interferon-beta.

Some improved biosimilars might be approved through the biosimilar regulatory pathways. For example, Teva Pharmaceutical' s long-acting G-CSF is based on a different technology from the long-acting G-CSF product already on the market, but Teva hopes to have its product approved as a biosimilar drug.

Other improved biosimilar products might be considered second-generation biologics and could obtain patent protection and premium pricing. Most of Merck & Co' s biosimilars in development can be considered second-generation biologics, reformulated or improved versions of branded drugs. The current development period for a first-generation biosimilar ranges from seven to ten years, which is not vastly shorter than that for a biopharmaceutical product. Improved biosimilars which will need to be approved via the same pathways as innovator drugs will not require the same extensive investment as an innovator drug, nor will they carry the same level of risk.

Use this report to:

• Understand the existing market for biologic drugs, including production methods, drug characterization techniques, and therapeutic indications;
• Examine the EU biosimilar legislation, requirements for comparability and immunogenicity testing, and lessons learned from biosimilar launches to date;
• Analyze the proposed US biosimilar legislation under consideration;
• Examine strategic implications of the biopharma patent landscape and expiry dates of the first US patents issued on top-selling biologics
• Explore technologies for producing improved biologics (biobetters), including drug delivery, half-life extension, cell production, and glycoengineering methods;
• Identify the most promising peptide, protein, monoclonal antibody, and glycan targets for biosimilar development;
• Establish the nature of the existing and pipeline competition for potential specific peptide, protein, monoclonal antibody, and glycan biosimilars;
• Identify the characteristics of companies developing biosimilars, including their strategies, proprietary technologies for developing improved biologics, biosimilar portfolios and collaborations;
• Analyze the biosimilar-susceptible segment of the global biologic market and get market forecasts to 2013 for the leading biologics currently susceptible to biosimilar competition.

Table of Contents

Front Cover

List of Tables

About Biophoenix

About the Authors

Legal Notice

Executive Summary

• Chapter 1 First-generation biologics
• Chapter 2 Biosimilars and follow-on biologics
• Chapter 3 Biobetters
• Chapter 4 Peptide, protein and other biosimilar targets
• Chapter 5 Monoclonal antibody biosimilar targets
• Chapter 6 Company profiles
• Chapter 7 Market analysis

Chapter 1 First-generation biologics

• 1.0 Chapter Summary
• 1.1 Introduction
• 1.2 Background on proteins
  • 1.2.1 Post-translational modifications
    • 1.2.1.1 Glycosylation
• 1.3 Production of therapeutic peptides and proteins
  • 1.3.1 Chemical synthesis
  • 1.3.2 Recombinant technology
    • 1.3.2.1 Traditional mammalian cell culture
    • 1.3.2.2 Increasing production yields
• 1.4 Characterization and equivalence testing
  • 1.4.1 Analytical methods
  • 1.4.2 Bioassays
  • 1.4.3 Limitations
  • 1.4.4 Pharmacokinetics and pharmacodynamics
  • 1.4.5 Clinical studies
  • 1.4.6 Immunogenicity studies
• 1.5 Regulatory pathways
  • 1.5.1 EU
  • 1.5.2 US

Chapter 2 Biosimilars and follow-on biologics

• 2.0 Chapter Summary
• 2.1 Introduction
• 2.2 Issues of comparability
• 2.3 The INN nomenclature system
• 2.4 Regulatory pathway: EU
  • 2.4.1 General guidelines
  • 2.4.2 Guidelines on non-clinical issues
  • 2.4.3 Guidelines on clinical issues
  • 2.4.4 Guidelines on immunogenicity assessment
  • 2.4.5 Biosimilars approved, rejected and withdrawn
  • 2.4.6 Outstanding issues
• 2.5 Regulatory developments in the US
  • 2.5.1 Biologics regulated under NDAs
  • 2.5.2 Proposals for a biosimilars pathway
    • 2.5.2.1 H.R. 1427 biosimilars bill
    • 1.5.2.2 Pathway for Biosimilars Act
  • 2.5.3 FDA' s stance on immunogenicity issues
• 2.6 Initiatives outside the EU/US
• 2.7 Patenting issues
  • 2.7.1 Background
  • 2.7.2 Patent expirations of biologics

Chapter 3 Biobetters

• 3.0 Chapter Summary
• 3.1 Technologies for improving biologics
• 3.2 Improving parenteral delivery of biologics
  • 3.2.1 Introduction
  • 3.2.2 Formulations and devices
  • 3.2.3 Half-life extension technologies
    • 3.2.3.1 PEGylation
    • 3.2.3.2 Alternatives to PEGylation
    • 3.2.3.3 Glyco-engineering
    • 3.2.3.4 Other approaches
  • 3.2.4 Depot systems
• 3.3 Advances in nonparenteral delivery
  • 3.3.1 Nasal delivery
  • 3.3.2 Pulmonary delivery
  • 3.3.3 Other approachers
• 3.4 Enhanced production systems
  • 3.4.1 Mammalian cells
  • 3.4.2 Non-mammalian cells
  • 3.4.3 Transgenic animal bioreactors
• 3.5 Chemical protein synthesis
  • 3.5.1 Chemoselective ligation

Chapter 4 Peptide, protein and other biosimilar targets

• 4.0 Chapter Summary
• 4.1 Introduction
• 4.2 Peptides
  • 4.2.1 Somatostatins and other hGH antagonists
  • 4.2.2 Vasopressins
  • 4.2.3 Cyclosporins
  • 4.2.4 Calcitonins
  • 4.2.5 LHRH
  • 4.2.6 Hirudins
  • 4.2.7 Glucagons and their analogs
  • 4.2.8 Glatiramer
  • 4.2.9 Selected other peptides
• 4.3 Recombinant unglycosylated proteins
  • 4.3.1 Insulins
    • 4.3.1.1 Biosimilars rejected (EU)
  • 4.3.2 IGF-1
  • 4.3.3 Growth hormone
    • 4.3.3.1 Biosimilars approved (EU)
    • 4.3.3.2 Biosimilar for approval (EU)
• 4.4 Recombinant proteins (mainly unglycosylated)
  • 4.4.1 Il-2 and other interleukins
  • 4.4.2 Interferons-alpha
  • 4.4.2.1 Biosimilars rejected (EU)
  • 4.4.3 Interferons-beta
  • 4.4.4 Interferons-gamma
  • 4.4.5 G-CSF
    • 4.4.5.1 Biosimilars approved (EU)
• 4.5 Recombinant glycosylated proteins
  • 4.5.1 FSH
  • 4.5.2 Lysosomal enzymes
  • 4.5.3 GM-CSF
  • 4.5.4 Erythropoietins
    • 4.5.4.1 First-generation products
    • 4.5.4.2 Next-generation products
    • 4.5.4.3 Biosimilars approved (EU)
  • 4.5.5 Factors VIII
  • 4.5.6 Factors IX
  • 4.5.7 Factors VIIa
  • 4.5.8 Plasminogen activators (thrombolytics)
  • 4.5.9 Protein C-based anticoagulants
  • 4.5.10 Selected other proteins
• 4.6 Thrombin inhibitors (anticoagulants)
• 4.7 Vaccines
• 4.8 Botulinum toxins

Chapter 5 Monoclonal antibody biosimilar targets

• 5.0 Chapter Summary
• 5.1 Introduction
  • 5.1.1 Intact mAbs
  • 5.1.2 mAb fragments
  • 5.1.3 Fc-based fusion proteins
  • 5.1.4 Other mAb formats
• 5.2 Evolution of mAbs
  • 5.2.1 Murine mAbs
  • 5.2.2 Chimeric mAbs
  • 5.2.3 Humanized mAbs
  • 5.2.4 Fully human mAbs
• 5.3 Production of therapeutic recombinant mAbs
  • 5.3.1 Mammalian cell culture production systems
  • 5.3.1.1 Manipulating mAb glycosylation profiles
  • 5.3.2 Nonmammalian production systems
  • 5.3.3 Enhancing mAb serum half-life
  • 5.3.4 Patenting of mAbs
• 5.4 Monoclonals for chronic inflammatory diseases
  • 5.4.1 TNF antagonists
    • 5.4.1.1 Etanercept
    • 5.4.1.2 Infliximab
    • 5.4.1.3 Adalimumab
    • 5.4.1.4 Cimzia (certolizumab pegol)
  • 5.4.2 Other monoclonals
    • 5.4.2.1 Natalizumab
    • 5.4.2.2 Abatacept and belatacept
    • 5.4.2.3 Rituximab
    • 5.4.2.4 Tocilizumab
    • 5.4.2.5 Omalizumab
    • 5.4.2.6 Efalizumab
    • 5.4.2.7 Daclizumab
• 5.5 Cancer monoclonals
  • 5.5.1 Unconjugated intact mAbs
    • 5.5.1.1 Rituximab
    • 5.5.1.2 Trastuzumab
    • 5.5.1.3 Cetuximab
    • 5.5.1.4 Panitumumab
    • 5.5.1.5 Bevacizumab
  • 5.5.2 Immunoconjugates
• 5.6 Other monoclonals
  • 5.6.1 Ranibizumab
  • 5.6.2 Palivizumab
  • 5.6.3 Abciximab

Chapter 6 Company profiles

• 6.0 Chapter Summary
• 6.1 Companies headquartered in the US
  • 6.1.1 Abraxis BioScience Inc
  • 6.1.2 Aequus BioPharma Inc
  • 6.1.3 Biogen Idec Inc
  • 6.1.4 Dynavax Technologies Corp
  • 6.1.5 GTC Biotherapeutics Inc
  • 6.1.6 Hospira Inc
  • 6.1.7 Itero Biopharmaceuticals
  • 6.1.8 Merck & Co Inc
  • 6.1.9 Momenta Pharmaceuticals Inc
  • 6.1.10 Mylan Inc
  • 6.1.11 Phage Biotechnology Corp
  • 6.1.12 Prolong Pharmaceuticals
• 6.2 Companies headquartered in Canada
  • 6.2.1 Apotex Inc
  • 6.2.2 Viropro Inc
• 6.3 Companies headquartered in Germany
  • 6.3.1 BioGeneriX AG
  • 6.3.2 Sandoz
  • 6.3.3 Stada Arzneimittel AG
• 6.4 Companies headquartered in France
  • 6.4.1 LFB S.A.
  • 6.4.2 Merieux Alliance
• 6.5 Companies headquartered in Poland
  • 6.5.1 Bioton SA
• 6.6 Companies headquartered in the Netherlands
  • 6.6.1 DSM NV
• 6.7 Companies headquartered in Switzerland
  • 6.7.1 Lonza Group Ltd
  • 6.7.2 Selexis SA
• 6.8 Companies headquartered in India
  • 6.8.1 Avesta Biotherapeutic and Research Pvt Ltd
  • 6.8.2 Biocon Ltd
  • 6.8.3 Dr Reddy' s Laboratories Ltd
  • 6.8.4 Emcure Pharmaceuticals Ltd
  • 6.8.5 Intas Biopharmaceuticals Ltd
  • 6.8.6 Ranbaxy Laboratories Ltd
  • 6.8.7 Reliance Life Sciences Pvt Ltd
  • 6.8.8 Wockhardt Ltd
  • 6.8.9 Zenotech Technologies Ltd
• 6.9 Companies headquartered in Israel
  • 6.9.1 Teva Pharmaceutical Industries Ltd
• 6.10 Companies headquartered in South Korea
  • 6.10.1 Green Cross
  • 6.10.2 LG Life Sciences Ltd
• 6.11 Companies headquartered in China
  • 6.11.1 3SBio Inc
  • 6.11.2 GeneScience Pharmaceuticals Co Ltd
  • 6.11.3 Shenzhen Kexing Biotech Co Ltd
• 6.12 Companies headquartered in South Africa
  • 5.12.1 Bioclones
• 6.13 Companies headquartered in Iran
  • 6.13.1 CinnaGen Inc

Chapter 7 Market analysis

• 7.0 Chapter Summary
• 7.1 Introduction
• 7.2 Sales of Innovator and Related Products
  • 7.2.1 Anti-TNF antibodies
  • 7.2.2 Cancer antibodies
  • 7.2.3 Vaccines
  • 7.2.4 Peptides and Glycans
  • 7.2.5 Erythropoiesis stimulating agents
  • 7.2.6 Insulins and IGF-1
  • 7.2.7 Interferon-beta
  • 7.2.8 Granulocyte Colony Stimulating factor
  • 7.2.9 Other antibodies
  • 7.2.10 Coagulation Factors
  • 7.2.11 Miscellaneous proteins
  • 7.2.12 Lysosomal enzymes
  • 7.2.13 Human Growth Hormone
  • 7.2.14 Interferon-alpha
  • 7.2.15 Follicle Stimulating Hormone
• 7.3 Product Analysis and Forecasts to 2013
• 7.4 Geographic Analysis and Forecasts to 2013
  • 7.4.1 Effect of uncertain economic conditions
  • 7.4.2 European Biosimilars Market
  • 7.4.3 US Biosimilars Market
  • 7.4.4 Emerging markets
  • 7.4.5 Japan
  • 7.4.6 Forecasts
• 7.5 Biosimilar challenges and market drivers

Appendix 1 Abbreviations and Acronyms

Appendix 2 Research Methodology

Appendix 3 List of Tables

List of Tables

• Table 1.1 Analytical Procedures Useful for Assessing the Equivalence of Biotechnological Products
• Table 2.1 Biosimilars in the EU; Outcome of Marketing Authorisation Applications
• Table 2.2 First US patent expiries of the 25 top-selling biologics (in 2008)
• Table 3.1 Half-life extension technologies for injectable protein delivery
• Table 3.2 Depot technologies for injectable protein delivery
• Table 4.1 Somatostatins and other hGH antagonists
• Table 4.2 Vasopressins
• Table 4.3 Cyclosporins
• Table 4.4 Calcitonins
• Table 4.5 LHRH (luteinizing hormone-releasing hormone) analogs
• Table 4.6 Glucagons and their analogues
• Table 4.7 Insulins and IGF1
• Table 4.8 Human growth hormone (hGH)
• Table 4.9 Interleukin 2 Agents
• Table 4.10 Interferons α
• Table 4.11 Interferons β
• Table 4.12 Interferons γ
• Table 4.13 Granulocyte-colony stimulating factors (G-CSFs)
• Table 4.14 Follicle-stimulating hormone (FSH) agonists
• Table 4.15 Lysosomal Enzymes
• Table 4.16 Granulocyte monocyte colony stimulating factor (GM-CSFs)
• Table 4.17 Erythropoietins (EPOs)
• Table 4.18 Factors VIII
• Table 4.19 Factors IX
• Table 4.20 Factors VIIa
• Table 4.21 Plasminogen Activators
• Table 4.22 Protein C-based Anticoagulants
• Table 4.23 Thrombin Inhibitors
• Table 4.24 Vaccines
• Table 4.25 Miscellaneous Agents
• Table 5.1 TNF Antagonists
• Table 5.2 Monoclonals for cancer and other indications
• Table 5.3 Immunoconjugates for cancer and other indications
• Table 6.1 Characteristics of North American companies developing biosimilars
• Table 6.2 Characteristics of European companies developing biosimilars
• Table 6.3 Characteristics of Rest-of-World companies developing biosimilars
• Table 7.1 Top Biologics Categories in 2008, with Forecasts to 2013
• Table 7.2 Prominent Biologics by Product Category and Sales in 2008, with Forecasts to 2013
• Table 7.3 Top 25 Biologics Sales in 2008, with Forecasts to 2013
• Table 7.4 Biosimilars Analysis in 2008 and Forecasts to 2013 ($USM)
• Table 7.5 World Pharma Market by Country, 2008-2013 ($USM)
• Table 7.6 World Biologic Market by Country, 2008-2013 ($USM)
• Table 7.7 World Biosimilar-Susceptible Market by Country, 2008-2013 ($USM)
• Table 7.8 World Biosimilar Market by Country, 2008-2013 ($USM)

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