Biosimilars/Research

The case for health economic studies on biopharmaceuticals

In the not too distant future, patents will expire on some major biopharmaceuticals, such as interferons, insulins and granulocyte-colony stimulating factors [1]. This is likely to lead to the market entry of a number of biosimilars. A health economic approach to market access for biopharmaceuticals and biosimilars serves to aid researchers and decision makers in pharmaceutical companies and government to identify those products in the development process that are likely to be safe, effective and cost-effective. This approach should also guide the rationale for registration, pricing and reimbursement decisions.

Biopharmaceuticals: the start of personalised medicine

Biopharmaceuticals typically bind to their biological target, e.g. a protein linked to a disease [1]. Therefore, a biopharmaceutical is likely to be particularly efficacious in a specific subgroup of the patient population. For instance, trastuzumab is a monoclonal antibody that binds to the human epidermal growth factor receptor 2 (HER2) protein and has been shown to be efficacious in the treatment of patients with metastatic breast cancer whose tumours over-express HER2 [2]. This has implications for the clinical development of biopharmaceuticals in that it highlights the need to select the most responsive target population, to collect information on relevant patient characteristics, and to identify suitable biomarkers for responders [3]. It could be argued that, in this respect, biopharmaceuticals involve a paradigm shift towards personalised medicine.

Health economic challenges for biosimilars

Biopharmaceuticals represent a fast-growing segment of the pharmaceutical market, making up one third of products in the development pipeline and accounting for 9% of pharmaceutical expenditure [1]. Whereas the first generation of biopharmaceuticals tended to consist of first-in-class products addressing unmet clinical needs in small populations, e.g. bevacizumab for metastatic colorectal cancer, the current wave of products targets larger populations, e.g. insulins for type 2 diabetes mellitus [2].

Market access for biopharmaceuticals and biosimilars: a case study

Filgrastim is one of the first biopharmaceuticals for which biosimilars have entered the market. This case study illustrates the health economic challenges and the issues that arose in the R & D, registration, pricing and reimbursement of the biopharmaceutical and its biosimilars [1].

Biosimilar EPOs show the same or better quality

Researchers have found biosimilar erythropoietin (EPO) products have the same or even better quality compared with the original branded products.

Epoetin alfa and pure red cell aplasia

Most therapeutic proteins have the potential to induce an immune response. Cases of pure red cell aplasia (PRCA) were reported after the formulation of Eprex (epoetin alfa) was changed. It is now known that ‘the process is the product’ and the formulation cannot be changed without approval by the relevant authorities.

Approval of biosimilar epoetins: how similar are they?

A consensus has emerged that approval of biosimilars requires both biological and clinical evidence. The ‘comparability exercise’ requires consideration of a wide range of aspects, including analytical and physico-chemical characterisation by several methods, comparative biological assays, comparative immunogenicity assessment, among others. The use of different host cells for the biosimilar product and the comparator in principle is possible.

Phase I trial of a biosimilar erythropoietin

A Phase I clinical trial of Hospira’s biosimilar erythropoietin (EPO) in patients with anaemia associated with chronic renal failure and chemotherapy has started in the US.

What clinical trials will be required for biosimilar mAbs?

The relevant European guideline states that if the reference medicinal product has more than one indication, the efficacy and safety of a biosimilar has to be justified, if necessary by demonstrating it separately for each indication claimed. The guideline brings up the possibility of ‘extrapolating’ efficacy (granting several clinical indications that are licensed for the reference product, although only one of the indications has been studied in the clinical development programme of the biosimilar). This would not be done without serious consideration. The mechanism of action of monoclonal antibodies (mAbs) is usually complex and in many cases only partially understood.

Technical challenges in defining mAbs

Monoclonal antibodies (mAbs) are highly complex molecules with secondary and tertiary structures. The drug substance (the molecule itself) and drug product (the pharmaceutically formulated final product) are heterogeneous, i.e. a mixture of several slightly different structures. Although the molecular characterisation of a mAb molecule itself might have reached a high level of precision, reliability, quality and reproducibility, various possibilities for mAb heterogeneity exist. Variations to the mAb protein include alternative disulfide pairings/disulfide shuffling, deamidation, (methionine) oxidation, cyclisation of N-terminal glutamine residues and partial enzymatic cleavage during manufacturing. Variations of post-translational modifications such as glycosylation patterns include differential addition of sugars, alternative branching of sugar chains and others. Physicochemical characterisation of these characteristics currently remains cumbersome.

How far does similarity go?

How much similarity does a biosimilar monoclonal antibody (mAb) have to show to its reference mAb? The European overarching biosimilar guideline states that a biosimilar needs to be ‘similar, in molecular and biological terms, to the active substance of the reference medicinal product.’ The guideline gives an example to highlight this, stating that an interferon alfa-2b would not be acceptable as a reference product to a biosimilar interferon alfa-2a1. Because interferon alfa-2a and alfa-2b differ in only one amino acid, the guideline thus indicates that the entire amino acid sequence of the two molecules should be identical.

The biosimilars challenge

What are the challenges facing biosimilars? This was the question broached in a paper by Professor Håkan Mellstedt of the Department of Oncology, at the Karolinska University Hospital Solna, Stockholm, Sweden.

Development of biosimilars mAbs

Is the development of biosimilar monoclonal antibodies (mAbs) possible in Europe? This was the question broached in a paper by Dr Christian Schneider – Chairman of both the Committee for Advanced Therapies and Biosimilar Medicinal Products Working Party and Co-opted member of the Committee for Medicinal Products for Human Use.

Challenges in the development of biosimilars mAbs

What are the challenges facing development of biosimilar monoclonal antibodies (mAbs) in Europe? This was the question broached in a paper by Dr Christian Schneider – Chairman of both the Committee for Advanced Therapies and Biosimilar Medicinal Products Working Party and Co-opted member of the Committee for Medicinal Products for Human Use.

Phase III study of a new biosimilar filgrastim product (Zarzio) published

A biosimilar recombinant human granulocyte colony-stimulating factor (filgrastim) (rhG-CSF), Zarzio (Sandoz GmbH), was evaluated in healthy volunteers in four phase I studies and in neutropenic patients in a phase III study.

Phase I studies of a new biosimilar filgrastim product (Zarzio) published

Zarzio (Sandoz GmbH), a biosimilar recombinant human granulocyte colony-stimulating factor (filgrastim), was evaluated in healthy volunteers in four phase I studies and in neutropenic patients in a phase III study.

Include health economics in development of biosimilars

The early inclusion of health economics in the process of developing biopharmaceuticals and biosimilars is imperative with a view to demonstrating their relative (cost) effectiveness and informing registration, pricing and reimbursement decisions, writes Professor Steven Simoens of the Katholieke Universiteit Leuven, Belgium, in the Journal of Medical Economics in 2009.

In the article he discusses health economic challenges of research and development, registration, pricing and reimbursement of biopharmaceuticals and biosimilars. Professor Simoens identified relevant studies by searching PubMed, Centre for Reviews and Dissemination databases (Database of Abstracts of Reviews of Effects, National Health Service Economic Evaluation Database, and Health Technology Assessments Database), Cochrane Database of Systematic Reviews and EconLit up to March 2009. Additionally, the bibliography of included studies was checked for other relevant studies.

For complex biosimilars in EU: drop clinical comparability

Clinical trials required by European regulators to compare biosimilar products with corresponding biologic brands are surplus to requirements and may even be a barrier for the development of biosimilars of more complicated biologics, state Professor Huub Schellekens and Dr Ellen Moors of Utrecht University, The Netherlands, in a Nature Biotechnology Commentary of January 2010. “If you look in detail at the accepted and rejected biosimilars and the differences, then you might conclude that proof of clinical equivalence is actually overdue,” comments Professor Arnold Vulto of the Erasmus MC, Rotterdam.

New method for producing human-like glycosylated MAbs

As reported online on 28 February 2010 in Nature Chemical Biology, Professor Lai-Xi Wang, Professor Markus Aebi and colleagues describe a new bacterial method for producing homogeneous eukaryotic N-glycoproteins.

Glycosylation technologies for biosimilars and ‘biobetters’

According to Mr Hans Baumeister and Mr Steffen Goletz of Glycotope, human cell lines providing a human glycosylation pattern – such as those of Crucell (PER.C6), Cevec (CAP) and Glycotope (GlycoExpress) – have attracted increasing amounts of attention over the past years. In the case of biosimilars, regulatory approval now requires an extensive programme of bioequivalence studies to be undertaken to characterise the product in terms of its biochemical properties, safety and activity. As a consequence, glycosylated biosimilars need to be equipped with a similar pattern of glycosylation. For example, the degree of sialylation should not deviate by more than 20% from that of the original product. Hence, the chosen cell clone with high productivity has to be able to provide post-translational modifications as closely related to the originator’s cell line as possible. However, since glycosylation differs within clones, during the bioequivalence study it is often realised that the product carries different carbohydrates, usually resulting in a hyposialylation; this requires the screening process to be repeated in order to identify a new cell clone that is able to provide the equivalent glycosylation. Several glycosylation analysis technologies are available for the development and production of glycosylated biotherapeutics, applicable to both biosimilars and second-generation ‘biobetters’ (see Table 1).

Will the EU biosimilars pathway be applicable to monoclonal antibodies?

To what extent is the existing framework for biosimilars in Europe likely to be applicable to monoclonal antibodies (mAbs)? This question was verified in a paper by Dr Christian Schneider –member of the EMA’s Committee for Medicinal products for Human Use (CHMP), Chairman of EMA’s Biological Medicines Working Party (BMWP) and the Paul-Ehrlich-Institut in Langen, Germany– and Dr Ulrich Kalinke of the Paul-Ehrlich-Institut and Twincore Center for Experimental and Clinical Infection Research in Hannover, Germany, as published in Nature Biotechnology of September 2008.

A follow-on biologic drug is not a ‘biogeneric’: Lessons from Omnitrope and Valtropin

In an article by Dr Robert Roth and Dr Nicholas Fleischer of the Weinberg Group published in Journal of Generic Medicines of May 2009, it is stated that a follow-on biologic drug is not a ‘biogeneric’, based on lessons from Sandoz’s biosimilar human growth hormone Omnitrope (somatropin) and BioPartners’ Valtropin (somatropin).

PhRMA, Amgen correct NEJM article on biologics exclusivity

In a NEJM Letter to the Editor of 18 February 2010, Mr David Wheadon, Senior Vice President of the Scientific & Regulatory Affairs team of the Pharmaceutical Research and Manufacturers of America 
(PhRMA) –having been employed by several pharmaceutical companies (Eli Lilly, GlaxoSmithKline, Abbott) and holding stock in Abbott Laboratories and GlaxoSmithKline– corrects the NEJM Perspective article by Mr Engelberg et al. of 12 November 2009, writing that “the record should be set straight” with regard to the market exclusivity of biologicals in the biosimilars debate.

Improving effector functions of MAbs for cancer treatment: Enhancing antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC)

Mr Akito Natsume et al. of Kyowa Hakko Kirin, Machida-shi, Tokyo, Japan, have shown to improve effector functions of monoclonal antibodies (MAbs) for cancer treatment by enhancing ADCC and CDC, as published in their review article in Drug Design, Development and Therapy 2009:3 of December 2008.

Abbott: Non-responding RA patients with anti-infliximab antibodies may switch to less immunogenic anti-TNF

In the race for biosimilar/biobetter monoclonal antibodies (MAbs), it is interesting to compare originator MAbs, e.g. mouse-human chimeric infliximab (Remicade) of Johnson & Johnson’s Centocor versus Abbott’s fully human – and thus less immunogenic – adalimumab (HUMIRA).

ADCC enhancement technologies for monoclonal antibodies

In a 2009 article by Dr Cheng Liu, founder and CEO of Eureka Therapeutics in California, and Andreia Lee in Trends in Bio/Pharmaceutical Industry on Antibody Therapeutics, it is stated that ADCC (Antibody Dependent Cell-mediated Cytotoxicity) enhancement is a key strategy for improving therapeutic antibody drug efficacy against cell-surface targets in cancer and chronic inflammation. It takes advantage of patients’ innate immune cells to kill target cells. The functions are primarily triggered through direct interaction of the Fc domain of human immunoglobulin (in most cases IgG1) with the corresponding receptors. Therapeutic antibodies with enhanced ADCC are anticipated to have a clinical advantage owing to increased specific lysis of target cells, such as cancer cells, mediated by Fc receptors present on natural killer cells, macrophages, and other immune cell types.

Xencor: Via Fc engineering enhanced antibody half-life improves in vivo activity

Improved affinity for the neonatal Fc receptor (FcRn) is known to extend antibody half-life in vivo. However, this has never been linked with enhanced therapeutic efficacy. Mr Jonathan Zalevsky and Dr John Desjarlais et al. of Xencor at Monrovia, CA, USA, studied if such enhanced antibody half-life improves in vivo activity, as published online in Nature Biotechnology on 17 January 2010.

Ustekinumab better than etanercept in psoriasis trial

In a study by Christopher Griffiths et al. of the University of Manchester, UK, Johnson & Johnson (J&J)’s monoclonal antibody STELARA (ustekinumab, an interleukin-12 and interleukin-23 blocker) and Amgen’s Enbrel (etanercept, an inhibitor of tumour necrosis factor: anti-TNF) have been compared for the treatment of psoriasis, as published in The New England Journal of Medicine (NEJM) of 14 January 2010. The Phase 3, Multicenter, Randomized Study Comparing CNTO 1275 and Etanercept for the Treatment of Moderate to Severe Plaque Psoriasis’ was sponsored by J&J’s Centocor.

FTC- Biosimilars to spur innovation and competitive prices

In the Journal of Generic Medicines (published online 8 September 2009), Michael Wroblewski and Elizabeth Jex of the US Federal Trade Commission (FTC) write about the promise of follow-on biologics (FOBs) to spur both biological drug innovation and competitive prices.

Time for a re-evaluation of ESAs

In an article in The New England Journal of Medicine (NEJM) by Ellis F Unger, Aliza M Thompson, Melanie J Blank, and Robert Temple, published on 6 January 2010 at NEJM.org, it is stated that it is time for a re-evaluation of erythropoiesis-stimulating agents (ESAs).

Modify Fc fucosylation and β-galactosylation for biobetter MAbs

In an article by Dr Claire Morgan and Dr Daryl Fernandes of Ludger, published in IPI of Autumn 2009, it is shown how both the original drug manufacturers and the designers of follow-on biologics could produce biobetter monoclonal antibodies (MAbs) through glycoengineering. (see also Ludger’s GTO-QbD: Defining glycovariant biobetter MAbs, When is a glycoengineered biobetter commercially better than a biosimilar? and Strategy and tools for building glycoengineered biobetter MAbs)

When is a glycoengineered biobetter commercially better than a biosimilar?

In an article by Dr Claire Morgan and Dr Daryl Fernandes of Ludger, published in IPI of Autumn 2009, it is shown how both the original drug manufacturers and the designers of follow-on biologics could produce biobetter monoclonal antibodies (MAbs) through glycoengineering. (see also Modify Fc fucosylation and β-galactosylation for biobetter MAbs, Design out NeuGc, Fab glycosylation for biobetter MAbs, Design out Gal-α(1,3)-Gal for biobetter MAbs, Strategy and tools for building glycoengineered biobetter MAbs and Ludger’s GTO-QbD: Defining glycovariant biobetter MAbs)

Design out NeuGc, Fab glycosylation for biobetter MAbs

In an article by Dr Claire Morgan and Dr Daryl Fernandes of Ludger, published in IPI of Autumn 2009, it is shown how both the original drug manufacturers and the designers of follow-on biologics could produce biobetter monoclonal antibodies (MAbs) through glycoengineering. (see also Ludger’s GTO-QbD: Defining glycovariant biobetter MAbs, When is a glycoengineered biobetter commercially better than a biosimilar? and Strategy and tools for building glycoengineered biobetter MAbs)

Design out Gal-α(1,3)-Gal for biobetter MAbs

In an article by Dr Claire Morgan and Dr Daryl Fernandes of Ludger, published in IPI of Autumn 2009, it is shown how both the original drug manufacturers and the designers of follow-on biologics could produce biobetter monoclonal antibodies (MAbs) through glycoengineering. (see also Ludger’s GTO-QbD: Defining glycovariant biobetter MAbs, When is a glycoengineered biobetter commercially better than a biosimilar? and Strategy and tools for building glycoengineered biobetter MAbs)

Strategy and tools for building glycoengineered biobetter MAbs

In an article by Dr Claire Morgan and Dr Daryl Fernandes of Ludger, published in IPI of Autumn 2009, it is shown how both the original drug manufacturers and the designers of follow-on biologics could produce biobetter monoclonal antibodies (MAbs) through glycoengineering. (see also Modify Fc fucosylation and β-galactosylation for biobetter MAbs, Design out NeuGc, Fab glycosylation for biobetter MAbs, Design out Gal-α(1,3)-Gal for biobetter MAbs, When is a glycoengineered biobetter commercially better than a biosimilar? and Ludger’s GTO-QbD: Defining glycovariant biobetter MAbs)

Ludger’s GTO-QbD: Defining glycovariant biobetter MAbs

One area of great interest to developers, copiers and improvers of therapeutic antibodies is glycosylation, since it can significantly influence the safety and efficacy profiles of the drug. In an article by Claire Morgan and Daryl Fernandes of Ludger published in IPI of Autumn 2009, it is shown how both the original drug manufacturers and the designers of follow-on biologics could produce biobetter antibodies through glycoengineering. In particular, they examine strategies for optimising both fragment antigen-binding (Fab) and fragment crystallisable (Fc) region glycosylation to produce monoclonal antibodies (MAbs) with improved clinical performance and better commercial profiles compared to existing drugs.

Why are there suddenly ‘biosimilars’ besides ‘biologicals’?

“Isn’t everything already complicated enough?” asked Professor Theo Dingermann of the Goethe University in Frankfurt, Germany, at the Weekend Workshop ‘Patient and Pharmaceutical Care’ of the German Union of Pharmacists Societies (Bundesvereinigung Deutscher Apothekerverbände, ABDA) held on 17–18 October 2009 in Hannover, Germany.

Biologicals and biosimilars: how can we afford them?

Demand for biological drugs is putting pressure on health budgets. Medical student, Mr Christopher Kelly and Consultant Physician, Dr Fraz Mir of the University of Cambridge, UK, examine in the British Medical Journal of 19 September 2009 why they are so expensive and what can be done to increase access.

Why is “the process the product” for biosimilars?

“Why does the manufacturing process play such a prominent role in the definition of a biosimilar?” asked Professor Theo Dingermann of the Goethe University in Frankfurt, Germany, at the Weekend Workshop ‘Patient and Pharmaceutical Care’ of the German Union of Pharmacists Societies (Bundesvereinigung Deutscher Apothekerverbände, ABDA) held on 17–18 October 2009 in Hannover, Germany.

Dingermann: “Use biosimilars, but don’t force patients”

“Thanks to the stringent examinations of EMEA, patients can trust that approved biosimilars are effective and tolerable – a reassuring remark for those who are dependent on such medicines,” said Professor Theo Dingermann of the Goethe University in Frankfurt, Germany, at the Weekend Workshop ;Patient and Pharmaceutical Care’ of the German Union of Pharmacists Societies (Bundesvereinigung Deutscher Apothekerverbände, ABDA) held on 17–18 October 2009 in Hannover, Germany.