生技仿製藥(生技學名藥•後繼生物製劑)產業與市場

The first generation of biopharmaceuticals manufactured using recombinant technologies was launched in the 1980s, and patents protecting them are now nearing expiration. As with small molecule drugs, the expiration of patents creates an opportunity for generic biologicals to enter the market. Due to the complexity of biological drugs, such products are usually referred to as ‘biosimilars' or ‘follow-on biologics' , although the term ‘biogenerics' may be applied to simple peptides.

Despite delays by the US FDA, and opposition from originator companies, biosimilars now represent one of the most rapidly evolving areas of product development in the pharmaceutical industry. The EU already has legislation in place for the approval of biosimilars, and the US is set to follow suit following the passing of landmark legislation by the US Senate Health Committee in June 2007. In the same month another significant milestone in the development of biosimilars was reached when the EMEA recommended three biosimilar versions of recombinant erythropoietin (EPO), a complex glycoprotein, for approval.

As discussed in this Report, companies active in the biosimilars sector are currently targeting products which are now off-patent in Europe: in particular human growth hormone (hGH), EPO and granulocyte colonystimulating factor (G-CSF). However, there are many more potential targets for development in areas, which have so far attracted fewer developers in the Western markets.

This Report focuses on 59 protein and 14 peptide therapeutics, which achieved high-volume global sales in 2006. Half of the protein products generated sales in excess of $500 million. We analyse these potential targets in the context of other commercial products based on the same active ingredient which are on the market or in development worldwide. This information, derived from the Pharmaprojects database, will provide the reader with a snapshot of the commercial landscape relevant to each target product, and highlight related or improved products which may themselves become targets for biosimilar development.

Table of Contents

• 1.1 The advent of biosimilars
• 1.2 The role of patents in the drug industry
• 1.3 Protein-based biopharmaceuticals
  • 1.3.1 Background
  • 1.3.2 Manufacturing processes
  • 1.3.3 Protein characterisation
  • 1.3.4 The global market
• 1.4 Biosimilars
  • 1.4.1 Market drivers and inhibitors
  • 1.4.2 The INN nomenclature system
• 1.5 Biosimilars regulation
  • 1.5.1 The EU position
  • 1.5.2 US pathways
    • 1.5.2.1 Government initiatives

• 2.1 Introduction
  • 2.1.1 Approved follow-on proteins/biosimilars
• 2.2 Characteristics of high-selling peptides and proteins
  • 2.2.1 Products with expired patents
  • 2.2.2 Challenging originator' s patents
• 2.3 Target products for FOB/biosimilar development
• 2.4 Peptides (NDA Pathway)
  • 2.4.1 Octreotide
  • 2.4.2 Desmopressin
  • 2.4.3 Cyclosporine
  • 2.4.4 Calcitonin
  • 2.4.5 Eptifibatide
  • 2.4.6 LHRH
  • 2.4.7 Bivalirudin
  • 2.4.8 Enfuvirtide
  • 2.4.9 Glucagon
  • 2.4.10 Nesiritide
  • 2.4.11 Teriparatide
• 2.5 Recombinant non-glycosylated proteins (NDA Pathway)
  • 2.5.1 Insulin
  • 2.5.2 Somatropin
  • 2.5.3 Lepirudin
• 2.6 Recombinant non-glycosylated proteins (BLA pathway)
  • 2.6.1 Interleukin-2
  • 2.6.2 Interferons
    • 2.6.2.1 Interferon-alfa
    • 2.6.2.2 Interferon-beta
    • 2.6.2.3 Interferon-gamma
  • 2.6.3 Granulocyte-CSF
  • 2.6.4 Interleukin-11
  • 2.6.5 Anakinra
  • 2.6.6 Other proteins
• 2.7 Recombinant glycosylated proteins (NDA pathway)
  • 2.7.1 Follitropin
  • 2.7.2 Thyrotropin
  • 2.7.3 Urokinase
  • 2.7.4 Glucocerebrosidase
  • 2.7.5 Other products
• 2.8 Recombinant glycosylated proteins (BLA pathway)
  • 2.8.1 Becaplermin
  • 2.8.2 Granulocyte-macrophage-CSF
  • 2.8.3 Erythropoietin
  • 2.8.4 DNase
  • 2.8.5 Factor VIIa
  • 2.8.6 Factor IX
  • 2.8.7 Factor VIII
  • 2.8.8 Activated protein C
  • 2.8.9 Tissue plasminogen activator
  • 2.8.10 Monoclonal antibodies
    • 2.8.10.1 Chimaeric mAbs
    • 2.8.10.2 Humanised mAbs
    • 2.8.10.3 Human mAbs and fusion proteins
  • 2.8.11 Other proteins
• 2.9 Strategies of originator companies
  • 2.9.1 Increasing product patent protection
  • 2.9.2 Next-generation branded products
  • 2.9.3 Development of authorised generics
  • 2.9.4 Price reduction of the branded product

• 3.1 Introduction
• 3.2 Problems in characterising biologics
  • 3.2.1 Definitions
  • 3.2.2 Types of biologic
    • 3.2.2.1 Peptides
    • 3.2.2.2 Non-glycosylated proteins
    • 3.2.2.3 Glycosylated proteins
    • 3.2.2.4 Monoclonal antibodies
  • 3.2.3 Equivalence issues
  • 3.2.4 Post-translational modifications
  • 3.2.5 Effect of microheterogeneity
  • 3.2.6 Pharmacokinetics
  • 3.2.7 Pharmacodynamics
  • 3.2.8 Clinical efficacy
  • 3.2.9 Immunogenicity
• 3.3 Analytical methods
  • 3.3.1 Introduction
  • 3.3.2 Chromatography
  • 3.3.3 Protein sequencing
  • 3.3.4 Mass spectrometry
  • 3.3.5 Nuclear magnetic resonance
  • 3.3.6 Electrophoresis
  • 3.3.7 Western blotting
  • 3.3.8 Bioassays
  • 3.3.9 Other procedures
• 3.4 Case studies
  • 3.4.1 Introduction
  • 3.4.2 Erythropoietin
    • 3.4.2.1 European position
    • 3.4.2.2 US position
    • 3.4.2.3 Immunogenicity: pure red cell aplasia
    • 3.4.2.4 Immunogenicity: product consistency issues
  • 3.4.3 Somatotropin
    • 3.4.3.1 European position
    • 3.4.3.2 US position
    • 3.4.3.3 Immunogenicity issues
  • 3.4.4 Alpha interferon
    • 3.4.4.1 European position
    • 3.4.4.2 US position

• 4.1 Preface
• 4.2 India-based companies
  • 4.2.1 Biocon
    • 4.2.1.1 Company overview
    • 4.2.1.2 Biosimilar strategy
    • 4.2.1.3 Biosimilar pipeline
    • 4.2.1.4 Biosimilar collaborations
  • 4.2.2 Dr Reddy' s
    • 4.2.2.1 Company overview
    • 4.2.2.2 Biosimilar strategy
    • 4.2.2.3 Biosimilar pipeline
  • 4.2.3 Reliance Life Sciences/Genemedix
    • 4.2.3.1 Company overview
    • 4.2.3.2 Biosimilar strategy
    • 4.2.3.3 Biosimilar pipeline
    • 4.2.3.4 Biosimilar collaborations
  • 4.2.4 Ranbaxy Laboratories
    • 4.2.4.1 Company overview
    • 4.2.4.2 Biosimilar strategy
    • 4.2.4.3 Biosimilar pipeline
    • 4.2.4.4 Biosimilar collaborations
• 4.3 Germany-based companies
  • 4.3.1 Ratiopharm/Biogenerix
    • 4.3.1.1 Overview
    • 4.3.1.2 Biosimilar strategy
    • 4.3.1.3 Biosimilar pipeline
    • 4.3.1.4 Biosimilar collaborations
  • 4.3.2 Sandoz International (Novartis)
    • 4.3.2.1 Company overview
    • 4.3.2.2 Biosimilar strategy
    • 4.3.2.3 Biosimilar pipeline
    • 4.3.2.4 Biosimilar collaborations
  • 4.3.3 Stada Arzneimittel/Bioceuticals Arzneimittel
    • 4.3.3.1 Company overview
    • 4.3.3.2 Biosimilar strategy
    • 4.3.3.3 Biosimilar pipeline
    • 4.3.3.4 Biosimilar collaborations
• 4.4 Other EU-based companies
  • 4.4.1 Bioton/Biopartners
    • 4.4.1.1 Company overview
    • 4.4.1.2 Biosimilar strategy
    • 4.4.1.3 Biosimilar pipeline
    • 4.4.1.4 Biosimilar collaborations
  • 4.4.2 DSM (DSM Biologicals)
    • 4.4.2.1 Company overview
    • 4.4.2.2 Biosimilar strategy
    • 4.4.2.3 Biosimilar pipeline
    • 4.4.2.4 Biosimilar collaborations
• 4.5 US-based companies
  • 4.5.1 Barr Pharmaceuticals/Pliva
    • 4.5.1.1 Company overview
    • 4.5.1.2 Biosimilar strategy
    • 4.5.1.3 Biosimilar pipeline
    • 4.5.1.4 Biosimilar collaborations
  • 4.5.2 Hospira/Mayne Pharma
    • 4.5.2.1 Company overview
    • 4.5.2.2 Biosimilar strategy
    • 4.5.2.3 Biosimilar pipeline
    • 4.5.2.4 Biosimilar collaborations
  • 4.5.3 Dynavax Technologies/Rhein Biotech
    • 4.5.3.1 Company overview
    • 4.5.3.2 Biosimilar strategy
    • 4.5.3.3 Biosimilar pipeline
    • 4.5.3.4 Biosimilar collaborations
• 4.6 Canada-based companies
  • 4.6.1 Cangene
    • 4.6.1.1 Company overview
    • 4.6.1.2 Biosimilar strategy
    • 4.6.1.3 Biosimilar pipeline
  • 4.6.2 Microbix
    • 4.6.2.1 Company overview
    • 4.6.2.2 Biosimilar strategy
    • 4.6.2.3 Biosimilar pipeline
    • 4.6.2.4 Biosimilar collaborations
• 4.7 Other companies
  • 4.7.1 Teva Pharmaceutical Industries/Sicor
    • 4.7.1.1 Company overview
    • 4.7.1.2 Biosimilar strategy
    • 4.7.1.3 Biosimilar pipeline
    • 4.7.1.4 Biosimilar collaborations

• 5.1 Introduction
• 5.2 Leading drug classes
• 5.3 Major players
• 5.4 Market outlook
• 5.5 Pricing of biosimilars
• 5.6 Profitability of biosimilars
• 5.7 Substitutability and interchangeability
• 5.8 World pharmaceutical market overview
• 5.9 World market for protein biopharmaceuticals
• 5.10 Approved biosimilar products
  • 5.10.1 US
  • 5.10.2 Europe
• 5.11 Forecasts by product
  • 5.11.1 Erythropoietin
  • 5.11.2 Insulin
  • 5.11.3 Interferons
  • 5.11.4 Granulocyte colony stimulating factor
  • 5.11.5 Somatotropins
  • 5.11.6 Other proteins and peptides
• 5.12 Forecasts by Region

• 6.1 Biosimilars market gaining momentum
• 6.2 Competing through superior delivery
• 6.3 Diversifying biosimilar pipelines
• 6.4 Tackling immunogenicity
• 6.5 Expanding the range of cell production systems
• 6.6 Exploring transgenic production systems
• 6.7 Developing cell-free protein synthesis

• Table 1.1 Leading protein products in 2006
• Table 1.2 Leading monoclonal antibody products in 2006
• Table 2.1 Peptides (NDA pathway)
• Table 2.2 Recombinant non-glycosylated proteins (NDA pathway)
• Table 2.3 Recombinant non-glycosylated proteins (BLA pathway)
• Table 2.4 Recombinant glycosylated proteins (NDA pathway)
• Table 2.5 Recombinant glycosylated proteins (BLA pathway)
• Table 2.6 Patents - peptides (NDA pathway)
• Table 2.7 Patents - recombinant non-glycosylated proteins (NDA pathway)
• Table 2.8 Patents - recombinant non-glycosylated proteins (BLA pathway)
• Table 2.9 Patents - recombinant glycosylated proteins (NDA pathway)
• Table 2.10 Patents - recombinant glycosylated proteins (BLA pathway)
• Table 2.11 Commercialisation of candidate biosimilars
• Table 2.12 Candidate biosimilars by gene target
• Table 2.13 Launched peptides and proteins by primary pharmacology description
• Table 2.14 Candidate biosimilars (interferon alpha)
• Table 2.15 Candidate biosimilars (insulin)
• Table 2.16 Candidate biosimilars (erythropoietin)
• Table 2.17 Candidate biosimilars (factor VIII)
• Table 2.18 Candidate biosimilars (cyclosporin)
• Table 2.19 Candidate biosimilars (granulocyte stimulating factor)
• Table 2.20 Candidate biosimilars (interferon beta)
• Table 2.21 Candidate biosimilars (calcitonin)
• Table 2.22 Candidate biosimilars (LHRH)
• Table 2.23 Candidate biosimilars (interleukin 2)
• Table 2.24 Candidate biosimilars (factor IX)
• Table 2.25 Candidate biosimilars (tissue plasminogen activator)
• Table 2.26 Candidate biosimilars (urokinase plasminogen activator)
• Table 2.27 Candidate biosimilars (follitropin)
• Table 2.28 Candidate biosimilars (somatotropin)
• Table 2.29 Candidate biosimilars (granulocyte macrophage colony stimulating factor)
• Table 2.30 Candidate biosimilars (interferon gamma)
• Table 2.31 Candidate biosimilars (octreotide)
• Table 2.32 Candidate biosimilars (desmopressin)
• Table 2.33 Candidate biosimilars (factor VIIa)
• Table 2.34 Candidate biosimilars (protein C)
• Table 2.35 Candidate biosimilars (teriparatide)
• Table 2.36 Candidate biosimilars (glucocerebrosidase)
• Table 2.37 Candidate biosimilars (hirudin)
• Table 2.38 Candidate biosimilars (bevacizumab)
• Table 2.39 Candidate biosimilars (enfuvirtide)
• Table 2.40 Candidate biosimilars (glucagon)
• Table 2.41 Candidate biosimilars (interleukin 11)
• Table 2.42 Candidate biosimilars (thyrotropin)
• Table 2.43 Candidate biosimilars (abciximab)
• Table 2.44 Candidate biosimilars (adalimumab)
• Table 2.45 Candidate biosimilars (alemtuzumab)
• Table 2.46 Candidate biosimilars (anakinra)
• Table 2.47 Candidate biosimilars (aprotinin)
• Table 2.48 Candidate biosimilars (becaplermin)
• Table 2.49 Candidate biosimilars (cetuximab)
• Table 2.50 Candidate biosimilars (DNase)
• Table 2.51 Candidate biosimilars (efalizumab)
• Table 2.52 Candidate biosimilars (eptifibatide)
• Table 2.53 Candidate biosimilars (etanercept)
• Table 2.54 Candidate biosimilars (gemtuzumab)
• Table 2.55 Candidate biosimilars (infliximab)
• Table 2.56 Candidate biosimilars (natalizumab)
• Table 2.57 Candidate biosimilars (nesiritide)
• Table 2.58 Candidate biosimilars (omalizumab)
• Table 2.59 Candidate biosimilars (palivizumab)
• Table 2.60 Candidate biosimilars (rituximab)
• Table 2.61 Candidate biosimilars (trastuzumab)
• Table 3.1 Examples of post-translational modifications
• Table 3.2 Analytical procedures useful for assessing the equivalence of biotechnological products
• Table 5.1 Leading protein drug classes in 2006
• Table 5.2 World pharma market by therapeutic category, 2006-2011
• Table 5.3 World pharma market by region, 2006-2011
• Table 5.4 Biopharmaceuticals market by application in 2006 and 2011
• Table 5.5 Biopharmaceuticals market by company in 2006 and 2011
• Table 5.6 Biopharmaceuticals market by protein in 2006 and 2011
• Table 5.7 Biosimilars market by protein in 2006 and 2011
• Table 5.8 Biopharmaceuticals market by region in 2006 and 2011
• Table 5.9 Biosimilars market by region in 2006 and 2011
• Table 6.1 Recently published cell-free protein synthesis patents and applications