Contents:

Foreword 1 Executive Summary 3 What is a biologic drug? 4 What’s in a name? 5 Why are Biosimilars an issue? 6 The current state of the market for each of the major products 7 Erythropoietin (Epoetin, EPO) 7 What is it? 7 Who makes it? 7 Developments on the Horizon 8 Mircera 8 EU Approval for Mircera 8 Dynepo 9 Summary sales data 10 Company-specific sales data 13 Procrit/Eprex 13 Epogen/Aranesp 13 Neorecormon/Epogin 15 Current biosimilar activity 16 Current biosimilar activity in the USA 17 Current biosimilar activity in the EU 17 Sandoz 17 Hospira/Stada Arzneimittel 18 Others in Europe 18 EMEA proposes tighter labelling for EPO products in cancer patients 19 Current biosimilar activity in the rest of the world 19 Human Growth Hormone (somatropin) 20 What is it? 20 Who makes it? 20 Developments on the Horizon 20 Summary Sales data 21 Company specific sales data 24 Genotropin 24 Humatrope 24 Norditropin/other Novo Nordisk HGH products 25 Nutropin 25 Saizen/Serostim 26 Bio-Tropin 26 Current biosimilar activity 27 Current biosimilar activity in the USA 27 Accretropin receives FDA approval 27 Current biosimilar activity in the European Union 28 Biopartners makes Valtropin Phase III data available 28 Current biosimilar activity in the rest of the world 28 DEA action against Chinese HGH imports 29 G-CSF 30 What is it? 30 Who makes it? 30 Developments of the Horizon 30 Summary Sales data 30 Company specific sales data 33 Neupogen/Neulasta 33 Neutrogin/Granocyte 33 Leukine 34 Current Biosimilar Activity 35 Current biosimilar activity in the USA 35 Insmed 36 Apotex and Intas announce agreement to develop G-CSF 36 Current biosimilar activity in the European Union 36 CT, ratiopharm and Teva receive positive opinions 36 Lithuania referred to European Court over Biosimilar G-CSF 38 Current biosimilar activity in the rest of the world 38 Human Insulin 39 What is it? 39 Who makes it? 39 Summary Sales data 39 Company specific sales data 43 Novo Nordisk recombinant insulin products 43 Aventis recombinant insulin products: Lantus, Apidra 44 Current biosimilar activity 46 Current biosimilar activity in the USA 46 Current biosimilar activity in the European Union 46 Marvel LifeSciences withdraws EU application 46 Current biosimilar activity in the rest of the world 47 Interferon 48 What is it? 48 Who makes it? 48 Summary Sales data 48 Company specific sales data 52 Schering Plough Interferon A (Intron A range) 52 Betaseron/Betaferon 53 Rebif 54 Current Biosimilar Activity 55 Current biosimilar activity in the USA 55 Current biosimilar activity in the European Union 55 EMEA rejects Biopartners‘ Interferon A application 55 EMEA issues concept paper for biosimilar Interferon A 56 Biopartners submits Interferon beta to EMEA 56 Current biosimilar activity in the rest of the world 57 Beyond the First wave 58 Monoclonal Antibodies 58 Rituximab 61 Summary sales data 61 Current Biosimilar activity 62 Dr Reddy‘s 62 GTC Biotherapeutics/LFB 63 Factors in favour 64 Rising cost of healthcare 64 US pharmaceutical expenditure increases 65 Factors against 69 Science 69 The INN naming issue 69 EBE-EFPIA position paper on naming of biosimilars 70 Response from the generic industry 71 USP publishes monographs on somatropin 71 No strict definition of a biologic 72 High cost of development and marketing 73 Product complexity 73 Will manufacturers have sufficient capacity? 73 Detail of regulatory requirements 74 Different international requirements 74 Postmarket surveillance requirements. 75 Marketing requirements 75 Regulatory obstacles 76 US pathway still a long way off 76 What does the FDA really think? 76 Legal problems 77 Patent challenges 77 Exclusivity of test data 77 Product acceptance 78 Interchangeability and substitutability 79 Does biosimilar = obsolete? 80 Is there a commercially viable market? 80 Just what will the savings from biosimilars be? 81 PCMA 82 Express Scripts 83 Avalere report 84 Insmed releases report on cost savings 84 CBO issues report on impact of biosimilars 85 Originator Strategies to Combat Biosimilars 88 The position in the USA 89 Hatch-Waxman is not applicable to biologics 89 Exceptions 89 FDA transfer of biologic responsibility to CDER 90 How feasible is the 505(b)(2) route ? 91 Omnitrope in the USA 92 The FDA‘s reasoning 92 FDA Response to Citizen Petitions regarding Omnitrope 93 The Scope of Clinical Trials Required for FDA Approval of Omnitrope 97 Conclusions regarding the FDA‘s approval of Omnitrope: 98 Easier not to seek an abridged application? 99 Moves in Congress 100 Access to Life Saving Medicine Act (HR. 1038, S. 623) 101 Patient Protection and Innovative Biologic Medicines Act of 2007 (HR. 1956) 103 Biologics Price Competition and Innovation Act of 2007 (S. 1695) 104 Interchangeability an option, not a requirement 104 Data exclusivity 104 Marketing exclusivity 104 Resolving patent disputes 105 Pathway for Biosimilars Act (HR. 5629) 106 Determination of interchangeability 106 Originator market exclusivity 106 FDA required to issue guidance documents 107 Patent dispute resolution process 107 House Committee releases responses to biosimilar questionnaire 108 Data exclusivity 108 Interchangeability 109 Clinical trials 109 Should biosimilars have a separate INN? 110 FDA issue product class guidance? 110 Should the US follow the EU model? 110 Prospects for legislation 111 Originator support for stringent legislation 111 Biosimilar industry more cautious 112 What will the final legislation look like? 113 When will it appear? 114 FDA Testimony to Congress 115 State Governors urges FDA to publish guidance, August 2006 117 FDA Briefing Paper issued 118 Conclusion 119 The position in Europe 120 The new EU approval process 120 Regulation of biosimilars 121 EMEA Guideline Documents 122 EPO 124 G-CSF 124 Somatropin 124 rH Insulin 124 Interferon alfa 124 The first EU biosimilar approvals: somatropin 125 Omnitrope 125 Omnitrope listed in the UK BNF 126 Valtropin 126 BioPartners releases Phase III details for Valtropin 126 Sandoz receives EPO approvals, 2007 127 Stada and Hospira receive EPO approval 128 Hospira presents trial data for Retacrit 128 EMEA issues positive opinions for biosimilar G-CSF 129 Attitudes to Biosimilars: UK Parliamentary Panel Reports 130 MHRA issues biosimilar prescribing guidance 130 Potential use of biosimilars in the NHS 131 Panel recommendations 132 Conclusions 133 The position elsewhere 134 Other developed markets 134 Canada 134 Australia and New Zealand 134 Japan 135 Developing markets 136 Why are these markets worth a look? 136 India 137 Indonesia 138 Saudi Arabia 139 Thailand 139 Who will be the players in the market? 140 Manufacturer profiles 143 Abraxis BioScience 143 Anhui Anke Biotech 144 Barr Pharmaceuticals 145 Pliva agreement for G-CSF 145 Bioclones 146 Biocon 147 Insugen 147 Abraxis and Biocon announce G-CSF partnership 148 Biocon buys majority stake in German marketing company 148 BioGeneriX 149 Merckle Biotech 149 Cangene 149 Neose Technologies 149 BioPartners 151 Bioton S.A. 153 Cangene 155 Accretropin 155 Leucotropin 155 Cell Therapeutics 156 CIGB (Cuba) 157 Cipla 158 CheilJedang (CJ Corp) 159 Claris Lifesciences 160 Dr Reddy?s 161 Dongbao Biopharmaceutical 162 Dragon Pharmaceuticals 163 GeneScience Pharmaceuticals 164 GTC Biotherapeutics 165 Deal with LFB Biotechnologies 165 Hospira 166 Mayne Pharma 166 Stada Arzneimittel 166 BresaGen 166 Inno Biologics 167 Insmed 168 Intas Biopharmaceuticals 169 Intas and Apotex sign G-CSF agreement 169 Itero Biopharmaceuticals 170 LG Life Sciences 171 Marvel Lifesciences 172 Momenta Pharmaceuticals 173 NCPC Genetech 174 Pliva 175 EPO, Croatian approval granted 175 G-CSF, agreement with Barr Laboratories 175 Mayne Pharma 176 New biotech facility announced 176 Ranbaxy 177 G-CSF Agreement with Zenotech 177 Ranbaxy launches =bio-generic‘ osteoporosis treatment 178 Reliance Life Sciences 179 GeneMedix 179 RLS acquisition 179 Sandoz 180 Lek 181 Sandoz biotech plants, Austria 181 Lek biotech plant, Slovenia 181 SciGen 182 Shreya Biotech 182 Chinese JV 182 Marketed Products 182 Pipeline Products 183 Shantha Biotechnics 184 3SBio 185 EPIAO 185 Other products 185 Sales data 186 Shenzhen Kexing Biotech 187 Stada Arzneimittel 188 EPO-zeta gains EU approval 188 Teva Pharmaceuticals 189 G-CSF 189 Stada Arzneimittel? 189 Teva set to acquire Barr 189 Teva acquires CoGenesys 190 Sicor 190 Tianjin Hualida Biotechnology Pharmaceutical Co 191 Three Rivers Pharmaceuticals 192 Viropro 193 Deal with Intas Biopharmaceutical 193 Biochallenge agreement signed 194 Wockhardt 195 Zenotech Laboratories 196 Conclusions 197 Sources 198 Directory 199 Regulators 199 Industry Associations 199 Manufacturers 200 Index 203 INDEX OF TABLES Leading EPO Brands, World Sales, 2001-2007 (US$ millions) 10 Leading EPO Brands, % Change, 2002-07 11 Leading EPO Brands, % of Subtotal, 2001-2007 11 J&J Sales of Procrit/Eprex, 2001-2007 (US$ millions) 13 Amgen Sales of Epogen/Aranesp, 2001-2008 (US$ millions) 14 Amgen EPO Patents in the USA 14 Roche Sales of Neorecormon/Epogin, 2002-2007 (SwF millions) 15 Manufacturers' summary 16 Leading HGH Brands, World Sales, 2001-2007 (US$ millions) 21 Leading HGH Brands, % Change (US$ sales), 2002-07 22 Leading HGH Brands, % of Subtotal, 2001-2007 22 Genotropin Sales, 2001-07 (US$ millions) 24 Humatrope Sales, 2001-07 (US$ millions) 25 Novo Nordisk HGH Sales, 2001-07 (DKK millions) 25 Genentech HGH Sales, 2001-06 (US$ millions) 26 Merck/Serono HGH Sales, 2001-2007 (US$ millions) 26 Manufacturers' Summary 27 Leading G-CSF Brands, World Sales, 2001-2007 (US$ millions) 30 Leading G-CSF Brands, % Change 2003-07 31 Leading G-CSF Brands, % of Total, 2002-07 31 Neupogen/Neulasta Sales, 2001-07 (US$ billions) 33 Sales of Neutrogin/Granocyte, 2002-07 (billion yen) 34 Manufacturers' Summary 35 Leading Human Insulin brands, World Sales, 2001-2007 (US$ millions) 40 Leading Human Insulin Brands, % Change, 2002-2007 40 Leading Human Insulin Brands, % of Subtotal, 2001-2007 41 Sales of Novo Nordisk Insulin Analogues, 2001-2007 (DKK million) 43 Sales of Humulin and Humalog, 2001-2007 (US$000s) 44 Lantus Sales by Region, 2004-07 (euro millions) 45 Manufacturers' Summary 46 Leading Interferon Brands, World Sales, 2001-2007 (US$ millions) 48 Leading Interferon Brands, % of Subtotal, 2002-2007 49 Sales of Intron A and PEG-Intron, 2002-2007 (US$ millions) 52 Sales of Pegasys, 2002-07 (SwF millions) 53 Sales of Betaseron/Betaferon, 2001-07 (euro millions) 53 Sales of Avonex, 2001-07 (US$ millions) 54 Sales of Rebif, 2001-07 (US$ millions) 54 Manufacturers' Summary 55 Summary, factors in favour of the development of biosimilars 64 US Research-Based Pharmaceutical Manufacturers' Sales, 1990-2006 (US$ millions) 65 US Pharmaceutical Expenditure as % of GDP, 1990-2006 66 Growth of Medicaid Pharmaceutical Expenditure, 1997-2005 (US$ millions) 67 FDA Response to Originator Arguments Against Omnitrope 95 Omnitrope Phase III Trials Conducted In Support of NDA 97 Adopted Guidelines 122 Documents submitted for ongoing comment 123 CHMP Concept Papers, 2006 123 Summary Requirements, Chemical Generic v Biosimilars 140 Summary of Biosimilar Manufacturers and Products 142 2007 US$ exchange rates used in this report 198

Summary:

The promise of profits from biosimilars grows greater, but only when a number of significant market, regulatory and clinical hurdles can be overcome. This critical 200-page management report addresses key issues of concern. Companies want profits, health payers want cost reductions and clinicians want efficacy. Squaring the circle will take some doing. The biosimilar sector continues to attract huge interest and controversy. Most generic manufacturers are actively involved in it, either directly or indirectly. The successful ones will be those with the patience, resources and above all money to invest now, in order to gain in the future. Even for the vanguard, however, those gains are some years off. Reimbursement: How will payers treat biosimilars? Ideally for generic manufacturers they will regard them as therapeutically equivalent and therefore substitutable by pharmacists, in countries where this is an option. Originator companies want to see the opposite, where biosimilars are regarded as different products and therefore not substitutable. This is a major reason for the recent arguments regarding INN naming, since products with different INNs are less likely to be regarded as interchangeable. This issue is one for national healthcare systems and currently remains unresolved. Will physicians prescribe biosimilars? In countries with high generic usage, and where physicians are trained to prescribe by INN, prospects are theoretically good, the issue of different INNs notwithstanding. In the UK, for example, around 80% of prescriptions are written by INN. The overriding issue for physicians is going to be safety and efficacy; they need to be confident about a new drug’s capabilities in order to switch. But the likelihood of their doing so without some financial incentive is less certain. Physicians prescribe generics in order to save money, either from their own drug bill or that of the patient. It is not clear whether biosimilars will offer enough of a saving in this regard. Will patients accept biosimilars? In countries where generics are widely-used, patients should have little problem with properly approved biosimilars, although they are likely to want the latest drug available, if it is affordable. Many of the conditions treated by the drugs in this report are serious and require hospital administration, which allows less opportunity for ‘shopping around’. Products which are administered on a long term basis require more patient input. Biosimilar insulin, for example, may be able to save patients a lot of money over time, although they might prefer to spend more on a newer product which has to be injected less often or not at all. Interchangeability and substitutability A key point for developers of biosimilars is the issue of interchangeability. This is going to be a hard sell in regulated markets. Much of the legislation before Congress in the USA contains specific provisions which allow applicants to try to demonstrate this, but the FDA currently takes a dim view of the idea. In Europe, the biosimilar pathway speaks of ‘therapeutic similarity’ and leaves it at that. Issues of reimbursement are left to individual member states. There is little public sign that governments have begun to address the issue. A step further is substitutability, i.e. can the hospital pharmacist provide a biosimilar version if the physician has prescribed the original. Or, going further still, can insurers mandate substitution for prescriptions they are paying for? This is extremely unlikely to occur, even in countries which have a generally pro-generic outlook. Countries such as France, the Netherlands and Spain, for example, have explicitly stated that biosimilars will not be substitutable, while the UK government has indicated that it does not expect substitution to occur. For a thought-provoking, well argued and cost-effective management analysis on this critical generics sector, make sure you order this report today.

Companies Mentioned

- Abraxis BioScience - Anhui Anke Biotech - Barr Pharmaceuticals - Bioclones - Biocon - BioGeneriX - BioPartners - Bioton S.A. - Cangene - Cell Therapeutics - CIGB (Cuba) - Cipla - CheilJedang (CJ Corp) - Claris Lifesciences - Dr Reddy’s - Dongbao Biopharmaceutical - Dragon Pharmaceuticals - GeneScience Pharmaceuticals - GTC Biotherapeutics - Hospira - Inno Biologics - Insmed - Intas Biopharmaceuticals - Itero Biopharmaceuticals - LG Life Sciences - Marvel Lifesciences - Momenta Pharmaceuticals - NCPC Genetech - Pliva - Ranbaxy - Reliance Life Sciences - Sandoz - SciGen - Shantha Biotechnics - 3SBio - Shenzhen Kexing Biotech - Stada Arzneimittel - Teva Pharmaceuticals - Three Rivers Pharmaceuticals - Viropro - Wockhardt - Zenotech Laboratories