Publications by Biophoenix' Principals

Biosimilars, Biogenerics and Follow-On Biologics
Publisher:Informa UK (Scrip)
Year of publication:2007
Type of publication:Management report
Publisher's reference (if any):BS1342
Author(s):Sreten Bogdanovic and Beata Langlands
Approximate page count:234
Price when published:$2300
Remarks:
  1. Page numbers, where given, refer to the draft manuscript (which may differ from the published version).
  2. The copyright in this report is owned by the publisher, to whom any requests for copies should be addressed.
  3. The price shown is for a single copy of the print version. Multiple copies and electronic copies usually have different prices. 

                 TABLE OF CONTENTS

CHAPTER 1 INTRODUCTION

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

CHAPTER 2 PRODUCT OVERVIEW

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

CHAPTER 3 APPROACHES TO THE CHARACTERISATION OF BIOSIMILARS

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

CHAPTER 4 KEY BIOSIMILARS PLAYERS

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

CHAPTER 5 MARKETS FOR BIOSIMILARS

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

CHAPTER 6 TRENDS AND OPPORTUNITIES

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

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 2.23  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
EXECUTIVE 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 colony- stimulating 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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