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A Guide to Biosimilars, Biogenerics and Follow-On Biologics
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Description: |
This report will give readers a broad overview of the key drivers and players involved in the biosimilars revolution today. It will also arm readers with the strategic information they need to face the new opportunities presented by this market trend, as well as its challenges.
With regulation playing a key role in the evolving landscape for biosimilar products, the report places particular emphasis on the regulatory situation in two of the largest markets; the US and Europe. While the European regulatory framework for biosimilars is more defined, there have been significant developments in the US too, notably the FDAs approval of Omnitrope, which demostrated that the simplified approval process is available to biosimilars that demostrate comparability with biologics regulated under NDAs. The report discusses the various factors at play in these two markets.
It analyses the situation from the perspectives of both biosimilar manufacturers and innovator companies. For firms looking to develop biosimilars, some 75 proteins and peptide therapeutics were recently identified as potential profitable targets for new products. And significantly, a substantial proportion of these were approved as NDAs, meaning that biosimilar firms can target them knowing that a clear regulatory pathway exists.
Originator companies, meanwhile, are looking to use a range of strategies to delay biogeneric competition; these strategies include patenting preferred formulations, manufacturing methods and protein modifications.
The report will spotlight the most prominent companies in the biosimilars field, not only the well established generics manufacturers but emerging biosimilar developers too. It will also assess the various geographical markets for therapeutic proteins, including North America, Europe and Brazil.
Use this report provides:
- an overview of the market for therapeutic proteins, including growth factors, anticoagulants, insulins, interferons, hormones, enzymes and vaccines
- an analysis of the drivers of the nascent biosimilars market and current obstacles to entry
- a review of the global regulatory situation; essential knowledge for any company looking to introduce biosimilar products to market
- sales and patent expiry information on the products identified as profitable targets for biosimilars
- an examination of the issues involved in assessing the similarity of biosimilars and in the prediction of immunogenicity
- profiles of the most active companies in the biosimilars field - their pipelines, business strategies and collaborations in the biosimilars space
- assessments of factors such as the level of competition, ease of product development and characterisation and the level of patient support required, to predict the market potential for different classes of biosimilars
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Contents: |
CHAPTER 1 INTRODUCTION 9
1.1 The advent of biosimilars 9
1.2 The role of patents in the drug industry 9
1.3 Protein-based biopharmaceuticals 10
1.3.1 Background 11
1.3.2 Manufacturing processes 12
1.3.3 Protein characterisation 13
1.3.4 The global market 14
1.4 Biosimilars 15
1.4.1 Market drivers and inhibitors 15
1.4.2 The INN nomenclature system 16
1.5 Biosimilars regulation 17
1.5.1 The EU position 17
1.5.2 US pathways 18
1.5.2.1 Government initiatives 18
CHAPTER 2 PRODUCT OVERVIEW 23
2.1 Introduction 23
2.1.1 Approved follow-on proteins/biosimilars 23
2.2 Characteristics of high-selling peptides and proteins 24
2.2.1 Products with expired patents 24
2.2.2 Challenging originator’s patents 24
2.3 Target products for FOB/biosimilar development 25
2.4 Peptides (NDA Pathway) 25
2.4.1 Octreotide 25
2.4.2 Desmopressin 26
2.4.3 Cyclosporine 26
2.4.4 Calcitonin 26
2.4.5 Eptifibatide 27
2.4.6 LHRH 27
2.4.7 Bivalirudin 27
2.4.8 Enfuvirtide 27
2.4.9 Glucagon 28
2.4.10 Nesiritide 28
2.4.11 Teriparatide 28
2.5 Recombinant non-glycosylated proteins (NDA Pathway) 28
2.5.1 Insulin 28
2.5.2 Somatropin 30
2.5.3 Lepirudin 31
2.6 Recombinant non-glycosylated proteins (BLA pathway) 31
2.6.1 Interleukin-2 31
2.6.2 Interferons 32
2.6.2.1 Interferon-alfa 32
2.6.2.2 Interferon-beta 33
2.6.2.3 Interferon-gamma 34
2.6.3 Granulocyte-CSF 35
2.6.4 Interleukin-11 35
2.6.5 Anakinra 35
2.6.6 Other proteins 36
2.7 Recombinant glycosylated proteins (NDA pathway) 36
2.7.1 Follitropin 36
2.7.2 Thyrotropin 36
2.7.3 Urokinase 36
2.7.4 Glucocerebrosidase 37
2.7.5 Other products 37
2.8 Recombinant glycosylated proteins (BLA pathway) 37
2.8.1 Becaplermin 37
2.8.2 Granulocyte-macrophage-CSF 38
2.8.3 Erythropoietin 38
2.8.4 DNase 39
2.8.5 Factor VIIa 40
2.8.6 Factor IX 40
2.8.7 Factor VIII 40
2.8.8 Activated protein C 41
2.8.9 Tissue plasminogen activator 41
2.8.10 Monoclonal antibodies 42
2.8.10.1 Chimaeric mAbs 43
2.8.10.2 Humanised mAbs 43
2.8.10.3 Human mAbs and fusion proteins 44
2.8.11 Other proteins 44
2.9 Strategies of originator companies 44
2.9.1 Increasing product patent protection 44
2.9.2 Next-generation branded products 44
2.9.3 Development of authorised generics 45
2.9.4 Price reduction of the branded product 46
CHAPTER 3 APPROACHES TO THE CHARACTERISATION OF BIOSIMILARS 163
3.1 Introduction 163
3.2 Problems in characterising biologics 163
3.2.1 Definitions 163
3.2.2 Types of biologic 163
3.2.2.1 Peptides 163
3.2.2.2 Non-glycosylated proteins 164
3.2.2.3 Glycosylated proteins 164
3.2.2.4 Monoclonal antibodies 165
3.2.3 Equivalence issues 165
3.2.4 Post-translational modifications 166
3.2.5 Effect of microheterogeneity 166
3.2.6 Pharmacokinetics 167
3.2.7 Pharmacodynamics 167
3.2.8 Clinical efficacy 167
3.2.9 Immunogenicity 168
3.3 Analytical methods 168
3.3.1 Introduction 168
3.3.2 Chromatography 168
3.3.3 Protein sequencing 169
3.3.4 Mass spectrometry 170
3.3.5 Nuclear magnetic resonance 171
3.3.6 Electrophoresis 173
3.3.7 Western blotting 174
3.3.8 Bioassays 174
3.3.9 Other procedures 175
3.4 Case studies 175
3.4.1 Introduction 175
3.4.2 Erythropoietin 175
3.4.2.1 European position 176
3.4.2.2 US position 176
3.4.2.3 Immunogenicity: pure red cell aplasia 176
3.4.2.4 Immunogenicity: product consistency issues 177
3.4.3 Somatotropin 178
3.4.3.1 European position 178
3.4.3.2 US position 178
3.4.3.3 Immunogenicity issues 179
3.4.4 Alpha interferon 180
3.4.4.1 European position 180
3.4.4.2 US position 180
CHAPTER 4 KEY BIOSIMILARS PLAYERS 183
4.1 Preface 183
4.2 India-based companies 183
4.2.1 Biocon 183
4.2.1.1 Company overview 183
4.2.1.2 Biosimilar strategy 184
4.2.1.3 Biosimilar pipeline 184
4.2.1.4 Biosimilar collaborations 184
4.2.2 Dr Reddy’s 184
4.2.2.1 Company overview 185
4.2.2.2 Biosimilar strategy 185
4.2.2.3 Biosimilar pipeline 185
4.2.3 Reliance Life Sciences/Genemedix 185
4.2.3.1 Company overview 186
4.2.3.2 Biosimilar strategy 186
4.2.3.3 Biosimilar pipeline 187
4.2.3.4 Biosimilar collaborations 187
4.2.4 Ranbaxy Laboratories 187
4.2.4.1 Company overview 187
4.2.4.2 Biosimilar strategy 187
4.2.4.3 Biosimilar pipeline 188
4.2.4.4 Biosimilar collaborations 188
4.3 Germany-based companies 188
4.3.1 Ratiopharm/Biogenerix 188
4.3.1.1 Overview 189
4.3.1.2 Biosimilar strategy 189
4.3.1.3 Biosimilar pipeline 189
4.3.1.4 Biosimilar collaborations 189
4.3.2 Sandoz International (Novartis) 189
4.3.2.1 Company overview 190
4.3.2.2 Biosimilar strategy 190
4.3.2.3 Biosimilar pipeline 190
4.3.2.4 Biosimilar collaborations 190
4.3.3 Stada Arzneimittel/Bioceuticals Arzneimittel 191
4.3.3.1 Company overview 191
4.3.3.2 Biosimilar strategy 191
4.3.3.3 Biosimilar pipeline 191
4.3.3.4 Biosimilar collaborations 192
4.4 Other EU-based companies 192
4.4.1 Bioton/Biopartners 192
4.4.1.1 Company overview 192
4.4.1.2 Biosimilar strategy 193
4.4.1.3 Biosimilar pipeline 193
4.4.1.4 Biosimilar collaborations 193
4.4.2 DSM (DSM Biologicals) 193
4.4.2.1 Company overview 194
4.4.2.2 Biosimilar strategy 194
4.4.2.3 Biosimilar pipeline 194
4.4.2.4 Biosimilar collaborations 194
4.5 US-based companies 195
4.5.1 Barr Pharmaceuticals/Pliva 195
4.5.1.1 Company overview 195
4.5.1.2 Biosimilar strategy 195
4.5.1.3 Biosimilar pipeline 196
4.5.1.4 Biosimilar collaborations 196
4.5.2 Hospira/Mayne Pharma 196
4.5.2.1 Company overview 197
4.5.2.2 Biosimilar strategy 197
4.5.2.3 Biosimilar pipeline 197
4.5.2.4 Biosimilar collaborations 197
4.5.3 Dynavax Technologies/Rhein Biotech 198
4.5.3.1 Company overview 198
4.5.3.2 Biosimilar strategy 198
4.5.3.3 Biosimilar pipeline 199
4.5.3.4 Biosimilar collaborations 199
4.6 Canada-based companies 199
4.6.1 Cangene 199
4.6.1.1 Company overview 199
4.6.1.2 Biosimilar strategy 199
4.6.1.3 Biosimilar pipeline 199
4.6.2 Microbix 200
4.6.2.1 Company overview 200
4.6.2.2 Biosimilar strategy 200
4.6.2.3 Biosimilar pipeline 200
4.6.2.4 Biosimilar collaborations 201
4.7 Other companies 201
4.7.1 Teva Pharmaceutical Industries/Sicor 201
4.7.1.1 Company overview 201
4.7.1.2 Biosimilar strategy 202
4.7.1.3 Biosimilar pipeline 202
4.7.1.4 Biosimilar collaborations 202
CHAPTER 5 MARKETS FOR BIOSIMILARS 203
5.1 Introduction 203
5.2 Leading drug classes 203
5.3 Major players 203
5.4 Market outlook 204
5.5 Pricing of biosimilars 204
5.6 Profitability of biosimilars 204
5.7 Substitutability and interchangeability 205
5.8 World pharmaceutical market overview 207
5.9 World market for protein biopharmaceuticals 208
5.10 Approved biosimilar products 210
5.10.1 US 210
5.10.2 Europe 211
5.11 Forecasts by product 212
5.11.1 Erythropoietin 212
5.11.2 Insulin 214
5.11.3 Interferons 216
5.11.4 Granulocyte colony stimulating factor 217
5.11.5 Somatotropins 218
5.11.6 Other proteins and peptides 219
5.12 Forecasts by Region 220
CHAPTER 6 TRENDS AND OPPORTUNITIES 223
6.1 Biosimilars market gaining momentum 223
6.2 Competing through superior delivery 223
6.3 Diversifying biosimilar pipelines 224
6.4 Tackling immunogenicity 225
6.5 Expanding the range of cell production systems 225
6.6 Exploring transgenic production systems 227
6.7 Developing cell-free protein synthesis 228
LIST OF TABLES
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 2.22 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 products182
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
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Summary: |
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.
We next examine the scientific issues involved in assessing the equivalence of biosimilar products and review the more important analytical procedures available for this purpose, including techniques with an established role in protein analysis, as well as emerging techniques like nuclear magnetic resonance spectroscopy and mass spectrometry. Regulatory requirements are likely to be more demanding for products bearing post-translational modifications, since relatively minor structural changes can alter therapeutically-relevant characteristics. Case studies focus on specific biosimilar products, which have recently undergone analytical and immunological evaluation.
The EU has been the initial target of most companies developing biosimilars for the regulated markets. Most development work in the biosimilars field is being conducted by large generic or speciality pharmaceutical companies. These firms have been busy setting up subsidiaries or spin-offs focused on biosimilars and linking up with smaller companies, which have enabling technologies for the production of biosimilars. We profile 15 selected companies based in India, Europe, the US, Canada and Israel, which are poised for competition in the (regulated) biosimilars market.
We forecast in detail the top five protein therapeutics categories open to biosimilar competition, worth over 50% of the total protein market in 2006. We estimate that total sales of follow-on proteins and biosimilars will rise from $30 million in 2006 to $3.2 billion in 2011, which represents a market penetration of 2.7% across the board. We appreciate that this figure, which is low by the standards of conventional generics, may disappoint some. It is partly due to the fact that certain important product groups, most notably the epoetins, cannot be sold in the important US market during the forecast period owing to patent restrictions. Also, widespread physician dispensing in Japan creates a bias against generics in that country. Thus, Europe will lead the way in biosimilar sales, with 45% of the world market. Apart from a few niche proteins and peptides, there is currently no available full-year sales history for any approved biosimilar.
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