December 2009

Biobetters – major players and market prospects
A FirstWord Market Intelligence Report

Biobetters -- major players and market prospects Published December 2009 © Copyright 2009 Doctor’s Guide Publishing Limited All rights reserved. No part of this publication may be reproduced or used in any form or by any means graphic, electronic or mechanical, including photocopying, recording, taping or storage in information retrieval systems without the express permission of the publisher. This report contains information from numerous sources that Doctor’s Guide Publishing Limited believes to be reliable but for which accuracy cannot be guaranteed. Doctor’s Guide Publishing Limited does not accept responsibility for any loss incurred by any person who acts or who fails to act as a result of information published in this document. Any views and opinions expressed by third parties and reproduced in this document are not necessarily the views and opinions of Doctor’s Guide Publishing Limited.

Biobetters -- major players and market prospects

Contents
Executive Summary............................................................................................. 1 Biosimilars and the High Demand for New Biological Drugs ........................................ 2 Biological Drugs ............................................................................................... 2 Table 1: Commercially Important Biological Drug Types .................................... 2 Biological Drug Market Growth............................................................................ 3 Biosimilars ...................................................................................................... 3 Definition of Biosimilars .................................................................................. 3 Biosimilar Regulatory Update........................................................................... 3 Follow-On Protein Products in the US ................................................................ 4 The Biosimilar Market ..................................................................................... 4 Biobetters .......................................................................................................... 5 Possible Repercussions of Biosimilars................................................................... 5 Combating Biosimilars with Biobetters ................................................................. 5 What Are Biobetters? ..................................................................................... 5 Types of Biobetter ......................................................................................... 5 Table 2: Biobetter Drug Design Techniques ..................................................... 6 Challenges in Biobetter Development ..................................................................... 7 Innovator Research and Development Strategies ................................................... 7 Rise of the Biobetter ...................................................................................... 7 Current Biological Research and Development Climate ......................................... 7 Difficult Financial Climate for Smaller Biotechnology Companies ............................ 7 The Need for Differentiation ............................................................................ 8 Active Comparator Clinical Trials ...................................................................... 8

December 2009
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Biobetters -- major players and market prospects
Manufacturing Challenges .................................................................................. 8 Biological Manufacturing ................................................................................. 8 New Manufacturing Methods are Arriving…......................................................... 9 …But Do Not Obviate the Need for Differentiation.............................................. 10 Regulatory Hurdles for Biobetters...................................................................... 10 Patent Issues .............................................................................................. 10 Immunogenicity and Safety Fears .................................................................. 10 Data Exclusivity in the US ............................................................................. 11 Marketing Challenges for Biobetters .................................................................. 11 The Challenge of Marketing Biobetter Drugs ..................................................... 11 Pricing and Reimbursement ........................................................................... 12 Possible Increasing Biosimilar Competition ....................................................... 13 Biosimilar Price Reductions............................................................................ 13 Opinions of Thought Leaders on the Future of Biobetters ......................................... 14 Biobetter Strategies........................................................................................... 16 Monoclonal Antibodies ..................................................................................... 16 Biosimilar Monoclonal Antibodies .................................................................... 16 The Future for Biobetter Monoclonal Antibodies ................................................ 16 Further Humanisation of Monoclonal Antibodies ................................................ 17 Table 3: Biobetter Monoclonal Antibodies: Towards Fully Human ...................... 17 Additional Antibody Targets........................................................................... 18 Table 4: Biobetter Monoclonal Antibodies: Additional Targets ........................... 19 Antibody-Drug Conjugates ............................................................................ 19 Antibody Fragments ..................................................................................... 19 Table 5: Biobetter Monoclonal Antibodies: Antibody Fragments ........................ 20 Glycoproteins ................................................................................................ 20

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December 2009

22 Biobetter Glycoproteins: Improved Manufacturing .............................................. 20 Table 6: Biobetter Pegylated Glycoproteins .................................. 24 The Vaccine Market................................................................. 23 Vaccines .................................................... 25 Biobetter Vaccines: New Technologies......... 21 Biobetter Glycoproteins: New Technologies .............................................................................. 24 Biobetter Vaccines: New Delivery Methods........................................................................New Recombinant Technologies ................................... 22 Erythropoietin Drugs .............................. 27 Dermatological Insulin .......... 22 Granulocyte Colony-Stimulating Factor (G-CSF)...................................................................New Technologies ...........New Manufacturing Technology ................................................................................. 24 Table 8: Biobetter Vaccines ........................................................................................... 25 Table 9: Biobetter Vaccines ......................................................... 27 New Insulin Delivery Methods ...........................Broader Spectrum of Activity ..................................................................................................... 27 The Insulin Market .................................................... 23 Interferons ........ 21 Table 7: Biobetter Glycoproteins ...........major players and market prospects Biobetter Pegylated Glycoproteins ................ 28 Table 13: Biobetter Insulin Devices ... 26 Table 12: Biobetter Vaccines ................................................................................ All Rights Reserved iii .............................................................................New Delivery Methods ................................................................................................................................... 27 Novel Formulations are the Key Biobetter Opportunity ...........New Adjuvants ............................................ 25 Table 11: Biobetter Vaccines ............................................................. 28 Inhaled Insulin ...... 26 Biobetter Vaccines: More Strains .................................................... 28 Oral Insulin..... 26 Protein Hormones............................ 25 Table 10: Biobetter Vaccines .......................Biobetters -................................................................................................................................................................. 29 December 2009 All Contents Copyright © 2009 Doctor's Guide Publishing Limited.................

...................................................................... 36 Conclusion ........................................................................................................................................................................................................... 29 Table 14: Other Biobetter Examples.........................................................................................................Biobetters -...... 32 Biogen Idec .................................................................................................................................................... 30 Novo Nordisk ......... 31 The Bioleaders ................................................................................................................................................................ 33 Eli Lilly........................................................ 39 Index ....................................................... 35 AstraZeneca .......................................................................................................................................................................................................................................... 30 Who are the Biobetter Leaders? .......................................................................... .............................................................................................................................. 33 Sanofi-Aventis.............................. 30 The Biobetter Strategists ...................................... 29 Other Biological Drugs....................................... 34 GlaxoSmithKline ...................... 32 Roche Group........................................................................ 33 Amgen..................................................................................................................................................................................................................... 40 iv All Contents Copyright © 2009 Doctor's Guide Publishing Limited................. 34 Novartis ................................................. 35 Pfizer....... 37 Abbreviations ............................... 29 Leading Biobetter Companies .................... 30 Merck & Co..................................................................................... All Rights Reserved December 2009 ................................................ 34 Other Large Pharmaceutical Companies .......................................major players and market prospects Biobetter Growth Hormones and other Hormones..........

In addition. the article looks at the current state of biobetter development in leading pharmaceutical companies and examines possible future strategies for these companies. including monoclonal antibodies. biological drugs now have patents that have expired or are about to expire. delivered by subcutaneous injection or infusion. reduce immunogenicity. vaccines and hormones and identifies where the key opportunities for biobetter drug development lie. reduce dosing frequency. Second-generation. This report examines biobetter strategies for the leading types of biological drug. in the form of clinical superiority or greater ease of use. they will need to have a clear competitive edge. or biobetter.major players and market prospects Executive Summary The earliest. or first-generation. Only these clearly differentiated biobetters will be successful in competing with biosimilars and gaining adequate reimbursement from payers. versions of these drugs are modified by various biochemical means in order to improve their efficacy. Biosimilars have arrived already in many jurisdictions and there is a distinct possibility for a rapid growth in the biosimilar market in the coming years. First-generation biological drugs are largely immediate-release formulations. December 2009 All Contents Copyright © 2009 Doctor's Guide Publishing Limited. improve the side-effect profile.Biobetters -. To be successful. or provide some other competitive advantage. however. Innovator pharmaceutical companies can use biobetters to compete with biosimilars. glycoproteins. similar to that of generic small-molecule drugs. Biobetters generally have lower early-stage research and development costs. have created an expectation for the future availability of biosimilars. All Rights Reserved 1 . These patent expiries. coupled with rising healthcare costs.

or recombinant proteins.major players and market prospects Biosimilars and the High Demand for New Biological Drugs Biological Drugs With annual revenues currently in excess of US$120 billion. blood factors and fibrinolytic agents Vaccines Protein hormones Fusion proteins Heparins Others 2 All Contents Copyright © 2009 Doctor's Guide Publishing Limited. used for hepatitis C and multiple sclerosis treatment G-CSF. for the treatment of a variety of cancers and autoimmune disorders Glycoprotein hormones and cytokines (cell-signalling proteins). monoclonal antibody therapies are the most important class of biological drug. Commercially. used to control red blood cell production in patients with anaemia Interferons. such as: Erythropoietin. most are manufactured using recombinant DNA technology. various interferons and recombinant granulocyte colony-stimulating factor (G-CSF) (types include filgrastim and lenograstim). Other commercially important biological drugs include fusion proteins and heparins. with annual revenues in excess of $30 billion (Table 1). Biological drugs – also known as biopharmaceuticals or biologics – contain an active agent made or derived from living organisms. All Rights Reserved December 2009 . biological drugs are an important sector of the pharmaceutical market. for disease prophylaxis Simple non-glycosylated hormones such as insulin and somatropin Pfizer (formerly Wyeth) and Amgen’s Enbrel (etanercept) for rheumatoid arthritis is the main example of this class of drug. Although some are obtained from natural sources. Glycoproteins (proteins with attached sugars) and vaccines are the next two most important biological drug classes. Glycoprotein drugs with highest sales revenues are recombinant forms of erythropoietin (epoetin). used for the stimulation of white blood cells in oncology Denatured micro-organisms. Annual global revenues for protein hormones – mainly recombinant forms of insulin for patients with diabetes and recombinant human growth hormone (somatropin) – are roughly $15 billion. created by joining two or more proteins by fusing their coding genes Polysaccharides used for anti-coagulation Examples include enzymes. Table 1: Commercially Important Biological Drug Types Biological Drug Type Monoclonal antibodies Glycoproteins Details Antibodies manufactured from a single DNA sequence. each having annual revenues of around $25 billion.Biobetters -.

All Rights Reserved 3 . the earliest recombinant forms of human growth hormone.are increasing in prevalence. in Europe and Asia. with the same active ingredient. Examples include human insulin.major players and market prospects Biological Drug Market Growth By most projections. Additionally. doses and indications. large pharmaceutical companies are racing to fill their dwindling pipelines with biological therapies. biological drug use will grow more rapidly than that of smallmolecule drugs. and many interferons. biological drugs will increasingly penetrate emerging markets in Asia and South America.particularly cancer and diabetes . coupled with the rising cost of already expensive biological drugs. to a marketed biological drug (the reference drug). Nevertheless. Biosimilar Regulatory Update Biosimilar medicines cannot gain regulatory approval using existing legislation intended for small-molecule drugs. Currently. especially in the US. although this practice is common for small-molecule generics. The large size of biological drug molecules. erythropoietin. but not identical. some clinical testing of the biosimilar is required. their sensitivity to slight changes in this production process and their potential for immunogenicity (eliciting an immune response to the drug) mean that biosimilars are not completely identical to the reference drug. As the global population grows and ages. erythropoietin and G-CSF. in order to show bioequivalence with the reference drug. which allows the approval of biosimilar versions of the simpler biological drugs. as incomes rise and chronic diseases become more common. have created an expectation for future availability of cheaper biological drugs. Therefore they cannot be regarded as true generic drugs. Biosimilars Definition of Biosimilars Cheaper versions of patent-expired biological therapies are available already. December 2009 All Contents Copyright © 2009 Doctor's Guide Publishing Limited. The European Medicines Agency (EMEA) defines these drugs as biosimilars: drugs that are similar. or first-generation. However. most European governments are not allowing automatic substitution of branded drugs with biosimilars at pharmacies. As a result. The earliest. including protein hormones and glycoproteins. The EMEA has introduced new legislation for the EU. major diseases treated by biological drugs . following the same model as that of generic small-molecule drugs.Biobetters -. This expectation is centred on the future availability of ‘generic’ biological drugs. These patent expiries. biological drugs have patents that have expired or are about to expire. expensive biological drugs for chronic diseases are confined largely to wealthy countries. Unlike small-molecule generics. the complexity of their manufacturing processes. the EMEA has approved multiple versions of biosimilar recombinant growth hormones.

although Health Canada has not yet issued final guidelines for the approval of what it terms ‘subsequententry biologics’. another boost to the biosimilar market will follow. 4 All Contents Copyright © 2009 Doctor's Guide Publishing Limited. the lack of substitution at pharmacies will mean high marketing costs. however. there is no regulatory pathway in place for the approval of biosimilars. there is a distinct possibility for rapid growth in the biosimilar market in the coming years. Biosimilars are therefore unlikely to offer the same sharp price discounts achieved by generics. Nevertheless. The Japanese regulatory authorities issued guidelines for biosimilars (termed ‘follow-on biologics’ in that country) in March 2009 and approved the first example. require the creation of new legislation. a somatropin. however. at the very earliest. The structure of the US Food and Drug Administration (FDA) regulations allows the approval of a few simple biological drugs – including somatropin – through an abbreviated regulatory pathway. The approval of all other biosimilars will. including Australia. Biosimilars are likely to remain more expensive to develop than small-molecule generics. the biosimilar drug market accounts for only around one percent of the total biological drug market and is largely restricted to less-regulated Asian markets.Biobetters -. the FDA is unlikely to be able to approve any biosimilars (commonly termed ‘follow-on protein products’ or ‘follow-on-biologics’ in the US) until 2013. in June 2009. have adopted the EMEA biosimilar guidelines. Additionally. Follow-On Protein Products in the US In the US.major players and market prospects Copies of biological drugs are also available in less-regulated Asian markets. Other countries. The current US administration has indicated it supports introduction of this legislation and two such bills were introduced to the House of Representatives in March 2009. All Rights Reserved December 2009 . owing to the clinical testing requirements. The Biosimilar Market Currently. A biosimilar somatropin is also approved in Canada. However. This will become increasingly likely if a biosimilar regulatory pathway is implemented in the US. If biosimilars build a good safety profile in Europe and Japan over a number of years and this leads to introduction of automatic substitution in pharmacies.

There is no guarantee that biosimilars will become accepted.major players and market prospects Biobetters Possible Repercussions of Biosimilars If lower-cost biosimilars become an established sector of the biological drug market in North America. First-generation biological drugs are largely immediate-release formulations. These injected biological drugs can be modified by various biochemical means in order to improve their efficacy. December 2009 All Contents Copyright © 2009 Doctor's Guide Publishing Limited. Further consequences of biosimilar competition could be a lowering of the commercial viability of biological drugs with smaller potential markets.which necessarily have a smaller potential patient pool . or provide some other competitive advantage. delivered by subcutaneous injection or infusion. Engineering can entail the alteration of the amino acid sequences or the glycocomponent of a glycosylated protein. often overlooked strategy that innovator pharmaceutical and biotechnology companies can use to compete with biosimilars: ‘biobetters’. what will be the repercussions? The major consequence is likely to be downward pressure on prices. second-generation drugs produced using such principles will be termed ‘biobetters’. improve the side-effect profile. Novel biological therapies for rarer diseases and personalised therapeutic approaches .Biobetters -. All Rights Reserved 5 . However. or the attachment of proteins or other chemicals such as polyethylene glycol (PEG: pegylation). reduce immunogenicity. reduce dosing frequency. Combating Biosimilars with Biobetters What Are Biobetters? Whether or not biosimilars become established will be revealed over the coming years. In this article. there is one.may be less viable when future biosimilar competition is expected to reduce revenues. Europe and Japan. even a modest undercutting of price will limit the pricing options for branded biological drugs. although some degree of biosimilar success is likely. Although biosimilars will not offer the large price reductions offered by small-molecule generics. Types of Biobetter Techniques for developing biobetters involve engineering the protein structure of the drug.

6 All Contents Copyright © 2009 Doctor's Guide Publishing Limited. addition of conjugates and adjuvants. oral. improved bioavailability and reduced toxicity. depending on their purpose (Table 2). albumin fusion or conjugation with carrier protein. Novel biobetter formulations allow alternative and more convenient dosage formats. Other methods for increasing a drug’s duration of action include controlled-release formulations. Table 2: Biobetter Drug Design Techniques Technique New formulation Engineering to produce longeracting drug Engineering to improve drug function New manufacturing method Description Development of controlled-release. reengineering live or inactivated vaccines as recombinant vaccines and altering the glycosylation pattern of a glycoprotein in order to alter its pharmacokinetic properties. A third design technique uses more radical protein engineering to alter the function and clinical effectiveness of a biological drug. Of course.Biobetters -. potentially leading to improved patient compliance. which has already been proved to increase the half-life of drugs in the body. and simple hormones All biological drugs All biological drugs Techniques to increase the half-life of a biological drug in the body can lead to reduced dosing frequency. glycosylation. Examples include conjugating a monoclonal antibody with a cytotoxic agent. glycoengineering of a protein may both improve its efficacy and increase its half-life. For example. Methods to achieve this include covalent conjugation with PEG (pegylation). A fourth technique is to improve the protein manufacturing system. dermatological or inhaled formulations Pegylation. fusion with human albumin serum and conjugation with fusion proteins. design of antibody fragments and others Development of microbial. subcutaneous injection. biobetters may be produced by combining a number of design techniques from the four available. insect and plantbased cell manufacturing systems Suitable Biological Drug Types All biological drugs Mainly glycoproteins. All Rights Reserved December 2009 . engineering a fragment of monoclonal antibody. in order to increase half life Protein engineering.major players and market prospects Design techniques for second-generation biologicals are grouped into four types.

the remaining targets often have lower patient populations. Competition from small-molecule drugs is increasing in some categories. they could precipitate price reductions among all competitor drugs in a given class. such as the erosion of sales of Roche’s breast cancer monoclonal antibody Herceptin (trastuzumab) by GlaxoSmithKline’s (GSK) Tykerb (lapatanib). As a result. It is true that these larger pharmaceutical companies are merging. Biological drugs have been developed for many of the more common cancers and autoimmune disorders. if lower-cost biosimilars become established in major markets. Smaller biotechnology companies need funding for late-stage development and marketing expertise.major players and market prospects Challenges in Biobetter Development Innovator Research and Development Strategies Rise of the Biobetter The expense of biological drug development. which require large amounts of capital. and the developing company can choose an active or placebo comparator in clinical trials. clear superiority in clinical outcome or ease of use will be essential in successful future biobetter development strategies. the global financial crisis and the imminent threat of biosimilars are leading to increasing interest in the development of biobetters. Large pharmaceutical companies need to buy innovation to fill thin pipelines. However. reducing in number and becoming more risk-averse. Often multiple drugs are in development in a crowded biological drug pipeline for these remaining targets. The current global economic crisis is causing a drought in funding for smaller biotechnology companies. Difficult Financial Climate for Smaller Biotechnology Companies The challenge of biological drug development is being heightened by today’s more difficult financial climate. In the longer term.Biobetters -. and are less commercially attractive. These higher costs must be recouped in higher selling-prices. which in turn can decrease the chances of obtaining satisfactory reimbursement from governments and healthcare providers. These generally have lower early-stage research and development costs. depending on what is more suitable for their development strategy. declining funds December 2009 All Contents Copyright © 2009 Doctor's Guide Publishing Limited. Furthermore. the established trend of large pharmaceutical companies licensing biological pipeline products and acquiring smaller biotechnology companies is likely to accelerate. Current Biological Research and Development Climate Biological drugs are much more expensive to develop than traditional small-molecule drugs. increasing competition from small-molecule drugs and other biological drugs for the same disease targets. however. All Rights Reserved 7 .

major players and market prospects for research and development in larger pharmaceutical companies should maintain their interest in acquiring pipeline biological drugs from external sources. for certain patients with cancer). In the near future. however. All Rights Reserved December 2009 . Active Comparator Clinical Trials Currently the FDA and the EMEA do not require the use of an active comparator in trials conducted for the approval of a new drug. The need for differentiation will be paramount. The motivation for pharmaceutical companies to conduct comparative testing is likely to increase over time. will leave them more vulnerable to biosimilar competition. With demonstrated clinical superiority of new biological drugs likely to become of critical importance. Examples include biobetters that are longer-acting versions of existing blockbuster biological drugs in a late stage of development. and technology platforms or delivery devices offering improved formulations. Such options will be particularly attractive for marketers of first-generation biologicals nearing the end of their patented period and requiring a follow-on version. if biosimilars become established in a particular section of the market. A majority of currently-marketed biological drug are manufactured in mammalian cells. such as a lack of clear clinical superiority or only marginally more convenient formulations. although developers often use them when it would be unethical to use placebo-controlled clinical trials (for example. Marginal differentiation among novel branded biological entrants. If this happens. although some simpler non-glycosylated biologicals are manufactured in 8 All Contents Copyright © 2009 Doctor's Guide Publishing Limited. active comparator trials will be required to convince both pharmaceutical companies to license a drug and also healthcare providers to adopt and reimburse such therapies. Manufacturing Challenges Biological Manufacturing Biologicals are manufactured using complex manufacturing processes involving living cells.Biobetters -. those most likely to attract their attention are candidates that allow clear differentiation from first-generation products. the use of active comparator trials is likely to become more common. as the marketplace demonstrates demand for this information. The Need for Differentiation As large pharmaceutical companies search the market for innovative biological technology and biological therapies to fill their pipelines. there is likely to be downward pricing pressure on all drugs in that particular class and only drugs clearly clinically superior will escape the effect.

Compared with mammalian cell lines these systems tend to be simpler and produce higher yields of therapeutic proteins at lower cost. Many Indian and Chinese pharmaceutical companies have biological manufacturing technologies comparable with those in North America and Europe but with a lower unit cost. glycosylated biologicals include yeast.can cause a degree of heterogeneity in the final product. Another newer manufacturing method that may help in the development of competitive biobetters is the production of therapeutic proteins from the milk of transgenic animals (animals with an implanted gene for the therapeutic protein). New Manufacturing Methods are Arriving… Compared with older. Asian manufacturing sites are increasingly complying with good manufacturing practice guidelines (GMP) and gaining FDA and EMEA approval. The variability in glycosylation patterns inherent in mammalian cell culture manufacturing methods is a particular problem because it may cause variations in the immunogenicity or potency of the final product. the process may subtly alter the three-dimensional and complex folding properties of the protein. are particularly suitable for manufacture in microbial and yeast systems. For example. Compared with small-molecule drug manufacture.Biobetters -.major players and market prospects Escherichia coli bacteria. These sites offer the opportunity for the contract manufacturing of cheaper biobetters. first-generation biological drugs. insect and plant cell-based systems.such as the purity of raw materials. biobetter manufacturers can take advantage of newer manufacturing methods. antibody fragments. and there is greater possibility of contamination. antibody fragments may prove to be cheaper and easier to manufacture. Inevitable minor variations in the biological manufacturing process . the cell culture conditions or storage conditions . The raw materials and cell lines required for manufacture may be subject to limited supply or be restricted by special regulations in multiple jurisdictions. Additionally. December 2009 All Contents Copyright © 2009 Doctor's Guide Publishing Limited. Also. Newer manufacturing systems for the more complex. destined to join fullsize monoclonal antibodies in usefulness as therapeutics. in the field of monoclonal antibodies. are promising methods to replace mammalian cell lines. All Rights Reserved 9 . Yeast. bacterial and plant strains. This method may allow the production of high volumes of proteins at low cost. The manufacturing process defines a particular biological drug in a way not applicable to small-molecule drugs. mammalian cell line manufacturing requires more stages and more rigorous quality control. they have the potential to yield a much more homogeneous product in terms of glycosylation patterns. engineered to eliminate immunogenic components and to better represent glycosylation patterns found in human proteins. In addition.

e. The decision to develop a biobetter version of an existing therapy will involve complex analysis of the expiry of patents. by making a very small change in a protein. it is now thought that leachates from the drug’s packaging served as immunological adjuvants causing immunogenicity and the adverse reactions. Immunogenicity and Safety Fears Future biobetter drug candidates are likely to face the challenge of increased regulatory concern over the safety and immunogenicity of biological drugs. immunogenicity issues might be reduced by 10 All Contents Copyright © 2009 Doctor's Guide Publishing Limited. However. In 2007. partly because Dynepo was not sufficiently clinically superior to any of its competitors. This point is illustrated by Shire’s ill-fated erythropoietin. Dynepo (epoetin delta). Additionally. but also humanisation techniques. production processes. that could affect the product. Regulatory Hurdles for Biobetters Patent Issues Biological drugs are protected by patent suites that protect not only the entire molecule or parts of it. In future. resulting in the production of antibodies against the drug and unintended clinical consequences. Shire launched Dynepo as a unique erythropoietin drug: the only one produced in human cells. methods of use and indications of use. The concern of regulatory authorities has been exacerbated by recent immunogenicity issues affecting biological drugs. On the other hand. and even the outcome of litigation.Biobetters -. unlike small molecules). These patents are more complex than those protecting smallmolecule drugs. the complexity of biological drugs and the patents protecting them means that these patents may offer only partial protection. Shire ceased commercialisation in 2008. A well-known example is the sudden increase in reports of pure red cell aplasia (PRCA) in patients receiving subcutaneous injection of erythropoietin drugs during 1999-2002. this does not obviate the need for differentiation. the FDA does not maintain the listing of the patents related to biological drugs (again. but preserving the core design. sales were disappointing. This involves the drug stimulating an immune reaction. It has long been known that biological drugs can cause immunogenicity.g. Although the exact reasons remain unclear. All Rights Reserved December 2009 . Biological drug patents may turn out to be easier to circumvent than those on small-molecule drugs. No standard method for the preclinical screening of protein therapeutics for immunogenicity currently exists.major players and market prospects …But Do Not Obviate the Need for Differentiation Although these new manufacturing methods may reduce the production costs of a biobetter.

These drugs are typically marketed to hospital-based specialists and require a more scientific. Data Exclusivity in the US The introduction of a pathway for biosimilars in the US is likely to be coupled with introduction a period of data exclusivity for innovative biological drugs. The need for extended pharmacovigilance will be reinforced by other safety fears affecting biological drugs. These include the increase in progressive multifocal leukoencephalopathy in patients with multiple sclerosis taking Biogen Idec and Elan’s Tysabri (natalizumab) and fears of increased risk of cancers and cardiovascular conditions in patients taking anti-TNF (tumour necrosis factor) biological therapies.major players and market prospects greater use of predictive animal modelling. Future biosimilar competition will exacerbate the difficulty in obtaining adequate reimbursement from governments and healthcare providers. immunogenicity remains a primary safety concern for regulators. and innovative marketing techniques.Biobetters -. however. Demonstrated clinical superiority. Marketing Challenges for Biobetters Biobetter drugs will face an increasingly challenging market environment in the coming years. Indeed. This will discourage the development of biobetters and favour biosimilars. Rarer immunogenic effects can only be detected and assessed when large numbers of patients have been treated with a product. All Rights Reserved 11 . who are likely to insist on stringent post-marketing monitoring programmes and risk management strategies for new biobetters. data-driven marketing campaign. are likely features of the commercially successful biobetters of future years. However. For the foreseeable future. generally they will have all the marketing costs associated with novel biological drugs. December 2009 All Contents Copyright © 2009 Doctor's Guide Publishing Limited. The Challenge of Marketing Biobetter Drugs Although biobetter drugs may benefit from lower early-stage research and development costs than novel biological drugs. Groups representing generic pharmaceutical manufacturers are calling for a much shorter data exclusivity period than groups representing companies relying on innovative biological drugs. Options for marketing biological drugs are often more limited and more time-consuming than for conventional small-molecule drugs. or by using computer models to avoid the inclusion of immunogenic portions of proteins early in drug development. the adoption of too short a period is likely to increase the difficulty for pharmaceutical companies of recouping their investment in the research and development costs of new biological drugs. the length of this data exclusivity period is the main issue holding up the introduction of biosimilar legislation.

and third-party payers through sponsorship. Novartis. These patients tend to be well informed about their condition. In the US. To combat future pressures on healthcare spending. Biobetter marketing to these patients will increasingly require sophisticated and personalised approaches. advertising and media releases. Returning to the case of Lucentis in the UK gives a recent example. However this may not continue for much longer. such as those conducted by centralised government bodies. The NICE has rejected a number of biological therapies as not cost-effective by their criteria. has struck an agreement with the UK National Health Service (NHS). Apart from the introduction of a regulatory pathway for the future approval of biosimilars. Other possible techniques that biobetter manufacturers may use to gain reimbursement include annual price caps for a therapy.0 marketing approaches.Biobetters -. the world's largest market for biological therapies. the current administration is intent on healthcare reform. help with patients’ co-payments where these 12 All Contents Copyright © 2009 Doctor's Guide Publishing Limited. reimbursement for biological therapies has been much more generous. Additionally biobetters must be marketed to consumers. direct advertising and sponsorship of education. This personalisation will help biobetters to compete against established market incumbents. Biological drugs are increasingly subjected to rigorous health economic assessments. such as the US or France. Pricing and Reimbursement The challenge of gaining adequate reimbursement for biological drugs is likely to increase in the coming years. such as life extension rather than mere life improvement. rather than broader-based techniques such as direct-to-consumer advertising (in the US and New Zealand). All Rights Reserved December 2009 . Newer biological therapies experience more access restrictions when payers do not value the incremental clinical benefit offered by the treatment. whereby the NHS funds the initial injections of Lucentis. Biobetters will often be marketing to patients with chronic conditions such as multiple sclerosis. which markets it in the UK. although this decision was later reversed. samples. including the National Institute for Health and Clinical Excellence (NICE) in the UK. Payers must be convinced of real clinical benefit. biobetter manufacturers are likely to employ innovative strategies. but Novartis covers the cost of the drug beyond 14 injections. such as use of Web2. including direct contact with physicians through representation.major players and market prospects The marketing of biobetters will require traditional methods of drug marketing. In other countries. This illustrates that innovation in itself will not be sufficient for a biobetter. an effort to reduce healthcare costs is likely to put downward pressure on all biological drugs in the US. This initially included Roche and Novartis’ Lucentis (ranibizumab) for age-related macular degeneration. diabetes or rheumatoid arthritis.

which would aid possible future automatic substitution. Estimates vary. as seems distinctly possible. This will not match those reductions achieved by small-molecule generics. the FDA does not hold the opinion that follow-on biologicals. owing to the higher manufacturing. owing to the already high price of biological drugs.major players and market prospects exist.Biobetters -. this will boost biosimilars considerably and provide strong competition for biobetter manufacturers. It is uncertain whether the automatic substitution of biosimilars will ever become common. but analysts typically envisage biosimilars retailing at a 10-25 percent reduction. Most European states have banned automatic substitution of biosimilars for branded biological drugs in pharmacies. lowering costs to the current standard of care and payment for only the first portion of a treatment. clinical testing and marketing costs of biosimilars. Similarly in the US. If patients and healthcare practitioners accept biosimilars and automatic substitution becomes common. the scope for price rises immediately after launch . this is likely to lead to price reductions. Even when a biobetter is markedly clinically superior. All Rights Reserved 13 . compared with innovator drugs. Unless biobetters are clearly demarcated as clinically superior they could struggle in the face of this biosimilar price-reducing effect.will be limited. A factor already favouring biosimilars is that regulations in Europe do not require biosimilars to have a unique international nonproprietary name (INN). This is likely to lead to a corresponding downward pressure on the prices of all biological drugs in a particular class. approved through an abbreviated pathway. are equivalent to branded versions. Biosimilar Price Reductions What will be the effect of increasing biosimilar market penetration? If biosimilars become an established sector of the pharmaceutical market in both North America and Europe. Possible Increasing Biosimilar Competition Currently the EMEA is of the opinion that healthcare practitioners must decide if a biosimilar is substituted for an innovator’s reference drug.in an attempt to recoup revenues lost to future biosimilar competition . December 2009 All Contents Copyright © 2009 Doctor's Guide Publishing Limited.

vaccines and insulin.’ For vaccines. Senior Vice President Biotherapeutics. President and Director. Areas that experts identified as areas favourable for biobetter development included antibody-drug conjugates. believes that influenza vaccines will be of key future importance.Biobetters -. David S Fedson MD. In the monoclonal antibody field. Dr. I expect numerous new monoclonal antibodies and immunoconjugates to deliver a high value to patients both as monotherapy and in combination with already established chemotherapies. Biotest (Germany) is of the opinion that antibody-drug conjugates will achieve future success: ‘After the success of monoclonal antibodies in the improvement of both efficacy as well as tolerability in rheumatoid arthritis and other autoimmune diseases compared to the conventional DMARDs [disease-modifying anti-rheumatic drugs]. Patients with cancers that are refractory to conventional therapies will profit most from these new agents. Chief Executive Officer. It would be possible to produce a larger number of doses of pandemic vaccines . and that cell culture manufacturing methods and novel adjuvants will be the two most important methods for improving existing influenza vaccines: ‘The only industrial capacity the world will have for manufacturing influenza vaccines over the next few years will be the egg-based facilities currently found in the producing countries. adjuvated influenza vaccines and oral formulations of interferons and insulin.if there were broad agreement on producing antigen-sparing adjuvated vaccines. Aventis Pasteur MSD (now Sanofi Pasteur MSD). Frank Osterroth. Their opinions on the future direction of biobetter development in these fields are reproduced below. Until then we will be stuck with existing systems. The next important example might be Genentech’s trastuzumab conjugated with DM1 for the treatment of refractory forms of metastatic breast cancer. Oramed (Israel) believes novel insulin formulations offer the greatest potential for improvements over existing therapies: 14 All Contents Copyright © 2009 Doctor's Guide Publishing Limited.’ Nadav Kidron. a number of thought-leaders were interviewed. All Rights Reserved December 2009 . I believe monoclonal antibodies will continue to increase their position in cancer indications. glycoproteins. There is not going to be a real increment in vaccine production capacity until cell culture facilities come online in late 2011 and 2012. former Professor of Medicine.and this would translate into sales for vaccine companies . They are involved in the development of improved monoclonal antibodies.major players and market prospects Opinions of Thought Leaders on the Future of Biobetters To gauge current opinion. University of Virginia School of Medicine and former Director of Medical Affairs.

All Rights Reserved 15 . these biobetter strategies are explored more fully. Secondly and the most important difference is that an oral insulin capsule mimics the natural physiological processes of the body and the insulin is delivered to the liver first and then the bloodstream. December 2009 All Contents Copyright © 2009 Doctor's Guide Publishing Limited. Recombinant interferon has been used orally with success in animals and man. founder and Chief Executive Officer. according to Dr. for each of the major types of biological drug. Firstly an oral insulin capsule would help improve the compliance rate. Joseph M.’ In the following section.major players and market prospects ‘I see the greatest clinical and commercial opportunities in improving insulin-based drugs in the development of an oral insulin capsule.Biobetters -. Amarillo Biosciences: ‘I believe that every clinical condition that is treated with high dose injectable interferon can be treated with low-dose oral interferon without the toxicity. Cummins.’ Biobetter oral formulations also have potential in the interferon sector.

rather than new formulations.’s Remicade (infliximab).Biobetters -. Key US and European patents on the current largest-selling. non-small cell lung and breast Roche’s Herceptin (trastuzumab). increasing the number of targets to which antibodies bind. These drugs will be the prime targets for biosimilar manufacturers: Roche and Biogen Idec’s Mabthera/Rituxan (rituximab). are likely to be the key means for producing biobetter monoclonal antibodies. 16 All Contents Copyright © 2009 Doctor's Guide Publishing Limited. targeting TNF-alpha (Remicade rights were shared by Johnson & Johnson and Schering-Plough prior to the November 2009 merger between Schering-Plough and Merck & Co. Mabthera/Rituxan. biosimilar monoclonal antibody therapeutics are already available in India. North American and Japanese markets has not yet arrived. may expire before 2014. These technologies are likely to include further humanisation of antibodies. Monoclonal Antibodies Biosimilar Monoclonal Antibodies The threat from biosimilar monoclonal antibodies in key European.major players and market prospects Biobetter Strategies The key strategy for biobetter developers is differentiation from first-generation biological drugs. targeting vascular endothelial growth factor (VEGF) and indicated for a number of cancers including colorectal. How much differentiation will be required and which technologies will allow the development of commercially viable biobetters in the different biological drug types? This section examines possible future strategies. antibody-drug conjugates and antibody fragments. targeting HER2 and indicated for HER2-positive breast cancer Johnson & Johnson and Merck & Co. Herceptin and Remicade. targeting CD20 and indicated for non-Hodgkin’s lymphoma and rheumatoid arthritis Roche’s Avastin (bevacizumab).) The Future for Biobetter Monoclonal Antibodies Technology improvements. Arbitration is in progress to determine whether Johnson & Johnson or Merck gain control after merger. Nevertheless. first-generation monoclonal antibodies. All Rights Reserved December 2009 . with Avastin following suit some years later.

2009) Submitted (US FDA.Biobetters -. GlaxoSmithKline/Genmab) Ocrelizumab (Roche/Biogen Idec) RG7159 (Roche) Veltuzumab (Immunomedics/Nycomed) Humanised monoclonal antibody targeting CD20 Potential biobetter for Mabthera/Rituxan Humanised monoclonal antibody targeting CD20 Potential biobetter for Mabthera/Rituxan Humanised monoclonal antibody targeting CD20 Potential biobetter for Approved (chronic lymphocytic leukaemia. 2008) Arzerra (ofatumumab. Table 3: Biobetter Monoclonal Antibodies: Towards Fully Human Biobetter Humira (adalimumab. Phase III (non-Hodgkin’s lymphoma.)* Motavizumab (AstraZeneca) Approved (US FDA and EMEA. Abbott) Description Fully human monoclonal antibody targeting TNF-alpha Potential biobetter for Remicade (infliximab. All Rights Reserved 17 . US FDA October 2009). Older. The main technique for achieving this will be reducing the proportion of murine sequences in monoclonal antibodies. will be replaced with humanised variants containing fewer murine sequences. For example Abbott’s Humira (adalimumab) is a fully human biobetter version of the chimaeric Remicade (Table 3). and increasing the number of human sequences. Johnson & Johnson/Merck & Co. Biobetter developers will replace humanised monoclonal antibodies (such as Avastin and Herceptin) with fully human biobetters. Roche) Current Development Phase Marketed Simponi (golimumab. AstraZeneca/Abbott) Fully human monoclonal antibody targeting CD20 Potential biobetter for Mabthera/Rituxan (rituximab. rheumatoid arthritis) Phase III Phase II Phase II December 2009 All Contents Copyright © 2009 Doctor's Guide Publishing Limited.*) Fully human monoclonal antibody targeting TNF-alpha Potential biobetter for Remicade Humanised monoclonal antibody binding to RSV F Potential biobetter for Synagis (palivizumab. Johnson & Johnson/Merck & Co.major players and market prospects Further Humanisation of Monoclonal Antibodies A key biobetter strategy in the monoclonal antibody sector of the biological drug market is likely to be re-engineering of monoclonal antibodies. This strategy is already underway and has been successfully employed by pharmaceutical companies. chimaeric monoclonal antibodies (those containing both murine and human protein sequences) such as Mabthera/Rituxan and Remicade. with the aim of reducing their immunogenicity or increasing their efficacy.

Trion’s Rexomun (ertumaxomab). RSV F: respiratory syncytial virus F protein *REMICADE/SIMPONI rights were shared by Johnson & Johnson and Schering-Plough prior to the November 2009 merger between Schering-Plough and Merck & Co. 18 All Contents Copyright © 2009 Doctor's Guide Publishing Limited. All Rights Reserved December 2009 . currently in Phase II testing. Pertuzumab inhibits the pairing of HER2 with other HER receptors. capable of binding to two different targets. Roche is investigating a novel monoclonal antibody. TNF: tumour necrosis factor.Biobetters -. Arbitration is in progress to determine whether Johnson & Johnson or Merck gain control after the merger Additional Antibody Targets Another technology improvement for existing monoclonal antibody therapeutics will be to increase the number of binding targets. that is. a key mechanism of tumour growth in patients with this type of breast cancer (Table 4). recruiting them in a second defence mechanism against the tumour. Roche) Fully human monoclonal antibody targeting EGFR Potential biobetter for Erbitux (cetuximab.major players and market prospects Biobetter Description Mabthera/Rituxan Potential biobetter for Mabthera/Rituxan Fully human monoclonal antibody targeting VEGFR-2 Potential biobetter for Avastin (bevacizumab. for use in combination with Herceptin for patients with HER2-positive breast cancer. pertuzumab. Rexomun is also able to bind to T-cells. is able to bind to the HER2 target in patients with breast cancer in a manner similar to that of Herceptin. a tumour-specific mouse antibody and a T-cell specific rat antibody in one molecule. Eli Lilly/Bristol-Myers Squibb/Merck KGaA) Fully human monoclonal antibody targeting EGFR Potential biobetter for Erbitux Current Development Phase Phase II Phase III CD20 antibody (Eli Lilly) Ramucirumab/IMC1121B (Eli Lilly) Zalutumumab/HuMax-EGFr (Genmab) Phase III Necitumumab/IMC-11F8 (Eli Lilly) Phase II VEGFR: vascular endothelial growth factor receptor. However. EGFR: epidermal growth factor receptor. as a bispecific antibody. Trion is developing engineered monoclonal antibodies that are bispecific. This is achieved by combining the halves of two distinct full-sized antibodies.

Certain antibody fragments have displayed increased stability and hence December 2009 All Contents Copyright © 2009 Doctor's Guide Publishing Limited.Biobetters -.major players and market prospects Table 4: Biobetter Monoclonal Antibodies: Additional Targets Biobetter Description Current Development Phase Phase II/III Pertuzumab in combination with Herceptin (trastuzumab. and destroy specific cancer cells. Some antibody-drug conjugates containing radioisotopes have already been launched. full-sized monoclonal antibodies are also biobetter candidates. Nevertheless. designed to bind to. for the treatment of HER2-positive metastatic breast cancer. Antibody-drug conjugates are monoclonal antibodies linked to cytotoxic drugs or radioactive isotopes. Opportunities to increase the number of targets for particular monoclonal antibodies are limited. but have not enjoyed great commercial success. Trastuzumab-DM1 is a humanised antibody conjugated with the cytotoxic agent DM1. It is undergoing Phase II/III testing. including antibody-drug conjugates and fragments. Roche is currently conducting clinical trials of a conjugated biobetter version of Herceptin in collaboration with ImmunoGen. rather than merely slowing their proliferation. Such fragments offer the possibility for easier manufacturing in microbial systems and the potential advantage of greater tissue penetration. All Rights Reserved 19 . Antibody Fragments Currently-marketed monoclonal antibody therapeutics are mostly full-sized antibodies. Antibody-drug conjugates are more challenging to design and manufacture than traditional monoclonal antibodies. Antibody-drug conjugates have potential for significant therapeutic benefit. Companies are therefore investigating other techniques. if they are capable of destroying cancer cells. matching the size of naturally-occurring human antibodies. Fragments of monoclonal antibodies have significant future therapeutic potential because their smaller size may allow them to reach a host of targets unavailable to full-sized monoclonal antibodies. biobetter conjugated versions of monoclonal antibodies are likely to achieve some future commercial viability. Roche) Rexomun (ertumaxomab. Antibody fragments targeting the same receptors as older. but has not always resulted in great clinical benefit or reduced immunogenicity and side effects. Trion) Humanised monoclonal antibody acting as HER2 dimerisation inhibitor Potential biobetter for Herceptin alone Bispecific antibody targeting HER2 Potential biobetter for Herceptin Phase II Antibody-Drug Conjugates The strategy of further humanisation has already been employed for some antibody targets.

both of which target VEGF. Table 5: Biobetter Monoclonal Antibodies: Antibody Fragments Biobetter Description Current Development Phase Marketed Marketed Lucentis (ranibizumab. Pegylated epoetin beta. Biobetter Pegylated Glycoproteins The most successful biobetter glycoproteins have been longer-acting. The most commercially important of these are erythropoietin.major players and market prospects potential for decreased dosing schedules or use in pulmonary or dermatological formulations. Other antibody fragments in development (Table 5) include those targeting TNF. UCB) ART621 (Arana) ESBA105 (ESBATech) Antibody fragment targeting VEGF. G-CSF. Following the serendipitous discovery that Avastin was of use in treating age-related macular degeneration. more-convenient pegylated versions of first-generation glycoprotein drugs (Table 6). Genentech (now Roche) developed Lucentis. which are hence potential biobetter versions of Remicade or Humira. Roche and Novartis’ Lucentis (ranibizumab) is a fragment of the parent monoclonal antibody Avastin. All Rights Reserved December 2009 . Roche/Novartis) Cimzia (certolizumab pegol.Biobetters -. although market opportunities remain for pegylated β-interferon and improved pegylated formulations of all glycoproteins. α-interferon and β-interferon. specifically designed for ophthalmic applications. developed from Avastin Pegylated humanised antibody fragment targeting TNF-alpha Potential biobetter for Remicade Antibody fragment (domain antibody) targeting TNF Potential biobetter for Remicade Antibody fragment targeting TNF Potential biobetter for Remicade Phase II Phase II Glycoproteins Carbohydrate groups are attached to many different proteins to form glycoproteins. G-CSF and α-interferon have enjoyed considerable commercial success. 20 All Contents Copyright © 2009 Doctor's Guide Publishing Limited.

Techniques include engineering the protein to alter its glycosylation pattern or its sequence of amino acids. a range of other new technologies is under development aimed at biobetter glycoproteins (Table 7). December 2009 All Contents Copyright © 2009 Doctor's Guide Publishing Limited. The device. Roche) Pegylated G-CSF Biobetter for Neupogen (filgrastim.major players and market prospects Table 6: Biobetter Pegylated Glycoproteins Biobetter Mircera (methoxy polyethylene glycolepoetin beta. a device to deliver a sustained dose of erythropoietin over a period of many months. Amgen) Pegylated interferon Biobetter for Roferon-A (interferon alfa-2a. termed a biopump. Many of these technologies attempt to lengthen the half-life of the drug in the body and hence increase convenience and patient compliance. Merck & Co. Roche) Pegylated interferon Biobetter for Intron A (interferon alfa-2b. Maxygen) Description Pegylated epoetin beta Biobetter for NeoRecormon/Epogin (epoetin beta. All Rights Reserved 21 . Biogen Idec) or Rebif (interferon beta-1a. Roche) Pegintron (peginterferon alfa2b. Merck KGaA) Pegylated G-CSF Possible biobetter for Neupogen Phase III Phase II Biobetter Glycoproteins: New Technologies In addition to pegylation. Biogen Idec) Maxy-G34 (pegylated G-CSF. is an explant of the patient’s own skin with genes inserted that express and secrete erythropoietin.Biobetters -. Roche) Neulasta (pegfilgrastim. and using controlled-release technology. [formerly Schering-Plough]) Current Development Phase Marketed Marketed Marketed Marketed Pegylated interferon Possible biobetter for Avonex (interferon beta1a. fusing it with albumin or a carrier protein. Amgen) Pegasys (peginterferon alfa2a. Merck & Co. Medgenics are developing Epodure. [formerly ScheringPlough]) PEG IFN (peginterferon beta-1a.

Amgen/Johnson & Johnson) Albumin-interferon fusion protein Possible biobetter for Intron A (interferon alfa-2b. Biolex) IFN Alpha XL (interferon alfa-2b. was withdrawn from the market in 2008 because it did not offer sufficient clinical benefits over competitor products. Patents protecting first-generation epoetin products have expired. combined with PolyActive controlled-release technology Possible biobetter for Pegasys or Pegintron Long-acting interferon alfa-2b adsorbed on carrier protein (Medusa platform) Possible biobetter for Pegintron Explanted biopump.Biobetters -. manufactured in human rather than animal cells. Roche’s NeoRecormon/Epogin (epoetin beta) and Amgen’s glycoengineered biobetter. Dynepo. although it has suffered from the lack of a US launch as a result of patent infringement litigation. Merck & Co. Merck & Co. glycoprotein biobetters will have to demonstrate a clinical advantage over competitors in addition to a superior manufacturing method. Amgen) Albuferon (ABF656. except those protecting Epogen in the US that run until 2013. Roche has launched a pegylated biobetter.New Technologies Biobetter Aranesp (darbepoetin alfa. Longer-acting Aranesp offers the advantage of requiring less frequent dosing. Flamel) Epodure (erythropoietin. Human Genome Sciences/Novartis) Locteron (interferon alfa-2. Aranesp is still protected by multiple patents.major players and market prospects Table 7: Biobetter Glycoproteins . expressing and producing erythropoietin Possible biobetter for Epogen Current Development Phase Marketed Phase III Phase II Phase II Phase I/II Biobetter Glycoproteins: Improved Manufacturing Biotechnology companies are developing improved manufacturing methods for glycoproteins. is carrying out Phase II testing on a darbepoetin alfa candidate drug (MK-2578) manufactured in yeast cells. For example. However. All these erythropoietin drugs treat anaemia following renal failure or chemotherapy. All Rights Reserved December 2009 . [formerly Schering-Plough]) Recombinant interferon alfa (BLX-883). Erythropoietin Drugs Three recombinant erythropoietin products dominate the global market: Amgen and Johnson & Johnson’s Epogen/Procrit/Eprex (epoetin alfa). Aranesp (darbepoetin alfa). Mircera (methoxy polyethylene glycol-epoetin beta). Medgenics) Description Hyper-glycosylated analogue of epoetin alfa Biobetter for Epogen/Procrit/Eprex (epoetin alfa. Shire’s epoetin delta product. 22 All Contents Copyright © 2009 Doctor's Guide Publishing Limited.

and β-interferon beta products treat patients with multiple sclerosis. Merck & Co.’s version of darbepoetin alfa manufactured in yeast cells currently in Phase II testing. including Roche’s Roferon-A (interferon alfa-2a) and Merck & Co. Hanmi is attempting to extend the half-life of filgrastim by conjugating it with a carrier protein. Shire’s decision to cease commercialisation of Dynepo illustrates this high level of competitiveness. Companies developing biobetter pegfilgrastim include Maxygen. all erythropoietins face possible future competition from biological and small-molecule drugs that are designed to control erythropoiesis by mechanisms other than replacing natural erythropoietin. Granulocyte Colony-Stimulating Factor (G-CSF) The two leading recombinant G-CSF drugs on the market are Amgen’s Neupogen (filgrastim) and Roche’s Neutrogin (lenograstim). All Rights Reserved 23 . However. They include AffyMax’s Hematide. Key US and European patents on these products have expired. used to treat neutropenia (low levels of white blood cells) in oncology applications.Biobetters -.major players and market prospects The EMEA has approved multiple biosimilar epoetin products in Europe and these have achieved significant market share in Germany. currently in Phase III clinical testing and FibroGen’s FG-4592. Neulasta’s key patents are expected to lapse in 2015.’s (formerly Schering-Plough’s) Pegintron (peginterferon alfa-2b) – have now eclipsed sales of first-generation α-interferon products. December 2009 All Contents Copyright © 2009 Doctor's Guide Publishing Limited. The erythropoietin market is now very competitive. Longer-acting epoetin biobetters currently in development are likely to struggle in competition with Aranesp. in Phase II testing. These biobetters include Merck & Co. Interferons Two types of interferon provide the largest revenues for manufacturers: α-interferon products are used primarily for hepatitis C and B treatment. and Medgenics’ erythropoietin-producing gene therapy implant in Phase I/II testing. In the G-CSF sector. and in Europe the EMEA has approved a number of biosimilar filgrastim products. and Bolder BioTechnology. Mircera and epoetin biosimilars.’s (formerly Schering-Plough’s) Intron A (interferon alfa-2b). the key threat will likely come from biosimilar pegfilgrastim. Key patents on Neupogen have expired in Europe but remain active in the US until 2013. Sales of the pegylated α-interferon products – Roche’s Pegasys (peginterferon alfa-2a and Merck & Co. G-CSF is an attractive biosimilar target for manufacturers. the main biobetter strategy will therefore be to develop G-CSF products that are longer acting than Neulasta. Additionally. A biobetter pegylated version of Neupogen – Amgen’s longer-acting Neulasta (pegfilgrastim) – now has annual sales exceeding those of Neupogen.

Again. All Rights Reserved December 2009 .Biobetters -. highrevenue vaccines such as Merck & Co. 24 All Contents Copyright © 2009 Doctor's Guide Publishing Limited.’s Gardasil (human papillomavirus vaccine). Vaccines The Vaccine Market Most vaccines have been in use for many years and the market is open to low-cost competition. Other pegylated interferons and protein-engineered β-interferon candidates are in preclinical development. Oral formulations of α-interferon and β-interferon are also in development. future biosimilar competition could emerge for newer. manufacturing and testing vaccines. and vaccines delivered via the skin. Three β-interferon products – Biogen Idec’s Avonex (interferon beta-1a). this sector of the pharmaceutical market is one of the most rapidly growing. A longer-acting pegylated β-interferon is likely to be the next major development in this drug group: Biogen Idec has a pegylated interferon beta-1a drug candidate in Phase III clinical testing. AstraZeneca has gained regulatory approval for an intranasal influenza vaccine in the US. key patents on these products have expired. Developing biobetter vaccines is a key strategy to access this growing market. There is a market opportunity for the development of more convenient oral. Flamel’s interferon-carrier protein drug conjugate and protein-engineered and improved pegylated interferon products. Merck KGaA’s Rebif (interferon beta-1a) and Bayer’s Betaferon/Betaseron (interferon-beta-1b) – account for the majority of the global market. Additionally. as vaccine programmes expand worldwide. especially influenza. either from a patch or through microneedles. Biobetter Vaccines: New Delivery Methods More convenient formulations are a strategy for adding value to existing injected vaccines. for the prevention of cervical cancer. Biolex’s controlled-release formulation. dermatological or inhaled formulations of β-interferon for patients with multiple sclerosis. These novel delivery methods will allow vaccines to be administered with less training. are also under development (Table 8). including Novartis’ and Human Genome’s albumin fusion protein.major players and market prospects Biobetter developers are now concentrating on developing longer-acting α-interferon products. children and in developing countries. and will be attractive to healthcare providers for programmes among the elderly. Despite the challenge and expense involved in developing.

) Current Development Phase Approved (EMEA.Biobetters -. 2009) Phase II Phase II Phase II Single-dose. All Rights Reserved 25 . 2009) Imojev (SanofiAventis) Varicella-zoster vaccine (GlaxoSmithKline) Submitted (Australia and Thailand) Phase II Table 10: Biobetter Vaccines . Again for influenza vaccines.major players and market prospects Table 8: Biobetter Vaccines . Particularly for influenza vaccines. Merck & Co. These include switching from live. live. the addition of adjuvants (Table 10) can improve the immune response they elicit.New Adjuvants Biobetter Description Current Development Phase December 2009 All Contents Copyright © 2009 Doctor's Guide Publishing Limited.New Delivery Methods Biobetter Flumist (AstraZeneca) Intanza/IDflu (Sanofi-Aventis) Influenza vaccine enhancement patch (Intercell) CholeraGarde (Celldex) Ty800 vaccine (Celldex/Vaccine Technologies [China]) Typhoid vaccine (Emergent BioSolutions) Description Live attenuated intranasal influenza vaccine Intradermal microinjection vaccine for seasonal influenza Transdermal vaccine patch with novel adjuvant (IC31) for pandemic H5N1 influenza Oral cholera vaccine Oral typhoid fever vaccine Current Development Phase Approved (FDA) Approved (EMEA.New Recombinant Technologies Biobetter Ixiaro (Novartis/Intercell) Description Two-dose inactivated Japanese encephalitis vaccine Biobetter for older multi-dose Japanese encephalitis vaccines Single-dose recombinant Japanese encephalitis vaccine Recombinant vaccine for shingles prevention Biobetter for Zostavax (zoster vaccine. attenuated or inactivated vaccines to recombinant products (Table 9). Table 9: Biobetter Vaccines . the introduction of newer cell culture manufacturing methods to replace egg-based systems will simplify production and allow a faster response to emerging influenza strains (Table 11). oral typhoid fever vaccine Phase II Biobetter Vaccines: New Technologies A number of technological improvements can be employed to develop biobetter versions of existing vaccines.

’s Gardasil (Table 12). Currently. Merck & Co.) Four-valent seasonal influenza vaccine Current Development Phase Approved (EMEA.Broader Spectrum of Activity Biobetter Synflorix (GlaxoSmithKline) Description Conjugate vaccine for the prevention of Streptococcus pneumoniae (10 strains) and Haemophilus influenzae infections Potential biobetter for Prevnar (seven-valent pneumococcal vaccine. compared with Gardasil’s four serotypes. Phase I (US) Biobetter Vaccines: More Strains The final strategy for designing biobetter versions of existing vaccines is increasing the number serotypes of a micro-organism against which a vaccine protects.6 influenza vaccine (SanofiAventis) Influvac TC (Solvay) Description Seasonal influenza vaccine manufactured by cell culture technology Seasonal influenza vaccine manufactured by cell culture technology (PerC.6) Cell culture influenza vaccine Current Development Phase Approved (EMEA.Biobetters -. 2009) Prevnar 13 (Pfizer [formerly Wyeth]) HPV Vaccine (Merck & Co. Merck & Co. This process is already in progress for two vaccines with high global revenues: Pfizer’s (formerly Wyeth’s) Prevnar (seven-valent pneumococcal vaccine) and Merck & Co. Table 12: Biobetter Vaccines . whilst biobetter versions contain 10 or 13 strains.major players and market prospects Fluad (Novartis) Grippol Neo (Solvay/Petrovax) Next-generation flu vaccine (GlaxoSmithKline) Vaccine with novel adjuvant (M59) for seasonal influenza Seasonal influenza vaccine with Polyoxidonium adjuvant Influenza vaccine with AS03 adjuvant for seasonal influenza in the elderly Approved (certain European markets) Approved (Russia. All Rights Reserved December 2009 .) Four-valent seasonal influenza vaccine (AstraZeneca) Submitted (EMEA. is developing a biobetter vaccine protecting against nine strains of the human papillomavirus. Pfizer [formerly Wyeth]) Thirteen-valent vaccine for prevention of Streptococcus pneumoniae infections Biobetter for Prevnar Nine-valent HPV vaccine Biobetter for Gardasil (four-valent HPV vaccine. 2007) Phase III Phase III (EU). 2008. 2009) Phase III Phase II HPV = human papillomavirus 26 All Contents Copyright © 2009 Doctor's Guide Publishing Limited. Prevnar protects against seven serotypes of Streptococcus pneumoniae.New Manufacturing Technology Biobetter Optaflu (Novartis) PerC. FDA. 2009) Phase III Table 11: Biobetter Vaccines .

All Rights Reserved 27 . December 2009 All Contents Copyright © 2009 Doctor's Guide Publishing Limited. Novel Formulations are the Key Biobetter Opportunity Subcutaneous injection using a variety of syringes and pens is by far the most common insulin delivery method employed by patients with diabetes. Pfizer and Sanofi-Aventis launched an inhaled insulin.major players and market prospects Protein Hormones The Insulin Market Insulin is the most commercially important of the simple nonglycosylated hormones. Biosimilar insulin may not gain in commercial importance if markedly more convenient biobetters are developed. was only marginally more convenient – in that it reduced the number of injections required rather than eliminating them – and suffered from safety fears over the risk of lung cancer in prolonged use. The main commercial opportunity for biobetter insulins in the future is for additional noninvasive formulations that may be more convenient to patients and thereby increase compliance. Patents protecting the leading human insulin products have expired in North America and Europe. The trend for replacing human insulin with novel insulin analogues for use in these subcutaneous injections is likely to continue.Biobetters -. hence promoting better patient compliance and ideally be more effective. Other formulations are available. which have an altered amino-acid sequence in order to modify their speed of absorption and utilization by the body. However. including continuous subcutaneous administration through an insulin pump. non-invasive insulin delivery methods currently in clinical trials are shown in Table 13. For a biobetter insulin to be successful it will have to be significantly easier to use than existing injection devices. In developed markets these novel formulations will provide the main opportunity for developing biobetter insulin products to compete with biosimilar products. However. The market is dominated by recombinant human insulin and insulin analogues marketed by Eli Lilly. Exubera. have patents set to expire during 2010-2014. and a dermatological formulation in which a jet of high-pressure air sends an insulin mist through the skin. Novo Nordisk and Sanofi-Aventis. The EMEA has not yet approved any biosimilar insulin products. The drug was not more effective than injections. it was withdrawn from the market in 2007. biosimilar insulin is available in certain Asian and Eastern European markets and is likely to reach Western European markets in the near future. owing to disappointing sales. The leading insulin analogues. In 2006. New Insulin Delivery Methods New.

major players and market prospects Dermatological Insulin Of the novel insulin formulations in development. including oral. Inhaled Insulin The commercial failure of Pfizer’s Exubera has discouraged the development of inhaled insulin and indeed this delivery method suffers from a relative lack of control over dosage. Insulin delivered by this method reaches the liver in higher concentration than that administered subcutaneously. dermatological formulations are perhaps the most promising. In 2008. 28 All Contents Copyright © 2009 Doctor's Guide Publishing Limited. MannKind has submitted its Afresa inhaled insulin to the FDA and expects a regulatory decision in 2010. These rely on the active delivery of insulin through the dermal layer aided by ultrasound. safety fears and the use of large amounts of insulin. electrical charges or air jets. Nevertheless. Oral formulations are challenging to develop and an alternative approach is Generex’s Oral-Lyn (in Phase III of development) in which the insulin in the form of a spray is absorbed by the mouth lining. Novo Nordisk decided to stop all further development of inhaled insulin. Oral Insulin Oral insulin formulations involve the incorporation of components to protect the insulin from the harsh gastrointestinal environment. dermatological and suppository. All Rights Reserved December 2009 . and may mitigate diabetes symptoms through hepatic glucose regulation. Patients are already familiar with insulin delivery through the skin and transdermal technologies can include systems for the continuous monitoring of blood sugar concentration.Biobetters -. in the manner of existing insulin pumps. and promote absorption through the intestine.

major players and market prospects Table 13: Biobetter Insulin Devices Biobetter Afresa (MannKind) Oral-Lyn (Generex) IN-105 (Biocon) TPM Insulin (Phosphagenics) ORMD 0801 (Oramed) Oral insulin (Emisphere) Nasulin (CPEX) Description Inhaled. Emisphere is developing an oral growth hormone (currently in Phase I testing). May 2009) Phase III (US) Phase III (India). SMC021 is currently in Phase III testing. Other Biological Drugs Other types of biobetter drug in development are shown in Table 14. absorbed via mouth lining Oral insulin analogue Transdermal insulin Oral insulin capsule Oral insulin Inhaled insulin Current Regulatory Status Submitted (FDA.Biobetters -. indicated for osteoporosis. Phase I (Europe) Phase II (Australia) Phase II Phase II Phase II Biobetter Growth Hormones and other Hormones Novo Nordisk is developing a pegylated growth hormone with a longer half-life. in collaboration with Nordic Bioscience and Emisphere is developing a biobetter oral formulation (SMC021) of their injected salmon calcitonin Miacalcin/Miacalcic. All Rights Reserved 29 . Table 14: Other Biobetter Examples Biobetter Recombinant factor XIII (Novo Nordisk) NN1731 (Novo Nordisk) NN7128 (Novo Nordisk) Kogenate (Bayer) Oral heparin (Emisphere) Long-acting factor IX (Biogen Idec/Biovitrum) Description Recombinant version of existing human-derived factor XIII Fast-acting analogue of recombinant factor VIIa Long-acting glycopegylated analogue of recombinant factor VIIa Pegylated recombinant factor VIII Oral heparin formulation Long-acting recombinant factor IX fusion protein Current Regulatory Status Phase III Phase II Phase II Phase II Phase II Phase I/II December 2009 All Contents Copyright © 2009 Doctor's Guide Publishing Limited. ultrafast-acting insulin Insulin formulated as oral spray. Novartis. which is currently in Phase II clinical development. Other biobetter hormone targets include calcitonin.

are already leading biological drug companies. including biobetters. Leading blockbuster brands include the insulin analogue Novorapid/Novolog (insulin aspart). These companies are Roche. Novo Nordisk is 30 All Contents Copyright © 2009 Doctor's Guide Publishing Limited. and sees biobetters as a method for gaining future biological market share. this is an exception and the trend of large pharmaceutical companies acquiring or licensing late-stage biological therapies. is likely to be consolidated by the current difficult financial climate. AstraZeneca and Pfizer – have little or no strategic biobetter development. The Biobetter Strategists Novo Nordisk Novo Nordisk has the leading biobetter strategy amongst major pharmaceutical companies. All Rights Reserved December 2009 . Novo Nordisk already has an extensive biological drug portfolio. Norditropin human growth hormone (somatropin) and Novoseven (recombinant factor VII). and sees biobetters as a key plank in its strategy of defence against biosimilars.. with biobetters taking lower priority. both of which have a specific strategy of developing biobetters.Biobetters -. Which large pharmaceutical companies are leading the field in the development of biobetters? The leading pharmaceutical companies involved in the development and marketing of biological medicines can be divided into three groups. Amgen. Amgen. Merck & Co. GSK. Firstly there are the ‘biobetter strategists’. is a late entrant to the biological drug market. the ‘bioleaders’. Biogen Idec. mainly insulin.. Nevertheless. Novartis is concentrating on the development of novel biological therapeutics and biosimilars. Sanofi-Aventis and Eli Lilly and are characterised by development strategies focussed on new biological therapies. has grown to be a top-20 pharmaceutical company since its inception in 1980 and markets five separate blockbuster biological drugs. Members of the third and final group – Novartis. the world’s largest biotechnology company. This group consists of Novo Nordisk and Merck & Co. by contrast. human insulin (marketed under brand names including Actrapid and Insulatard). The company obtains the majority of its sales revenues from biological drugs. These companies have biological drugs exposed to future biosimilar competition. blood factors and human growth hormone. The second group. Other companies in the group mostly rely on small-molecule drugs but are pursuing biological expansion through the development of novel biologicals.major players and market prospects Leading Biobetter Companies Who are the Biobetter Leaders? Large pharmaceutical companies market most of the biological therapies currently available to patients.

Merck & Co. the company is developing the new insulin analogue. In the past year. and potentially further biologicals. Both are potential biobetters for Novo Nordisk’s Novoseven. All Rights Reserved 31 . to develop biological therapies and what Merck terms ‘follow-on biologics’.major players and market prospects viewing the threat of biosimilar competition to these products very seriously and has responded by focussing a key part of its development pipeline activities on biobetters. MBV acquired a portfolio of biological drugs and biological manufacturing facilities from Insmed. glycoengineered drugs have the potential for increased specificity. Novo Nordisk is developing new premixes of its existing insulin analogues. Aware of the spread of biosimilar insulin in Asia and Eastern Europe. MBV has access to proprietary glycoengineering technology. A long-acting glycopegylated derivative of factor VIIa and a fast-acting analogue of factor VIIa are both in Phase II clinical testing. Phase III testing began at the end of 2009. in Phase II testing) and both filgrastim and pegfilgrastim (MK-4214 and MK-6302. and hence have a higher theoretical risk of transmitting infectious agents. In December 2008. Novo Nordisk has a biobetter recombinant factor XIII product in Phase III clinical testing. a long-acting nextgeneration insulin with a potential duration of action of more than 24 hours. with the aim of increasing glycaemic control and patient convenience.. December 2009 All Contents Copyright © 2009 Doctor's Guide Publishing Limited. giving it a pipeline of follow-on biologicals that includes darbepoetin alfa (MK-2578. According to Merck & Co. Merck BioVentures (MBV). Merck & Co. Novo Nordisk is developing a longer-acting version of its recombinant growth hormone. In February 2009. Merck may retain the option of marketing biosimilars. It improves on existing factor XIII products. Merck is likely to attempt to develop and market these pipeline products. Siba (soluble insulin basal analogue: NN1250). with claimed therapeutic advantages over existing biological drugs.Biobetters -. The technology allows yeast-based production of therapeutic proteins with a higher degree of uniformity of glycosylation than traditional mammalian cell culture manufacturing methods. which contain human-derived material. as glycoengineered biobetters. both in Phase I testing). The company hopes its pegylated candidate drug will improve patient convenience by reducing the number of injections needed. Other projects involving biobetter blood factors include a long-acting factor IX and an improved factor VIII product with no added animal or human proteins. gained during Merck’s $400 million acquisition of GlycoFi in 2006. has moved rapidly to enter the biobetter field. Another glycopegylated recombinant factor VIIa candidate is in Phase I testing as a subcutaneous injection. the company set up a dedicated biologicals unit. Also. instead of the standard intravenous injection. bioavailability and residence time in the body than those produced in mammalian cells. Of course. if an appropriate regulatory pathway is established in the US. Finally.

Pertuzumab is a humanised monoclonal antibody that inhibits the pairing of HER2 with other HER receptors. although Roche has extended its capabilities by acquisitions such as that of GlycArt in 2005. Arbitration is in progress to determine whether Johnson & Johnson or Merck & Co. The Bioleaders Roche Group The Roche Group. Roche has developed Pegasys. Mabthera/Rituxan (rituximab): R7159 for non-Hodgkin’s lymphoma and ocrelizumab (R1594) for rheumatoid arthritis and multiple sclerosis. Roche has also begun clinical trials in partnership with Halozyme. Roche is also developing two biobetters for the treatment of HER2-positive breast cancer. Genentech and Chugai. a key mechanism of tumour growth. GlycArt’s antibody glycosylation technology has the potential to improve the cell-killing capabilities and efficacy of existing antibodies.Biobetters -. Prior to this merger Schering-Plough and Johnson & Johnson shared rights to both of the monoclonal antibodies. investigating subcutaneous formulations of biologicals currently administered by intravenous injection. Roche and Genentech developed the majority of their biological drugs in-house. Gardasil (human papillomavirus vaccine). 32 All Contents Copyright © 2009 Doctor's Guide Publishing Limited. Pegintron (peginterferon alfa-2b). more than most other large pharmaceutical companies. The company is developing two different humanised versions of the chimaeric monoclonal antibody. a pegylated epoetin beta product. Merck is developing a biobetter version of its vaccine. As a result of the company’s merger with Schering-Plough in November 2009. comprising Roche. Roche’s pipeline also includes a fully human EGFR monoclonal antibody in early-stage development. Trastuzumab-DM1 is an antibody-drug conjugate. Genentech developed Lucentis (ranibizumab). Merck gained control of the pegylated biobetter. gain control after merger. The group has a history of developing second-generation biobetters of existing biological drugs. A key strategy is the development of biobetter versions of many of its highest-selling monoclonal antibodies. a pegylated interferon alfa-2a for hepatitis treatment and Mircera.major players and market prospects In addition to its MBV programme. The Roche Group has a development pipeline richer in both biobetters and novel biological therapies than many of its competitors. It is being investigated as a combination therapy with Herceptin. consisting of Herceptin (trastuzumab) conjugated with ImmunoGen’s cytotoxic agent DM1. Remicade (infliximab) and its recently-launched biobetter. derives over 50 percent of its pharmaceutical sales revenues from biological drugs. a fragment of the Avastin (bevacizumab) monoclonal antibody and currently marketed for age-related macular degeneration. Simponi (golimumab). All Rights Reserved December 2009 .

Acambis. Biogen Idec’s biobetters in development include a pegylated version of interferon beta1a for multiple sclerosis. a biobetter anti-CD20 monoclonal antibody under development in partnership with the Roche Group.major players and market prospects Biogen Idec Biogen Idec derives its revenues from the novel monoclonal antibody therapeutics Mabthera/Rituxan. Biogen Idec obtained this platform as a result of its 2007 acquisition of Syntonix. Additionally. and ocrelizumab. acquiring the vaccine developer. in 2008. Nevertheless. Amgen Amgen is the world’s largest biotechnology company and markets a number of blockbuster biological drugs: the fusion protein. Epogen (epoetin alfa). Long-acting factor IX for haemophilia B is in Phase II of development. Amgen markets two further blockbuster biobetters. and process development should give the company a competitive edge in developing biobetters of marketed drugs in the longer term. Since Amgen has already developed second-generation products for two of its major first-generation products. the company is developing longer-acting versions of two blood factors in partnership with Biovitrum. Tysabri (natalizumab). biological manufacturing. from which the company plans to achieve future growth. it is a biobetter pioneer and has significantly strengthened its position against future biosimilar competition. Sanofi-Aventis Sanofi-Aventis obtained roughly 30 percent of drug revenues in 2008 from biological drugs. a glycoengineered second-generation product to Epogen. December 2009 All Contents Copyright © 2009 Doctor's Guide Publishing Limited. whilst long-acting factor VIII is in preclinical testing for haemophilia A treatment. The company has a strategy of increasing its development of biological drugs through acquisitions. currently in Phase III of clinical testing. and Neulasta (pegfilgrastim). alliances and licence agreements. As a result. Amgen’s current research and development pipeline is centred exclusively on novel therapeutics. Aranesp (darbepoetin alfa). These longer-acting factors use a technology platform involving fusion with the Fc region of antibodies to produce recombinant fusion proteins. Enbrel (etanercept). Lantus (insulin glargine) and a wide range of vaccines. and Neupogen (filgrastim). for example. These included the low-molecular weight heparin Lovenox (enoxaparin). The company’s development pipeline contains a number of novel biological therapies and biobetter drug candidates.Biobetters -. Avonex (interferon beta-1a) and the multiple sclerosis treatment. a pegylated follow-on product for Neupogen. Amgen’s expertise in biological drug development. All Rights Reserved 33 .

a therapeutic antibody company. In 2007. GSK’s pipeline also includes novel vaccines for diseases with no available vaccine. but hopes to increase this through in-house discovery. It is currently in Phase III testing in patients with metastatic breast cancer. and improved influenza vaccines with novel adjuvants. All Rights Reserved December 2009 . Other Large Pharmaceutical Companies GlaxoSmithKline GlaxoSmithKline (GSK) reported that it derived only six percent of its 2008 drugs revenues from biological drugs.’s shingles vaccine Zostavax. including the biobetter candidate ramucirumab (IMC-1121B). GSK is aiming to expand its portfolio of biological therapies to antibody-based drugs. Late-stage improved vaccine projects include a nextgeneration influenza vaccine using cell culture manufacturing and an improved Japanese encephalitis vaccine requiring fewer doses. In 2008. GSK acquired Domantis. Other biobetter drug candidates include a fully human antibody targeting EGFR (IMC-11F8) and a biobetter CD20 antibody for non-Hodgkin’s lymphoma. Merck & Co. As a result.Biobetters -. acquisitions and in-licensing late-stage products. but could potentially compete effectively with Roche’s Avastin for the treatment of a wide range of solid tumours.major players and market prospects The company has a rich pipeline of vaccines. Biopharm. Improved vaccines in an earlier stage of development include a recombinant pneumococcal vaccine. The company’s vaccine development pipeline includes biobetter versions of Pfizer’s pneumococcal vaccine Prevnar. Sanofi’s recently approved influenza vaccine uses an intradermal delivery mechanism. the vast majority from vaccines. Eli Lilly has a pipeline of both innovative and biobetter biological drugs. a fully human monoclonal antibody targeting VEGFR-2. including both antibody fragments and full-sized monoclonal antibodies. Eli Lilly Eli Lilly has a relatively long history of biological drug development and markets blockbuster biological drugs including the growth hormone Humatrope (somatropin) and the insulin products Humulin (human insulin) and Humalog (insulin lispro). a biotechnology company that had developed antibody fragments (Domain Antibodies) with potential applications in delivery formulations other than 34 All Contents Copyright © 2009 Doctor's Guide Publishing Limited. a shingles vaccine and an improved second-generation version of Sanofi’s Menactra. GSK created a biologicals research and development unit. Eli Lilly boosted its biological drug products and biological development pipeline by the November 2008 acquisition of ImClone. including second-generation and improved versions of existing vaccines. a vaccine indicated for the prevention of meningococcal disease. Both of these are in Phase II clinical testing.

and is developing Numax (motavizumab). a biosimilar epoetin alfa and Zarzio. a reportedly more potent biobetter version of Synagis.major players and market prospects traditional injected formulations. ABF656) and an oral formulation of the hormone calcitonin for osteoporosis (SMC021). GSK’s immediate biobetter hopes are pinned on Arzerra (ofatumumab). AstraZeneca gained the nasal influenza vaccine Flumist and the monoclonal antibody Synagis (palivizumab). In its vaccines division. Novartis is developing a few biobetters. As a full-sized. AstraZeneca is pursuing biobetter versions of influenza vaccines. All Rights Reserved 35 . fully human monoclonal antibody. including Cambridge Antibody Technology in 2006 and MedImmune in 2007. December 2009 All Contents Copyright © 2009 Doctor's Guide Publishing Limited. which is the leading biosimilar developer and marketer in developed world markets. Novartis’s future biological strategy is focussed primarily on developing innovative biological drugs and biosimilars. In addition to this biobetter campaign. As a result. for the prevention of respiratory syncytial virus infection. a biosimilar filgrastim. Sandoz. the company created a biologicals unit. This biobetter monoclonal antibody is designed to achieve greater efficacy through greater affinity for its target. In 2007. These include an albumin-interferon alfa-2b fusion protein for hepatitis C (Albuferon. The generics manufacturer has gained EMEA approval for three biosimilars: the growth hormone. AstraZeneca is developing multiple novel monoclonal antibodies for diseases including asthma and rheumatoid arthritis. Novartis develops and markets biosimilars through its generics division. Despite having faith in the future commercial viability of biosimilars. Novartis Currently. approved by the FDA in October 2009. Arzerra may provide strong competition for Roche’s chimaeric monoclonal antibody Mabthera/Rituxan.Biobetters -. rather than biobetters. including a four-valent seasonal influenza vaccine. Novartis markets biological drugs in the form of vaccines and the monoclonal antibodies Xolair (omalizumab) and Lucentis (ranibizumab). designed to improve biotechnology innovation and drive future growth of novel biological therapies. However. Omnitrope. Novartis has developed an improved Japanese encephalitis vaccine in partnership with Intercell and improved influenza vaccines utilising novel adjuvants and cell culture manufacturing methods. AstraZeneca AstraZeneca has gained biological drugs and biological development capabilities through the acquisition of biotechnology companies.

however.Biobetters -. Pfizer had relied almost exclusively on business from small-molecule drugs. By acquiring Wyeth. Now. compared with the seven strains for Prevnar. A strategy of developing both innovative and biobetter biological drugs is being implemented by the acquisition of other companies. Wyeth heralded Prevnar 13 as a significant advance. since the biobetter vaccine protects against six extra pneumococcal strains. Pfizer has gained not only the blockbusters Enbrel (etanercept) and Prevnar (seven-valent pneumococcal vaccine). All Rights Reserved December 2009 . including most notably the $68 billion acquisition of Wyeth. but also important biological manufacturing knowledge and facilities and a useful biological drug pipeline. 36 All Contents Copyright © 2009 Doctor's Guide Publishing Limited.major players and market prospects Pfizer Until 2009. This pipeline includes biobetters such as Prevnar 13. the company sees the development of biological drugs as its most important future tactic. a vaccine for the prevention of pneumococcal disease in children caused by 13 strains of Streptococcus pneumoniae. completed in October 2009.

there is a distinct possibility for a rapid growth in the biosimilar market in the coming years. or engineering the protein structure of the drug. either through in-house development. have already adopted a biobetter strategy for their future development. biobetter versions of existing biological drugs. The resulting biobetter may gain a competitive advantage through an increase in the half-life in the body. sees biobetters as a key plank in its strategy for maintaining market share against lowcost competitors. improved bioavailability and reduced toxicity. Biobetter. biobetters could compete successfully with biosimilars and prevent them from gaining market share. versions of these drugs involve either improving their manufacturing process. Interest in biobetter development. with a drug portfolio vulnerable to biosimilar competition.major players and market prospects Conclusion Biosimilars already are a reality in Europe and much of Asia. or the attachment of other components such as PEG. With sufficient clinical superiority or improvement in convenience of use. albumin or proteins. First-generation biological drugs are largely immediate-release formulations of proteins. Although the degree to which biosimilars will become accepted and enjoy commercial success is as yet unknown. The aim of biobetter development will be to develop a product with a distinct clinical advantage or more convenient formulation for patients. Merck & Co. It is difficult to believe that the US will not adopt them within the next four years. For many companies. delivered by subcutaneous injection or infusion. sees biobetters as a method for gaining future biological market share. In many cases. protein engineering may allow creation of a biobetter with altered function and therefore improved clinical effectiveness or reduced side effects. All Rights Reserved 37 . Alternatively. development of biobetters will provide an essential complementary activity to the development of novel biological therapeutics. and have now arrived in Japan and Canada. for example by switching to microbial. the manufacturers of branded biologicals threatened by biosimilars have the opportunity of defence against this biosimilar threat by developing secondgeneration. insect or plant-based cell systems. Novo Nordisk. Engineering can entail the alteration of the amino acid sequences or the glycocomponent of a glycosylated protein. dermatoglocial or inhaled formulation having more convenient dosage formats and potentially improved patient compliance. which may lead to reduced dosing frequency. partnerships or acquisitions.Biobetters -. Finally. Novo Nordisk and Merck & Co. a late entrant to the biological drug market. is likely to increase amongst other large pharmaceutical companies in the coming years. Only these clearly differentiated biobetters will December 2009 All Contents Copyright © 2009 Doctor's Guide Publishing Limited. biobetter development may allow creation of an oral.

major players and market prospects provide strong competition for future biosimilars. 38 All Contents Copyright © 2009 Doctor's Guide Publishing Limited. All Rights Reserved December 2009 . gain satisfactory reimbursement from payers and achieve commercial success.Biobetters -.

Tumour necrosis factor VEGF .Human papillomavirus MBV .Vascular endothelial growth factor VEGFR .Polyethylene glycol RSV F .Respiratory syncytial virus F protein SIBA .Vascular endothelial growth factor receptor December 2009 All Contents Copyright © 2009 Doctor's Guide Publishing Limited.Biobetters -.Granulocyte colony-stimulating factor GSK .National Institute for Health and Clinical Excellence (UK) PEG .GlaxoSmithKline HPV .Merck BioVentures NICE .major players and market prospects Abbreviations EGFR .European Medicines Agency FDA – Food and Drug Administration (US) G-CSF .Epidermal growth factor receptor EMEA .Soluble insulin basal analogue TNF . All Rights Reserved 39 .

21. 4. 10. 35. 8. 34. 24. 36. 13. 13. 32.major players and market prospects Index A Abbott Acambis Actrapid adalimumab Albuferon Amarillo Biosciences Amgen anti-TNF Aranesp Arzerra Asia AstraZeneca Avastin Aventis Pasteur MSD Avonex 18 35 32 18 36 16 2. 31. 4. 33 35 35 18. 27. 26. 21. 35 18 26 33 H D darbepoetin alfa DMARDs Domantis 23. 34 19 G Gardasil G-CSF Genentech Genmab glargine GlaxoSmithKline GlycArt GlycoFi golimumab GSK 25. 40 C Cambridge Antibody Technology Canada CD20 antibody chimaeric monoclonal antibodies China Chugai 37 4. 38 18. 21. 32. 22. 27. 30. 11. 17. 24. 33 18. 10. 24. 34 18. 31. 25.Biobetters -. 19 35 7. 36 23. 40 30 2. 22. 30. 18. 36 26. 8. 4. 4. 21. 34 11 23. 32. 23. 35 3. 40 33 32 18. 19. 34 E Elan Eli Lilly EMEA Emisphere Enbrel enoxaparin epoetin Epogen Erbitux erythropoietin etanercept Europe 11 19. 21 35 40 All Contents Copyright © 2009 Doctor's Guide Publishing Limited. 37 17. 28. 34. 28. 3. 34 15 36 Halozyme Herceptin Humalog Humatrope Humira Humulin 33 7. 27. 38 19. 30. 31. 23. 25. 25. 26. 33 7. 29. 18. 28. 5. 18. 22. 22. 18. 37 35 2. 34 19 2. 19. 24. 26. 24. 22. 34. 32. 26. 34 36 15 30. 27. 28. 35 15 22. 40 15. 33. 37 3. 33 2. 18. 35. 21. 31. 24. 34. 36 3. 33. 36. 30 11. All Rights Reserved December 2009 . 40 2. 24. 10. 37 B Bayer Biogen Idec Biopharm Biotherapeutics Biovitrum Bristol-Myers Squibb 25. 20. 17. 23. 31. 24. 38 F FDA filgrastim Flumist 4. 10. 18. 13. 36. 22. 24 2. 10.

26. 32. 23. 31. 24. 17. 25 Miacalcin/Miacalcic 30 Mircera 22. 22. 25. 38 Merck BioVentures 32. 32. 38 26. 40 Merck KGaA 19. 18. 24. 33 RG7159 18 rheumatoid arthritis 2. 13. 33. 36 Remicade 17. 27. 34 2. 36 Roche 7. 23. 22. 34. 24. 27. 28. 34. 33. 19. 18. 34 18 18. 40 NN1731 30 non-Hodgkin’s lymphoma 17. 36. 17. 33. 29. 33. 3. 33. 22. 34 17. 33. 25. 16. 23. 30 J Japan Japanese encephalitis vaccine Johnson & Johnson 4. 31. 36 MedImmune 37 Menactra 35 Merck & Co 17. 33 L Lantus Lovenox Lucentis 35 35 12. 36 Novo Nordisk 28. 21. 34 12 Sandoz Sanofi Pasteur MSD Sanofi-Aventis Schering-Plough Siba Simponi 36 15 26. 34 22. 40 31 35 22. 36. 18. 34. 13. 12. 21. 23. 3. 37 Rituxan 17. 18. 28. 34 19 22. 24. 18.major players and market prospects I IMC-1121B ImClone ImmunoGen India Insmed Insulatard insulin insulin aspart insulin lispro interferon beta-1a interferons 35 35 20. 23. 21. 19. 32. 25 NICE 12. 20. 31. All Rights Reserved 41 . 12. 35 17. 24. 18. 30. 36 36 36 15. 31. 18. 25. 36 17. 33 December 2009 All Contents Copyright © 2009 Doctor's Guide Publishing Limited. 38 Novolog 31 Novorapid 31 Novoseven 32 Numax 37 O ocrelizumab Ocrelizumab ofatumumab omalizumab Omnitrope Oramed 33. 35 Nordic Bioscience 30 Novartis 12.Biobetters -. 23. 36. 24. 35. 23. 35. 33. 29. 31. 34 19. 24. 19. 36 S N natalizumab Necitumumab Neulasta Neupogen New Zealand 11. 15. 18. 30. 29. 33 MK-2578 23. 19. 37 27. 27. 21. 24. 27. 31. 15. 19. 21. 33. 31. 37 22. 29. 34 2. 33 32 18. 35. 19. 32 MK-4214 33 MK-6302 33 motavizumab 37 Motavizumab 18 R R1594 33 ramucirumab 35 Ramucirumab 19 ranibizumab 12. 33 22. 26. 30. 22. 20. 36 P palivizumab Pegasys pegfilgrastim Pertuzumab Pfizer Prevnar 18. 15. 30 32 32 2. 33. 5. 37 M Mabthera 17.

Biobetters -. 3. 37 T trastuzumab Tysabri 7. 27. 35 18. 27. 13. 24. 33. 34 11. 18. 38. 34 X Xolair 36 Z U US 2. 40 Zalutumumab Zarzio Zostavax 19 36 26. 37 34 W Wyeth 2. 15.major players and market prospects SMC021 somatropin Synagis Syntonix 30. 23. All Rights Reserved December 2009 . 17. 17. 30. 20. 4. 36 2. 4. 12. 25. 32. 11. 36 V Veltuzumab 18 42 All Contents Copyright © 2009 Doctor's Guide Publishing Limited.

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