Biosimilars and Biobetters: Positioning for a New Market

Patents on the earliest approved biologics, including many blockbusters with over $1 billion in annual sales, have started to expire. This has opened the market to biosimilar competition, initially in the EU, where a total of 12 biosimilar products have now been aproved. In the US a few follow-on-biologics (FOBs) of products regulated under NDAs have been approved, but there is no abbreviated approval pathway for biologics regulated under BLAs (which are the majority). However, biosimilar legislation is now under intensified consideration.

In preparing this Report, we reviewed the portfolios of almost 500 innovator companies. We analyze all the major classes of innovator biologicals on the market and in development; some launched innovator products are already, or will soon be targets for biosimilars, while other launched products and pipeline products represent potential competition. These products include improved biologicals ("biobetters") with specific enhanced characteristics. The technologies used to produce biobetters, reviewed in this Report, focus on drug delivery, half-life extension, glycoengineering, and cell production systems.

A comprehensive analysis of the market has led us to conclude that biosimilars, presently worth just $75 million worldwide, could generate a global market of $5.6 billion (7% of all biosimilar-susceptible biologic sales) by 2013. Current sales 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. In the short term, the latter issue can be addressed by quotas and other incentives. In the longer term, improvements to biosimilar products would help to differentiate competing products in an increasingly crowded market.

A vast array of peptide, protein and other biosimilar targets are examined in detail in this Report. Peptides reviewed include glatiramer and other high-selling products such as somatostatins and LHRH analogs; proteins include insulins, growth hormone, Il-2, interferons, G-CSF, GM-CSF, enzymes, erythropoietins, coagulation factors and plasminogen activators; other biologicals include enoxaparin, vaccines, and botulinum toxins.

Monoclonal antibodies (mAbs), which represent some of the largest selling biotechnology products, are reviewed separately. Efforts to improve mAbs are aimed at improving effector funtions or at extending the serum half-life. Blockbuster established mAbs include TNF-targeting etanercept and infliximab and tumor cell antigen-targeting rituximab.

The Report also profiles 40 biosimilar companies, highlighting their characteristics, biosimilar portfolios and collaborations. Overall, the picture that is emerging is of short-term strategies to compete on price with first-generation biosimilars and longer-term strategies to dominate the market with improved (biobetter) biosimilars. Significantly, at least half of the western biosimilar companies surveyed have developed or acquired proprietary technologies for producing improved biologics. 

 

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

3.4.5 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 Netherl