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Overview of Biosimilar Therapeutics
C H A P T E R
5 Overview of Biosimilar Therapeutics Danuta J. Herzyk Merck Research Laboratories, Merck & Co., Inc., West Point, PA, USA
INTRODUCTION As described in Section I of this book, biotechnology-derived pharmaceuticals represent a very broad group of medicines in terms of their structure and therapeutic indications. Also, there are fundamental differences between traditional, small-molecule pharmaceuticals and biological products. The physiochemical and structural properties of biologics are sensitive to changes in the manufacturing environment and/or processes, and because of the inherent variability in the biological systems (i.e., living cells) used in the manufacturing process, the resulting biologic product often consists of a mixture of protein isoforms. Because of the complexity of biopharmaceuticals, for many years it was believed their manufacturing could not be subject to generic competition. This view changed in the early 2000s in parallel with significantly increased knowledge and progress in biotechnological methods applied in biopharmaceutical manufacturing. At the same time greater public and governmental pressure on lower cost medicines and larger global access to novel therapeutics led to this evolutionary step in the biotechnology world. The primary focus on the discovery and development of novel biologics has been broadened to the development of copies of successful marketed biopharmaceuticals in a less expensive way. While it is widely accepted that in contrast to chemical drugs, generic versions of biologics are not attainable (because of the high complexity of their structure), the development and manufacturing of close copies of biopharmaceuticals is achievable, and the concept of “biosimilar” drugs has been introduced. The term “biosimilar” refers to a biological product that claims to be similar to a marketed biopharmaceutical (reference product) that has been approved in highly regulated markets, such as International Conference for Harmonization (ICH) regions (i.e. USA, Europe, Japan), for which patent and regulatory protection of data exclusivity have expired. There are other terms, such as “follow-on- biologics” and “subsequent entry biologics,” applied in different regions (USA and Canada, respectively) that refer to the same definition of biological products as “biosimilars.” In this chapter the term “biosimilar” has been adopted since it is the most broadly used term associated with copies of biological reference products. Nonclinical Development of Novel Biologics, Biosimilars, Vaccines and Specialty Biologics. http://dx.doi.org/10.1016/B978-0-12-394810-6.00005-8
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Development of biosimilar products encompasses great challenges on two fronts, the first related to the very complex nature of biopharmaceutical entities and the second linked to the multifaceted and highly protected manufacturing processes of these molecules. While information about any biopharmaceutical molecular structure becomes publicly known upon the receipt of marketing authorization, information about biopharmaceutical manufacturing and purification processes, specifications, and raw materials used is proprietary and not available in the public domain. Moreover, for many biopharmaceutical products patent protection is separate for the molecular structure and the formulation of the product, and patent for the formulation may last beyond the expiration of patent for the structure of the molecule. Biosimilar manufacturers do not have access to the innovator’s DNA clone or original cell bank and must engineer and clone a new cell line to produce a copy of the original product. Overall, biosimilar manufacturers face a certain “knowledge gap” regarding the development history and database with critical quality product attributes of the innovator’s product.
THE CONCEPT OF BIOSIMILARS In the past few decades most scientific discussions related to the development of novel biologics were focused on establishing optimal scientific and regulatory approaches to their safety evaluation, particularly in nonclinical and early clinical phases of the drug development process. These fruitful discussions and shared experience resulted in the generation of regulatory guidelines [1] and publications [2] that solidified the principles applied in the development of biopharmaceuticals. Since a large number of biological products have become very effective medicines and financially successful, recently the debate has been shifted toward the possibility of the development of biosimilar drugs. Clearly, there are two opposite positions within the biopharmaceutical industry and its representative organizations that influence the debate. The proponents state that the development and commercialization of biosimilars has become reality and these drugs can help address unmet medical needs by improving access to well-established therapeutic interventions by improving their affordability. However, this goal can only be achieved when an abbreviated, less costly development paradigm under a new regulatory framework is in place [3,4]. The opponents claim that the limited testing of biosimilar candidates, especially in the clinic, is insufficient to ensure the same safety and efficacy profile of biosimilars when compared to the clinically proven benefits of marketed reference products [5]. According to this view, a quite extensive nonclinical and clinical evaluation of biosimilar candidates should be required before their approval for marketing, which would maintain the high cost of the development and effectively prevent the emergence of biosimilars. From the scientific point view, the development of biosimilars involves reversed protein engineering of the reference product, generation of the best feasible copy of the reference product using updated biotechnology methods, and an extensive comparative characterization of the reference and the biosimilar candidate using state-of-the-art techniques. Given that at least a decade may have passed between the generation and testing of the original biologic molecule and the biosimilar, more advanced technology than what the innovator was able to use during the development of the original biopharmaceutical would likely be in place. Because of inevitable changes in both biotechnology processes and characterization methods
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over time and the intention to decrease the cost of manufacturing, a biosimilar candidate cannot be an exact replica of the innovator product. Chemistry, Manufacturing, and Control (CMC) processes required in the development of biological drugs are equally fundamental for both novel biologics and biosimilars, and need to be conducted according to the existing regulatory guidelines and standards. Twelve ICH documents have been put in place to address quality and CMC processes involved in the characterization and manufacturing of biopharmaceuticals [6–17], reflecting both the complexity of these products and the high regulatory scrutiny surrounding their quality. One fundamental difference in the development of a novel biologic drug candidate versus a biosimilar candidate is the extent of nonclinical and clinical studies. For the original novel biologic, it must be demonstrated in multiple animal and human studies that it will have the intended pharmacological properties and a good safety profile in relationship to its biochemical and physical characteristics. As these characteristics have been already established, for a biosimilar candidate, deemed to be a satisfactory copy of the reference product based on results generated in the CMC space, the goal is to confirm in relevant but limited studies that the pharmacological activity, efficacy, and safety profile is highly similar to its original biologic counterpart. In order to achieve this goal, great efforts are being made to understand the relationship between recombinant protein structure and CMC processes as well as potential consequences of small changes in CMC on functional characteristics and clinical activity of biotechnology products. As such, the challenges in the development of biosimilars may actually lead to scientific advances and innovation in biotechnology. The development of biosimilars is difficult not only because of the structural complexity of biologic drugs but also because the original biologic products often undergo changes in their manufacturing processes over the course of a product life cycle (i.e. after obtaining the marketing authorization). Manufacturers make post-marketing changes for many different reasons including manufacturing capacity, improving purity, increasing product yield, or optimizing the cost of goods [18]. When such manufacturing process changes are made, a manufacturer is mandated to demonstrate that the product pre- and post-change has comparable “identity, strength, quality, purity, and potency” [19] and the safety and efficacy data derived from nonclinical and clinical testing during the development of the pre-change product are relevant to the post-change product. The process of assuring product consistency pre- and post-change has been referred to as a “comparability” evaluation. To separate this comparability process performed within the same manufacturer (innovator) from the exercise involved in comparing characteristics of a biosimilar candidate with its reference product by another manufacturer (biosimilar developer) who, unlike the innovator, does not possess historical knowledge of the manufacturing processes involved in making the original product, the term “similarity” is applied to the comparative evaluation of biosimilars. Technically, however, it is difficult to distinguish between bioanalytical “comparability” and “similarity” as they involve the same parameters to determine quality characteristics of two biological products when tested side-by-side. In fact, the demonstration of biosmilarity requires both analytical comparability and similarity evaluation. The former involves the comparison of multiple lots of the innovator product to establish a range of product variance. The latter involves the comparison of the biosimilar candidate to the innovator product to confirm that multiple quality attributes remain inside the variability brackets (between the lowest and the highest values) for multiple lots of both products.
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Biosimilarity studies performed in recent years have shown that different lots of marketed biopharmaceuticals (e.g. rituximab, entanercept) can substantially vary in some attributes, such as glycosylation patterns due to process changes implemented during post-marketing manufacturing [3]. However, the analytically detectable changes did not appear to have any impact on the therapeutic (safety and efficacy) attributes of these biological drugs. This observation suggests that some degree of structural differences in biologics may be functionally inconsequential and, therefore, acceptable. On the other hand, biologic product safety and efficacy, primarily affected by increased immunogenicity, can be altered in the post-marketing phase by undetectable or unforeseen factors related not only to manufacturing process changes but also to modifications in formulation, container closure systems as well as in-use stability profiles. Each of these factors can affect product characteristics, including immunogenic potential [20,21]. Notably, aggregation in biologic drugs has been implicated as a critical factor in the induction of an immunogenic reaction and potential autoimmunity. The most discussed example of unforeseen increased immunogenicity, likely related to a change in the product formulation and its closure system, resulting in antibody-mediated pure red cell aplasia is Eprex, a recombinant human erythropoietin [22]. This case indicates that small differences in certain attributes of biological products can occur, despite the existing manufacturer’s experience in well-controlled and seemingly understood manufacturing process, and can have a detrimental impact on safety of the product after its approval. It is postulated that if some variability in quality attributes exists for the original biologic product manufactured based on acquired in-depth knowledge of the process, the probability of introducing much greater variability into its biosimilar counterpart is undoubtedly higher. The burden to prove that this postulate may not necessarily be true, upon application of high-quality reverse protein engineering and bioprocess expertise [3], is on biosimilar developers. In summary, existing experience in the development and approval of novel biopharmaceuticals, including comparability of pre- and post-change evaluation, is highly related and applicable to the emerging experience in the development and approval of biosimilars. Based on current scientific knowledge in characterization of the complex structure of biopharmaceuticals, detection of a small structural difference alone may or may not be meaningful and a “totality of the evidence” approach has been introduced as the most appropriate for assessing biosimilars [23].
GENERAL CONSIDERATIONS FOR DEVELOPMENT OF BIOSIMILARS The development of biosimilars requires significant resource investment in establishing manufacturing processes (bioprocess) and analytical method development to enable production and comparative characterization of the molecular structure and quality attributes of the target reference product and its copy. The early phase of biosimilar development is more extensive than the early development of novel biologics because it involves extensive analytical characterization of two products—the innovator and the biosimilar candidate. It may also be quite costly because of the necessity of purchasing a large quantity of the reference product, often manufactured at different sites and marketed as multiple versions in different countries, to be used in comparative evaluation. Thus, CMC work on biosimilars requires not only the development of a consistent and well-controlled manufacturing process of the biosimilar
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product itself but also extensive comparative side-by-side analyses of procured reference product lots and manufactured biosimilar candidate batches. Once the analytical characterization of the intended biosimilar candidate and the reference product has demonstrated a “highly similar quality profile” as described in the European Medicines Agency (EMA) guidance [24], the extent of nonclinical and clinical studies with the biosimilar candidate should be reduced compared to the development of novel biopharmaceuticals as the clinical efficacy and safety of the reference product is well understood. However, the challenge is to define “highly similar” in light of expected or detected structural variance between the reference product and its biosimilar, and to know “how similar is similar enough” as addressed by Kozlowski et al. [23]. The comparative nonclinical and clinical studies with a proposed biosimilar and the reference product should be designed to detect potential small differences and to minimize uncertainty around whether or not the detected differences could translate to any meaningful difference between the tested products in their clinical application. A biosimilarity assessment is typically performed in a stepwise manner as recommended by new regulatory guidelines described in Chapter 2. Comparison of the proposed biosimilar product and the reference product includes the evaluation of structure, function, animal pharmacokinetics (PK), pharmacodynamics (PD), and toxicity, human PKPD, safety, efficacy, and immunogenicity.
Comparative Nonclinical Studies The aim of comparative studies is to identify (qualitatively and quantitatively) potential differences in product attributes between the biosimilar candidate and reference product. In vitro tests Extensive structural and functional characterization is the first and most critical step in the development of biosimilars. This characterization requires the establishment of multiple in vitro assays and product-specific reagents as well as assay qualification and/or validation. Methods and model systems need to be tailored to a specific biologic product. In addition, the selected methods need to be demonstrated as capable of detecting small differences in all aspects of biochemical characterization of biologics. The conduct of comparative studies involves multiple batches of the biosimilar candidate and commercial lots of the innovator products. Using appropriate analytical methods with adequate sensitivity and specificity for structural characterization of the proteins, the comparisons of the biosimilar candidate and reference product should include: primary structures, such as amino acid sequence, higher order structures, including secondary, tertiary, and quaternary structure, post-translational modifications, such as glycosylation and phosphorylation, and other potential protein changes that can involve unintentional (e.g. deamidation and oxidation during storage) or intentional chemical modifications (e.g. PEGylation). Functional assays need to be designed to characterize pharmacologic activity of the biosimilar candidate in comparison to the reference product. These assays typically include cell-based assays (bioassays) and binding assays involving many different techniques (e.g. immunoassays) to evaluate potency of tested products. By nature, functional assays are highly variable and require careful optimization of testing conditions before they can be reliably used in comparative testing.
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If rigorous structural and functional comparisons in in vitro studies show minimal or no difference in these assays, the probability of achieving an adequate biosimilar candidate is high and the next step of in vivo evaluation is pursued. In vivo pharmacology, PK and PD studies Theoretically, a high degree of similarity between the biosimilar candidate and the reference product demonstrated by in vitro studies should allow for the reduction in the number of required in vivo tests. In practice, however, many animal studies are conducted for most biosimilar candidates to build a strong comparative database and maximize similarity information. Typically, at least one animal disease model is developed to conduct comparative pharmacology (efficacy) studies using multiple versions of the reference product and biosimilar candidate. For example, a neutropenic mouse model for the evaluation of granulocyte colony-stimulating factor activity, murine xenograft tumor models for comparison of the activity of anticancer monoclonal antibodies, and rheumatoid arthritis models in transgenic mice expressing human tumor necrosis factor (TNF) for the evaluation of TNF inhibitors have been used in the development of pertinent biosimilar candidates. Sometimes the animal models are newly established during the development of a biosimilar candidate because such models were not available at the time the innovator biologic was developed. Because of the comparative nature of these studies, they are rather costly as they require a large number of animals and the procurement of the innovator products. Similar to in vitro testing, if several versions of the reference product are marketed in different countries it is prudent to use multiple lots/versions of the reference product in the in vivo evaluation to determine the variability range of animal responses to this product. In addition to animal pharmacology experiments in disease models, similarity in PKPD characteristics between the biosimilar candidate and its reference product (multiple versions if applicable) is also assessed in normal healthy animals. In order to perform animal PKPD studies for comparative purposes, appropriate product-specific assays have to be developed and qualified by a biosimilar developer. Small differences in quality and/or in vitro functional characteristics between the reference product and the biosimilar candidate are typically detectable and should be expected. Small inconsistencies in animal pharmacology, PK and/or PD studies could also be observed, including some variation between multiple lots of the reference product. Therefore, the identified dissimilarities may or may not represent any meaningful differential response to the biosimilar candidate compared to the reference product and they are often confounded by natural inter-animal variability, including an immune response to a human biologic (i.e. immunogenicity of the tested products). When some differences between the biosimilar candidate and the reference product are observed (greater than the range of variability between reference lots) in PKPD animal studies, additional (larger) studies may be needed to understand the nature of the found variance. When animal testing does not reveal any significant difference between the biosimilar candidate and its reference product in side-by-side comparative studies, the confidence in developing of an adequate biosimilar product is increased. The most likely scenario (based on personal communication) in the development of biosimilars is that small CMC differences are detectable using in vitro assays (outside their variability range) while in vivo PKPD comparative studies do not show significant changes (beyond the natural or explainable variability) between the biosimilar candidate and the reference
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product. This scenario is in contrast to the position presented in the past that in vitro analytical methods used in characterization of biologics are less sensitive in detection of potential differences than the whole host (in vivo). A shift in thinking about the reliance on in vitro testing in comparative studies is evident in new regulatory guidelines for biosimilars [25,26]. Toxicology studies To address any uncertainty about translation of small CMC differences to the safety profile of a biosimilar candidate, a toxicology study is typically expected. Since the safety profile of the reference product is well understood in humans, the extent of the nonclinical toxicology program in the development of a biosimilar to support its clinical testing and registration should be abbreviated when compared to the toxicology program performed during the development of the reference product. At the same time, a toxicology program for a biosimilar candidate needs to be guided by information generated for the pertinent reference product and utilize product-specific approaches. Typically, one repeated dose toxicology study, comparative in nature in the same animal species as that used by the innovator, is conducted. The study design, including dose levels, frequency, and duration of dosing should be driven by results of the pivotal toxicity study performed by the innovator. Although a toxicity study with a biosimilar candidate should be based on product-specific characteristics, experience in toxicological sciences indicates that generally a repeat-dose study of a minimum duration of one-month in which the biosimilar and the reference product are tested side by side is considered sufficient. Such a study is quite resource intensive as it requires many groups of animals and the procurement of large amounts of the reference product. Unlike pharmacology and PKPD studies that include multiple lots/versions of the reference product, in toxicology studies testing one version of the reference product is considered sufficient based on guidelines for animal use and/ or data generated from comparative PKPD assessments. Regarding the biosimilar candidate material to be tested in a comparative toxicology study, it is highly desirable to use drug product from the optimized manufacturing process that is representative of the material to be tested in pivotal clinical trials designed to evaluate the safety profile of the biosimilar candidate. Typically, no other toxicology studies (i.e. safety pharmacology, chronic toxicity, reproductive and developmental toxicity) are expected for biosimilars unless there is a specific cause for concern. Additional consideration should be given when no toxicity was detected in animal studies performed by the innovator during the development of the reference product (e.g. TNFα inhibitors) and where no differences between the biosimilar candidate and the reference product are identified upon nonclinical comparative characterization using both in vitro (according to the current standards of quality testing) and in vivo (including PKPD) studies. It is highly debatable that a comparative toxicology study should be conducted in such a scenario. The regulatory guidelines for biosimilars [25,26] indicate that the lack of a comparative (presumably in the situation described above) or any toxicology study with a biosimilar candidate (e.g. due to lack of relevant toxicology species) can be justified by sponsors developing biosimilars. Limited experience to date (based on personal communication) suggests that comparative toxicology studies do not detect any meaningful differences (beyond the natural or explainable variability) between biosimilar candidates and their reference products even when some degree of “dissimilarity” in other nonclinical characterization has been observed.
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Comparative Clinical Studies Clinical development of biosimilars, although abbreviated, is still fairly extensive. The clinical program should always include at least one human comparative study using the biosimilar and the reference product side by side. The number and type of additional studies with the biosimilar candidate to confirm the expected efficacy and safety in patients can vary based on the characteristics of the reference products. The clinical studies provide the ultimate data to support the evidence of similarity between the biosimilar candidate and the reference product. The comparative nature of clinical studies with a biosimilar is focused on bioequivalence and requires new clinical trial expertise compared to conventional clinical trials, in which efficacy and safety are measured against placebo controls. In addition, most clinical trial investigators, primarily researchers at university hospitals, are much more interested in studying novel drug candidates than evaluating copies of the existing medicines, as the latter does not satisfy their pursuit of advancing clinical sciences. In some cases, where competition for patient enrollment in certain diseases is very high, clinical investigators are deeply critical of trials with biosimilars, viewing them as “stealing” patients from “real” clinical trials. This point of view can be countered, however, by the fact that in a comparative trial with the biosimilar candidate and the reference product, all patients benefit from being treated by a pharmacologically active and efficacious agent with no chance of being exposed to a placebo control, which does not provide any therapeutic effect. On top of such disputes, the new regulatory guidelines for biosimilars, either finalized or drafted [25–27], outline stringent requirements for clinical trials that should include a dose–response comparison between the biosimilar and the reference product, testing the most sensitive patient population to detect potential differences, and long-term monitoring of immunogenicity both prior to registration and during the post-marketing period. Also, the guidelines recommend using drug product from a large-scale commercial manufacturing process that is fully defined prior to the start of clinical trials. While such a rigorous evaluation would minimize any uncertainties associated with the approval of biosimilars, it will also minimize incentives and justification for investments in the development of biosimilars in light of only small reduction in costs compared to the development of new biologic entities. Because of this conundrum, the regulatory requirements for clinical development of biosimilars are still evolving and incomplete.
BIOSIMILAR CANDIDATES BASED ON MODALITY AND THERAPEUTIC CLASS Biopharmaceuticals include many different types of molecular constructs and can be grouped in three major categories: (1) therapeutic proteins (e.g. enzymes, hormones, cytokines); (2) monoclonal antibodies (mAbs), and modifications thereof, such as, mAbs conjugated to chemicals or immunoglobulin fragments (e.g. Fab); and (3) fusion proteins involving the Fc portion of immunoglobulin linked to other recombinant proteins. Lists of marketed biologics in these three categories are presented in Tables 5.1 (A, B, C) and 5.2 (A, B, C). Another categorization of biopharmaceuticals can be based on therapeutic area and disease indication. The major classes of biopharmaceuticals include drugs for treatment of cancer,
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TABLE 5.1 Biopharmaceuticals Approved for Marketing (US) in 1983–2005 Generic name (brand name) Year
Target /ligand
Indication
Therapeutic area
Interferon α-2b (Intron A) 1983
Interferon alfa-2b
Leukemias, melanoma, hepatitis C, hepatitis B
Oncology, infectious diseases
Interferon α-2a (Roferon A) 1984
Interferon alfa-2a
Leukemias, hepatitis C
Oncology, infectious diseases
Somatropin (Humatrope) 1987
Growth hormone
Growth hormone deficiency
Endocrinology
Interferon α-N3 (Alferon) 1989
Interferon alfa-N3
Genital warts
Various
Filgrastin (Neupogen) 1991
Granulocyte colony-stimulating factor Neutropenia (G-CSF)
Oncology and others
Sargramostim (Leukine) 1991
Granulocyte macrophage colonystimulating factor (GM-CSF)
Oncology
Aldesleukin (Proleukin) 1992
Interleukin-2 (IL-2) receptor on T and Metastatic renal cell carcinoma NK cells
Oncology
Dornase alpha (Pulmozyne) 1993
DNase
Cystic fibrosis
Pulmonary diseases
Epoetin alpha (Epogen/Procrit) 1993
Erythropoietin
Anemia
Oncology and others
Imiglucerase (Cerezyme) 1994
Glucocerebrosidase
Gaucher’s disease
Enzyme replacement therapy
Asparaginase (Elspar) 1994
l-Asparaginase
Acute lymphocytic leukemia
Oncology
Pegasparagase (Oncaspar) 1994
Pegylated l-asparaginase
Acute lymphoblastic leukemia
Oncology
Somatropine (Genotropine) 1995
Growth hormone
Growth hormone deficiency
Endocrinology
Alteplase (Activase) 1996
Tissue plasminogen activator
Restoration of function of central venous access devices
Cardiovascular diseases
A. THERAPEUTIC PROTEINS
Interferon beta-1a
Multiple sclerosis
Inflammation/autoimmunity
Mutation of tissue plasminogen activator
Acute myocardial infarction
Cardiovascular diseases
Follitropin (Follistim) 1997
Follicle-stimulating hormone
Infertility
Reproductive system
Interferon alphacon (Intergen) 1997
Interferon type 1
Hepatitis C
Infectious diseases
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Interferon β-1a (Avonex) 1996 Reteplase (Retavase) 1996
Biosimilar Candidates Based on Modality and Therapeutic Class
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Chemotherapy-related acute myelogenous leukemia
Continued
Generic name (brand name) Year
Target /ligand
150
TABLE 5.1 Biopharmaceuticals Approved for Marketing (US) in 1983–2005 (cont’d)
Indication
Therapeutic area
Interleukin-11 (IL-11)
Thrombocytopenia in chemotherapy
Oncology
Glucagon (Glucagen) 1998
Glucagon hormone
Hypoglycemic reactions in diabetic patients
Endocrinology
Interferon γ-1b (Actimune) 1999
Interferon gamma-1b
Infections with chronic granulomatous diseases, malignant osteoporosis
Infectious diseases, oncology
Insulin glargine (Lantus) 2000
Long-acting insulin
Diabetes
Endocrinology
Insulin aspart (Novolog) 2000
Rapid-acting insulin
Diabetes
Endocrinology
Tenecteplase (Tnkase) 2000
Tissue plasminogen activator
Myocardial infarction
Cardiovascular diseases
Darbepoetin alpha (Aranesp) 2001
Erythropoietin
Anemia
Oncology and others
Anakinra (Kineret) 2001
IL-1 receptor antagonist
Rheumatoid arthritis
Inflammation/autoimmunity
Drotrecogin alpha (Xigris) 2001
Activated protein C
Sepsis
Infectious diseases
PegInterferon α-2b (Peg-Intron) 2001
Interferon alfa-2b, pegylated
Hepatitis C
Infectious diseases
Interferon β-1a (Rebif) 2002
Interferon beta-1a, pegylated
Multiple sclerosis
Inflammation/autoimmunity
PegInterferon α-2a (Pegasys) 2002
Interferon alfa-2a, pegylated
Hepatitis C, hepatitis B
Infectious diseases
Pegfilgrastim (Neulasta) 2002
Pegylated G-CSF
Neutropenia
Oncology and others
Rasburicase (Elitek) 2002
Urate oxidase
Cancer-related hyperuricemia
Oncology
Teriparatide (Forteo) 2002
Parathyroid hormone
Osteoperosis
Bone diseases
Agalisdase beta (Fabrazyme) 2003
Alpha galactosidase
Fabry’s disease
Enzyme replacement therapy
Interferon β-1b (Betaseron) 2003
Interferon beta-1b
Multiple sclerosis
Inflammation/autoimmunity
Laronidase (Adlurazyme) 2003
α-l-iduronidase
Mucopolysaccharidosis I
Enzyme replacement therapy
Insulin glulisine (Apidra) 2004
Rapid-acting insulin
Diabetes
Endocrinology
Palifermin (Kepivance) 2004
Keratinocytes growth factor
Oral mucotitis in cancer
Oncology
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Oprelvekin (Neumega) 1997
Insulin (Levemir) 2005
Long-acting basal insulin
Diabetes
Endocrinology
Galsulfase (Naglazyme) 2005
N-Acetylgalactosamine 4-sulfase
Mucopolysaccharidosis VI
Enzyme replacement therapy
Mecasermin, (Increlex) 2005
Insulin growth factor-1 (IGF-1)
Growth failure secondary to severe primary IGF-1 deficiency
Endocrinology
Muromomab (Orthoclone OKT3) 1992
T-cell surface protein CD3 antagonist (murine antibody)
Rejection of transplanted organs
Organ transplant
Abciximab (Reopro) 1997
Platelet glycoprotein GpIIbIIIa receptor (Fab fragment) antagonist
Acute blood clot complications
Cardiovascular diseases
Daclizumab (Zenapax) 1997
IL-2 receptor (IL-2R, CD25) antagonist Rejection of transplanted organs
Organ transplant
Rituximab (Rituxan) 1997
B-cell surface protein CD20 antagonist
Non-Hodgkin’s lymphoma, rheumatoid arthritis
Oncology, inflammation/ autoimmunity
Trastuzumab (Herceptin) 1997
Human epidermal growth factor receptor 2 (HER2) antagonist
Breast cancer
Oncology
Infliximab (Remicade) 1998
Tumor necrosis factor (TNF) alpha antagonist
Rheumatoid arthritis, Crohn’s disease, psoriatic arthritis, ankylosing spondylitis, psoriaris
Inflammation/autoimmunity
Basiliximab (Simulect) 1998
IL-2R alpha chain (CD25) antagonist
Organ transplant
Immunology
Palivizumab (Synagis) 1998
F protein of respiratory syncytial virus (RSV) antagonist
Prophylaxis of serious lower respiratory tract disease
Infectious diseases
Gemtuzumab ozogamicin (Mylotarg) 2000
Anti-CD33 conjugated with calicheamicin
Acute myeloid leukemia
Oncology
Alemtuzumab (Campath) 2001
B-cell surface protein CD52 antagonist
B-cell chronic lymphocytic leukemia
Oncology
Adalimumab (Humira) 2002
TNF alpha antagonist
Rheumatoid arthritis, Crohn’s disease Inflammation/autoimmunity
Ibritumomab tiuxetan (Zevalin) 2002
Anti-CD20 linked to radioactive yttrium-90
Non-Hodgkin’s lymphoma
Oncology
131I-Tositumomab
Anti-CD20 linked to radioactive iodine-131
Non-Hodgkin’s lymphoma, chronic lymphocytic leukemia
Oncology
B. MONOCLONAL ANTIBODIES
151
Continued
Biosimilar Candidates Based on Modality and Therapeutic Class
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(Bexxar) 2003
152
TABLE 5.1 Biopharmaceuticals Approved for Marketing (US) in 1983–2005 (cont’d)
Target /ligand
Indication
Therapeutic area
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Efalizumab (Raptiva) 2003
Integrin lymphocyte functionassociated antigen-1 (CD11a) antagonist
Psoriasis
Inflammation/autoimmunity
Omalizumab (Xolair) 2003
IgE antagonist
Asthma
Pulmonary diseases
Bevacizumab (Avastin) 2004
Vascular endothelial growth factor (VEGF) antagonist
Colorectal cancer
Oncology
Cetuximab (Erbitux) 2004
Epidermal growth factor receptor (EGFR) antagonist
Colorectal cancer
Oncology
Etanercept (Enbrel) 1998
TNFalpha (TNFR:Fc) antagonist
Rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, psoriaris
Inflammation/autoimmunity
Alefacept (Amevive) 2003
Leukocyte function antigen-3 (LFA3:Fc) antagonist
Psoriasis
Inflammation/autoimmunity
C. FUSION PROTEINS
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Generic name (brand name) Year
153
Biosimilar Candidates Based on Modality and Therapeutic Class
TABLE 5.2 Biopharmaceuticals Approved for Marketing (US) after 2005 Generic name (brand name) Date
Target/ligand
Indication
Therapeutic area
A. THERAPEUTIC PROTEINS Alglucosidase α (Myozyme) 2006
Alglucosidase alpha
Pompe diseases
Enzyme replacement therapy
Insulin (Exubera) 2006
Glucose metabolism
Type 1 or type 2 diabetes
Endocrinology
Idursulfase (Elaprase) 2006
Idursulfase
Hunter syndrome mucopolysaccharidosis II
Enzyme replacement therapy
Somatropine (Omnitrope) 2006
Sustained release of growth hormone
Growth failure
Endocrinology
PegEpo (Mircera) 2007
Methoxy polyethylene glycol-epoetin beta
Anemia associated with chronic renal failure
Various
Ecallantide (Kalbitor) 2009
Plasma kallikrein inhibitor
Hereditary angioedema
Genetic disorders
Pegloticase (Krystexxa) 2010
Pegylated uricase
Refractory chronic gout
Inflammation/ autoimmunity
B. MONOCLONAL ANTIBODIES Natalizumab (Tysabri) 2006
Integrin alpha4beta1 antagonist
Multiple sclerosis
Inflammation/ autoimmunity
Panitumumab (V Ectibix) 2006
EGFR1 antagonist
Colorectal cancer
Oncology
Ranibizumab (Lucentis) 2006
VEGF-R antagonist (antibody fragment)
Macular degeneration, agerelated, wet; Retinal vein occlusion; Edema
Ophthalmology
Eculizumab (Soliris) 2007
Complement factor C5 inhibitor
Hemolytic anemia, hemolytic uremic syndrome
Hematology
Certolizumab pegol (Cimzia) 2008
TNFalpha antagonist (pegylated Fab fragment)
Crohn’s disease, rheumatoid arthritis
Inflammation/ autoimmunity
Canakinumab (Ilaris) 2009
IL-1beta antagonist
Muckle–Wells syndrome, familial cold autoinflammatory syndrome, neonatal onset multisystem inflammatory disease
Inflammation/ autoimmunity
Golimumab (Simponi) 2009
TNFalpha antagonist
Rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis
Inflammation/ autoimmunity
Ofatumumab (Arzerra) 2009
B-cell CD20 antagonist
Chronic lymphocytic leukemia
Oncology
Ustekinumab (Stelara) 2009
IL-12/IL-23 antagonist
Psoriasis
Inflammation/ autoimmunity Continued
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TABLE 5.2 Biopharmaceuticals Approved for Marketing (US) after 2005 (cont’d) Generic name (brand name) Date
Target/ligand
Indication
Therapeutic area
Denosumab (Xgeva, Prolia) 2010
Receptor activator of nuclear factor kappa-B ligand (RANKL) antagonist
Osteoporosis, bone regeneration (cancer-related bone loss)
Bone diseases
Tocilizumab (Actemra) 2010
IL-6R antagonist
Castleman’s disease, rheumatoid arthritis, juvenile arthritis
Inflammation/ autoimmunity
Belimumab (Benlysta) 2011
BLyS (B-cell survival factor) antagonist
Systemic lupus erythematosus, rheumatoid arthritis
Inflammation/ autoimmunity
Brentuximab Vendotin (Adcetris) 2011
Anti-CD30 (cell surface protein) conjugated to monomethyl auristatin
Refractory Hodgkin lymphoma
Oncology
Ipilimumab (Yervoy) 2011
CTLA-4 (extracellular domain) antagonist
Melanoma
Oncology
Abatacept (Orencia) 2006
T-cell CD80/CD86 co-stimulation (CTLA4:Fc) inhibitor
Rheumatoid arthritis
Inflammation/ autoimmunity
Rilonacept (Arcalyst) 2008
IL-1 receptor (IL-1R:Fc) antagonist
Cryopyrin-associated periodic syndromes
Inflammation/ autoimmunity
Romiplastim (Nplate) 2008
Thrombopoietin (TPO:Fc) receptor agonist
Chronic immune thrombocytopenia
Inflammation/ autoimmunity
Aflibercept (Eylea) 2011
VEGF trap (specific domain of VEGFR1/ VEGFR2:Fc)_
Neovascular (wet) age-related Ophthalmology macular degeneration
Belatacept (Nulojix) 2011
Cytotoxic T-cell inhibitor via CD28: CD80/CB86 interaction (extracellular CTLA-4:Fc)
Kidney transplant rejection
C. FUSION PROTEINS
Organ transplant
inflammatory, and autoimmune diseases, metabolic disorders, enzyme and hormone deficiencies, and others (Tables 5.1 and 5.2). The tables include biologic products approved for marketing in the US as new biological entities (NBE) in chronological order, allowing for the appreciation of evolutionary changes in the range and types of biotechnology-derived medicines. Some of the changes are focused on improving convenience of biologic drug administration (e.g. by pegylation of recombinant proteins, their half-life has been prolonged and frequency of parenteral administration reduced). Other modifications are focused on expanding disease indications by changing target binding specificity through additional engineering
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of biologic constructs. Such modifications could be made by the same innovator or a competitor, but in each case a new application for approval as a NBE had to be filed and marketing authorization received. A number of marketed biologics, with the expired or imminent loss of patent protection, have been selected as targets for biosimilars based on high revenues. In contrast to the desired and deliberate modifications to improve biologic products that are already effective therapeutics, biosimilars can not intentionally be modified. The first wave of biosimilars approved in EU markets represents a class of therapeutic proteins and include growth hormone (somatotropin), erythropoietin (epoetin), and granulocyte colony-stimulating factor (filgrastim). Based on publication of specific guidance for biosimilars to insulin and interferon [28,29] one can assume that biosimilar candidates to marketed insulin products and interferon products may be in development. The “blockbuster” biologics include several mAbs to treat inflammatory diseases and cancer, and these drugs are expected to be targets for biosimilars upon their patent expiration. The mAbs that may face competition from the development of their biosimilars include TNFblocking products (e.g. adalimumab), anti-CD20 antibody (rituximab), anti-HER2 antibody (trastuzumab), and anti-VEGF (bavacizumab). Particulars related to the nonclinical development of biosimilars, mainly to selected marketed therapeutic proteins, are discussed in Chapter 3.
SUMMARY Global interest in access to lower cost biopharmaceuticals in the form of biosimilars aligns with the concept of generic medications for chemical pharmaceuticals. However, based on experience to date, development of biosimilars poses much greater challenges not only due to demanding requirements in clinical development, but also uncertainty in manufacturing and marketing capabilities. The development costs of a biosimilar, while lower than the cost of developing a novel biopharmaceutical, are still high. Manufacturing capabilities that require sophisticated facilities, technologies, and processes have proven to be elevated barriers to developing biosimilars. Interactions with physicians and healthcare providers require new resources in educational processes both prior to conduct of clinical trials and after obtaining marketing authorization. Sales teams need to acquire deeper medical and technical knowledge to explain why biosimilars are not generic substitutions of their original biopharmaceutical counterparts and yet should be trusted as equally safe and efficacious medicines. Likewise, investment in market strategies to meet required post-marketing surveillance is very significant. Lastly, slowly shaping regulatory framework, especially in the US, makes the investments quite risky. Nonetheless, growing interest in biosimilars in emerging markets, including India, China, and Brazil, where health authorities have published or drafted their own guidelines, will likely increase investments in biosimilars in those regions. In conclusion, the value proposition of biosimilars is complex and has to be addressed by the full range of stakeholders, including manufacturers, regulators, physicians, payers, and patients. If development, registration, and marketing of biosimilars become broadly successful, it will likely happen over the long term.
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References [1] ICH. ICH S6(R1) Preclinical Safety Evaluation of Biotechnologically-Derived Pharmaceuticals. www.ich.org/ products/guidelines/safety/article/safety-guidelines.html. Fed Reg 2012;77(97):29665–6; May 18, 2012. [2] Cavagnaro Joy A, editor. Preclinical Safety Evaluation of Biopharmaceuticals: A Science-Based Approach to Facilitating clinical Trials. Hoboken, NJ: John Wiley & Sons; 2008. [3] McCamish M, Woollett G. The state of the art in the development of biosimilars. Clin Pharmacol Ther 2011;343:1–3. [4] Schneider CK, Kalinke U. Toward biosimilar monoclonal antibodies. Nat Biotechnol 2008;26:985–90. [5] Davis GC, Beals JM, Johnson C, Mayer MH, Meiklejohn BI, Mitak BH, et al. Recommendations regarding technical standars for follow-on biologics: Comparability, similarity, interchangeability. Commentary. Curr Med Res Opin 2009;25:1655–61. [6] ICH. ICH Q2(R1) Validation of Analytical Procedures. Text and Methodology. CPMP/ICH281/95. www.ich. org/products/guidelines/quality/article/quality-guidelines.html; 1996. [7] ICH. ICH Q3A(R2) Impurities in New Drug Substances. CPMP/ICH/142/95. www.ich.org/products/ guidelines/quality/article/quality-guidelines.html; 2006. [8] ICH. ICH Q5A(R1) Viral Safety Evaluation of Biotechnology Products Derived from Cell Lines of Human or Animal Origin. PMSB/ELD Notification No. 329. www.ich.org/products/guidelines/quality/article/qualityguidelines.html; 1999. [9] ICH. ICH Q5B Quality of Biotechnological Products: Analysis of the Expression Construct in Cells Used for Production of r-DNA Derived Protein Products. CPMP/ICH/139/95. www.ich.org/products/guidelines/ quality/article/quality-guidelines.html; 1995. [10] ICH. ICH Q5C Stability Testing of Biotechnological/Biological Products. CPMP/ICH/138/95. www.ich.org/ products/guidelines/quality/article/quality-guidelines.html; 1995. [11] ICH. ICH Q5D Quality of Biotechnological/Biological Products: Derivation and 662 Characterization of Cell Substrates Used for Production of Biotechnological/Biological Products. CPMP/ICH/294/95Q5D. www.ich. org/products/guidelines/quality/article/quality-guidelines.html; 1997. [12] ICH. ICH Q5E. Comparability of Biotechnological/Biological Products Subject to Changes in their Manufacturing Process. www.ich.org/products/guidelines/quality/article/quality-guidelines.html; 2004. [13] ICH. ICH Q6B Specifications: Test Procedures and Acceptance Criteria for 669 Biotechnological/Biological Products. CPMP/ICH/365/96. www.ich.org/products/guidelines/quality/article/quality-guidelines.html; 1999. [14] ICH. ICH Q7 Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients. CPMP/ ICH/4106/00. www.ich.org/products/guidelines/quality/article/quality-guidelines.html; 2000. [15] ICH. ICH Q8(R2) Pharmaceutical Development 674 675 19. CHMP/ICH/167068/0417. www.ich.org/products/ guidelines/quality/article/quality-guidelines.html; 2009. [16] ICH. ICH Q9 Quality Risk Management. EXT/24235/2006. www.ich.org/products/guidelines/quality/ article/quality-guidelines.html; 2005. [17] ICH. ICH Q10 Pharmaceutical Quality System. CHMP/ICH/214732/04. www.ich.org/products/guidelines/ quality/article/quality-guidelines.html; 2008. [18] Lewis RM. Demonstration of comparability of a lincensed product after a manufacturing change. In: Cavagnaro Joy A, editor. Preclinical Safety Evaluation of Biopharmaceuticals: A Science-Based Approach to Facilitating Clinical Trials. Hoboken, NJ, 8: John Wiley & Sons; 2008. p. 161–78. [19] US FDA. FDA Guidance Concerning Demonstration of Comparability of Human Biological Products, Including Therapeutic Biotechnology-derived Products. www.fda.gov/cder/Guidance/compare.htm; 1996. [20] Hermeling S, Crommelin DJ, Schellekens H, Jiskoot W. Structure-immunogenicity relationships of therapeutic proteins. Pharm Res 2004;21:897–903. [21] Chirino AJ. Minimizing the immunogenicity of protein therapeutics. Drug Discov Today 2004;9:82–90. [22] Schellekens H, Crommelin DJ. Equivocal role of micelles in Eprex adverse events. Nat Biotechnol 2003;21: 1255–62. [23] Kozlowski S, Woodcock J, Midhun K, Behrman Sherman R. Developing the nation’s biosimilars program. N Engl J Med 2011;363:385–8.
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[24] EMA. Guideline on Similar Biological Medicinal Products containing Biotechnology-derived Proteins as Active Substance. Quality Issues. London: 22 February 2006 EMEA/CHMP/BWP/49348/2005; 2006. http:// www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003953.pdf. [25] CHMP. CHMP Guideline on Similar Biological Medicinal Products containing Biotechnology-derived Proteins as Active Substance: Nonclinical and Clinical Issues. EMEA/CHMP/BMWP/42832/2005. www.ema.europa. eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003920.pdf; 2006. [26] FDA. FDA Scientific Considerations in Demonstrating Biosimilarity to a Reference Product. Draft Guidance. www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM291128.pdf; 2012. [27] EMA. Guideline on Similar Biological Medicinal Products containing Monoclonal Antibodies—DRAFT. Adoption by CHMP for release for consultation, 18 November. www.ema.europa.eu/docs/en_GB/document_ library/Scientific_guideline/2010/11/WC500099361.pdf; 2010. [28] EMEA. Annex to Guideline on Similar Biological Medicinal Products Containing Biotechnology-derived Proteins as Drug Substance—Nonclinical and Clinical Issues containing Recombinant Human Insulin. EMEA/ CHMP/32775/2005. http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_ content_000408.jsp; 2005. [29] EMEA. Guideline on Similar Biological Medicinal Products containing Recombinant Interferon alpha. EMEA/ CHMP/BMWP/102046/2006. www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/ 09/WC500003930.pdf; 2006.
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5 Overview of Biosimilar Therapeutics Danuta J. Herzyk Merck Research Laboratories, Merck & Co., Inc., West Point, PA, USA
INTRODUCTION As described in Section I of this book, biotechnology-derived pharmaceuticals represent a very broad group of medicines in terms of their structure and therapeutic indications. Also, there are fundamental differences between traditional, small-molecule pharmaceuticals and biological products. The physiochemical and structural properties of biologics are sensitive to changes in the manufacturing environment and/or processes, and because of the inherent variability in the biological systems (i.e., living cells) used in the manufacturing process, the resulting biologic product often consists of a mixture of protein isoforms. Because of the complexity of biopharmaceuticals, for many years it was believed their manufacturing could not be subject to generic competition. This view changed in the early 2000s in parallel with significantly increased knowledge and progress in biotechnological methods applied in biopharmaceutical manufacturing. At the same time greater public and governmental pressure on lower cost medicines and larger global access to novel therapeutics led to this evolutionary step in the biotechnology world. The primary focus on the discovery and development of novel biologics has been broadened to the development of copies of successful marketed biopharmaceuticals in a less expensive way. While it is widely accepted that in contrast to chemical drugs, generic versions of biologics are not attainable (because of the high complexity of their structure), the development and manufacturing of close copies of biopharmaceuticals is achievable, and the concept of “biosimilar” drugs has been introduced. The term “biosimilar” refers to a biological product that claims to be similar to a marketed biopharmaceutical (reference product) that has been approved in highly regulated markets, such as International Conference for Harmonization (ICH) regions (i.e. USA, Europe, Japan), for which patent and regulatory protection of data exclusivity have expired. There are other terms, such as “follow-on- biologics” and “subsequent entry biologics,” applied in different regions (USA and Canada, respectively) that refer to the same definition of biological products as “biosimilars.” In this chapter the term “biosimilar” has been adopted since it is the most broadly used term associated with copies of biological reference products. Nonclinical Development of Novel Biologics, Biosimilars, Vaccines and Specialty Biologics. http://dx.doi.org/10.1016/B978-0-12-394810-6.00005-8
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Development of biosimilar products encompasses great challenges on two fronts, the first related to the very complex nature of biopharmaceutical entities and the second linked to the multifaceted and highly protected manufacturing processes of these molecules. While information about any biopharmaceutical molecular structure becomes publicly known upon the receipt of marketing authorization, information about biopharmaceutical manufacturing and purification processes, specifications, and raw materials used is proprietary and not available in the public domain. Moreover, for many biopharmaceutical products patent protection is separate for the molecular structure and the formulation of the product, and patent for the formulation may last beyond the expiration of patent for the structure of the molecule. Biosimilar manufacturers do not have access to the innovator’s DNA clone or original cell bank and must engineer and clone a new cell line to produce a copy of the original product. Overall, biosimilar manufacturers face a certain “knowledge gap” regarding the development history and database with critical quality product attributes of the innovator’s product.
THE CONCEPT OF BIOSIMILARS In the past few decades most scientific discussions related to the development of novel biologics were focused on establishing optimal scientific and regulatory approaches to their safety evaluation, particularly in nonclinical and early clinical phases of the drug development process. These fruitful discussions and shared experience resulted in the generation of regulatory guidelines [1] and publications [2] that solidified the principles applied in the development of biopharmaceuticals. Since a large number of biological products have become very effective medicines and financially successful, recently the debate has been shifted toward the possibility of the development of biosimilar drugs. Clearly, there are two opposite positions within the biopharmaceutical industry and its representative organizations that influence the debate. The proponents state that the development and commercialization of biosimilars has become reality and these drugs can help address unmet medical needs by improving access to well-established therapeutic interventions by improving their affordability. However, this goal can only be achieved when an abbreviated, less costly development paradigm under a new regulatory framework is in place [3,4]. The opponents claim that the limited testing of biosimilar candidates, especially in the clinic, is insufficient to ensure the same safety and efficacy profile of biosimilars when compared to the clinically proven benefits of marketed reference products [5]. According to this view, a quite extensive nonclinical and clinical evaluation of biosimilar candidates should be required before their approval for marketing, which would maintain the high cost of the development and effectively prevent the emergence of biosimilars. From the scientific point view, the development of biosimilars involves reversed protein engineering of the reference product, generation of the best feasible copy of the reference product using updated biotechnology methods, and an extensive comparative characterization of the reference and the biosimilar candidate using state-of-the-art techniques. Given that at least a decade may have passed between the generation and testing of the original biologic molecule and the biosimilar, more advanced technology than what the innovator was able to use during the development of the original biopharmaceutical would likely be in place. Because of inevitable changes in both biotechnology processes and characterization methods
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over time and the intention to decrease the cost of manufacturing, a biosimilar candidate cannot be an exact replica of the innovator product. Chemistry, Manufacturing, and Control (CMC) processes required in the development of biological drugs are equally fundamental for both novel biologics and biosimilars, and need to be conducted according to the existing regulatory guidelines and standards. Twelve ICH documents have been put in place to address quality and CMC processes involved in the characterization and manufacturing of biopharmaceuticals [6–17], reflecting both the complexity of these products and the high regulatory scrutiny surrounding their quality. One fundamental difference in the development of a novel biologic drug candidate versus a biosimilar candidate is the extent of nonclinical and clinical studies. For the original novel biologic, it must be demonstrated in multiple animal and human studies that it will have the intended pharmacological properties and a good safety profile in relationship to its biochemical and physical characteristics. As these characteristics have been already established, for a biosimilar candidate, deemed to be a satisfactory copy of the reference product based on results generated in the CMC space, the goal is to confirm in relevant but limited studies that the pharmacological activity, efficacy, and safety profile is highly similar to its original biologic counterpart. In order to achieve this goal, great efforts are being made to understand the relationship between recombinant protein structure and CMC processes as well as potential consequences of small changes in CMC on functional characteristics and clinical activity of biotechnology products. As such, the challenges in the development of biosimilars may actually lead to scientific advances and innovation in biotechnology. The development of biosimilars is difficult not only because of the structural complexity of biologic drugs but also because the original biologic products often undergo changes in their manufacturing processes over the course of a product life cycle (i.e. after obtaining the marketing authorization). Manufacturers make post-marketing changes for many different reasons including manufacturing capacity, improving purity, increasing product yield, or optimizing the cost of goods [18]. When such manufacturing process changes are made, a manufacturer is mandated to demonstrate that the product pre- and post-change has comparable “identity, strength, quality, purity, and potency” [19] and the safety and efficacy data derived from nonclinical and clinical testing during the development of the pre-change product are relevant to the post-change product. The process of assuring product consistency pre- and post-change has been referred to as a “comparability” evaluation. To separate this comparability process performed within the same manufacturer (innovator) from the exercise involved in comparing characteristics of a biosimilar candidate with its reference product by another manufacturer (biosimilar developer) who, unlike the innovator, does not possess historical knowledge of the manufacturing processes involved in making the original product, the term “similarity” is applied to the comparative evaluation of biosimilars. Technically, however, it is difficult to distinguish between bioanalytical “comparability” and “similarity” as they involve the same parameters to determine quality characteristics of two biological products when tested side-by-side. In fact, the demonstration of biosmilarity requires both analytical comparability and similarity evaluation. The former involves the comparison of multiple lots of the innovator product to establish a range of product variance. The latter involves the comparison of the biosimilar candidate to the innovator product to confirm that multiple quality attributes remain inside the variability brackets (between the lowest and the highest values) for multiple lots of both products.
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Biosimilarity studies performed in recent years have shown that different lots of marketed biopharmaceuticals (e.g. rituximab, entanercept) can substantially vary in some attributes, such as glycosylation patterns due to process changes implemented during post-marketing manufacturing [3]. However, the analytically detectable changes did not appear to have any impact on the therapeutic (safety and efficacy) attributes of these biological drugs. This observation suggests that some degree of structural differences in biologics may be functionally inconsequential and, therefore, acceptable. On the other hand, biologic product safety and efficacy, primarily affected by increased immunogenicity, can be altered in the post-marketing phase by undetectable or unforeseen factors related not only to manufacturing process changes but also to modifications in formulation, container closure systems as well as in-use stability profiles. Each of these factors can affect product characteristics, including immunogenic potential [20,21]. Notably, aggregation in biologic drugs has been implicated as a critical factor in the induction of an immunogenic reaction and potential autoimmunity. The most discussed example of unforeseen increased immunogenicity, likely related to a change in the product formulation and its closure system, resulting in antibody-mediated pure red cell aplasia is Eprex, a recombinant human erythropoietin [22]. This case indicates that small differences in certain attributes of biological products can occur, despite the existing manufacturer’s experience in well-controlled and seemingly understood manufacturing process, and can have a detrimental impact on safety of the product after its approval. It is postulated that if some variability in quality attributes exists for the original biologic product manufactured based on acquired in-depth knowledge of the process, the probability of introducing much greater variability into its biosimilar counterpart is undoubtedly higher. The burden to prove that this postulate may not necessarily be true, upon application of high-quality reverse protein engineering and bioprocess expertise [3], is on biosimilar developers. In summary, existing experience in the development and approval of novel biopharmaceuticals, including comparability of pre- and post-change evaluation, is highly related and applicable to the emerging experience in the development and approval of biosimilars. Based on current scientific knowledge in characterization of the complex structure of biopharmaceuticals, detection of a small structural difference alone may or may not be meaningful and a “totality of the evidence” approach has been introduced as the most appropriate for assessing biosimilars [23].
GENERAL CONSIDERATIONS FOR DEVELOPMENT OF BIOSIMILARS The development of biosimilars requires significant resource investment in establishing manufacturing processes (bioprocess) and analytical method development to enable production and comparative characterization of the molecular structure and quality attributes of the target reference product and its copy. The early phase of biosimilar development is more extensive than the early development of novel biologics because it involves extensive analytical characterization of two products—the innovator and the biosimilar candidate. It may also be quite costly because of the necessity of purchasing a large quantity of the reference product, often manufactured at different sites and marketed as multiple versions in different countries, to be used in comparative evaluation. Thus, CMC work on biosimilars requires not only the development of a consistent and well-controlled manufacturing process of the biosimilar
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product itself but also extensive comparative side-by-side analyses of procured reference product lots and manufactured biosimilar candidate batches. Once the analytical characterization of the intended biosimilar candidate and the reference product has demonstrated a “highly similar quality profile” as described in the European Medicines Agency (EMA) guidance [24], the extent of nonclinical and clinical studies with the biosimilar candidate should be reduced compared to the development of novel biopharmaceuticals as the clinical efficacy and safety of the reference product is well understood. However, the challenge is to define “highly similar” in light of expected or detected structural variance between the reference product and its biosimilar, and to know “how similar is similar enough” as addressed by Kozlowski et al. [23]. The comparative nonclinical and clinical studies with a proposed biosimilar and the reference product should be designed to detect potential small differences and to minimize uncertainty around whether or not the detected differences could translate to any meaningful difference between the tested products in their clinical application. A biosimilarity assessment is typically performed in a stepwise manner as recommended by new regulatory guidelines described in Chapter 2. Comparison of the proposed biosimilar product and the reference product includes the evaluation of structure, function, animal pharmacokinetics (PK), pharmacodynamics (PD), and toxicity, human PKPD, safety, efficacy, and immunogenicity.
Comparative Nonclinical Studies The aim of comparative studies is to identify (qualitatively and quantitatively) potential differences in product attributes between the biosimilar candidate and reference product. In vitro tests Extensive structural and functional characterization is the first and most critical step in the development of biosimilars. This characterization requires the establishment of multiple in vitro assays and product-specific reagents as well as assay qualification and/or validation. Methods and model systems need to be tailored to a specific biologic product. In addition, the selected methods need to be demonstrated as capable of detecting small differences in all aspects of biochemical characterization of biologics. The conduct of comparative studies involves multiple batches of the biosimilar candidate and commercial lots of the innovator products. Using appropriate analytical methods with adequate sensitivity and specificity for structural characterization of the proteins, the comparisons of the biosimilar candidate and reference product should include: primary structures, such as amino acid sequence, higher order structures, including secondary, tertiary, and quaternary structure, post-translational modifications, such as glycosylation and phosphorylation, and other potential protein changes that can involve unintentional (e.g. deamidation and oxidation during storage) or intentional chemical modifications (e.g. PEGylation). Functional assays need to be designed to characterize pharmacologic activity of the biosimilar candidate in comparison to the reference product. These assays typically include cell-based assays (bioassays) and binding assays involving many different techniques (e.g. immunoassays) to evaluate potency of tested products. By nature, functional assays are highly variable and require careful optimization of testing conditions before they can be reliably used in comparative testing.
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If rigorous structural and functional comparisons in in vitro studies show minimal or no difference in these assays, the probability of achieving an adequate biosimilar candidate is high and the next step of in vivo evaluation is pursued. In vivo pharmacology, PK and PD studies Theoretically, a high degree of similarity between the biosimilar candidate and the reference product demonstrated by in vitro studies should allow for the reduction in the number of required in vivo tests. In practice, however, many animal studies are conducted for most biosimilar candidates to build a strong comparative database and maximize similarity information. Typically, at least one animal disease model is developed to conduct comparative pharmacology (efficacy) studies using multiple versions of the reference product and biosimilar candidate. For example, a neutropenic mouse model for the evaluation of granulocyte colony-stimulating factor activity, murine xenograft tumor models for comparison of the activity of anticancer monoclonal antibodies, and rheumatoid arthritis models in transgenic mice expressing human tumor necrosis factor (TNF) for the evaluation of TNF inhibitors have been used in the development of pertinent biosimilar candidates. Sometimes the animal models are newly established during the development of a biosimilar candidate because such models were not available at the time the innovator biologic was developed. Because of the comparative nature of these studies, they are rather costly as they require a large number of animals and the procurement of the innovator products. Similar to in vitro testing, if several versions of the reference product are marketed in different countries it is prudent to use multiple lots/versions of the reference product in the in vivo evaluation to determine the variability range of animal responses to this product. In addition to animal pharmacology experiments in disease models, similarity in PKPD characteristics between the biosimilar candidate and its reference product (multiple versions if applicable) is also assessed in normal healthy animals. In order to perform animal PKPD studies for comparative purposes, appropriate product-specific assays have to be developed and qualified by a biosimilar developer. Small differences in quality and/or in vitro functional characteristics between the reference product and the biosimilar candidate are typically detectable and should be expected. Small inconsistencies in animal pharmacology, PK and/or PD studies could also be observed, including some variation between multiple lots of the reference product. Therefore, the identified dissimilarities may or may not represent any meaningful differential response to the biosimilar candidate compared to the reference product and they are often confounded by natural inter-animal variability, including an immune response to a human biologic (i.e. immunogenicity of the tested products). When some differences between the biosimilar candidate and the reference product are observed (greater than the range of variability between reference lots) in PKPD animal studies, additional (larger) studies may be needed to understand the nature of the found variance. When animal testing does not reveal any significant difference between the biosimilar candidate and its reference product in side-by-side comparative studies, the confidence in developing of an adequate biosimilar product is increased. The most likely scenario (based on personal communication) in the development of biosimilars is that small CMC differences are detectable using in vitro assays (outside their variability range) while in vivo PKPD comparative studies do not show significant changes (beyond the natural or explainable variability) between the biosimilar candidate and the reference
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product. This scenario is in contrast to the position presented in the past that in vitro analytical methods used in characterization of biologics are less sensitive in detection of potential differences than the whole host (in vivo). A shift in thinking about the reliance on in vitro testing in comparative studies is evident in new regulatory guidelines for biosimilars [25,26]. Toxicology studies To address any uncertainty about translation of small CMC differences to the safety profile of a biosimilar candidate, a toxicology study is typically expected. Since the safety profile of the reference product is well understood in humans, the extent of the nonclinical toxicology program in the development of a biosimilar to support its clinical testing and registration should be abbreviated when compared to the toxicology program performed during the development of the reference product. At the same time, a toxicology program for a biosimilar candidate needs to be guided by information generated for the pertinent reference product and utilize product-specific approaches. Typically, one repeated dose toxicology study, comparative in nature in the same animal species as that used by the innovator, is conducted. The study design, including dose levels, frequency, and duration of dosing should be driven by results of the pivotal toxicity study performed by the innovator. Although a toxicity study with a biosimilar candidate should be based on product-specific characteristics, experience in toxicological sciences indicates that generally a repeat-dose study of a minimum duration of one-month in which the biosimilar and the reference product are tested side by side is considered sufficient. Such a study is quite resource intensive as it requires many groups of animals and the procurement of large amounts of the reference product. Unlike pharmacology and PKPD studies that include multiple lots/versions of the reference product, in toxicology studies testing one version of the reference product is considered sufficient based on guidelines for animal use and/ or data generated from comparative PKPD assessments. Regarding the biosimilar candidate material to be tested in a comparative toxicology study, it is highly desirable to use drug product from the optimized manufacturing process that is representative of the material to be tested in pivotal clinical trials designed to evaluate the safety profile of the biosimilar candidate. Typically, no other toxicology studies (i.e. safety pharmacology, chronic toxicity, reproductive and developmental toxicity) are expected for biosimilars unless there is a specific cause for concern. Additional consideration should be given when no toxicity was detected in animal studies performed by the innovator during the development of the reference product (e.g. TNFα inhibitors) and where no differences between the biosimilar candidate and the reference product are identified upon nonclinical comparative characterization using both in vitro (according to the current standards of quality testing) and in vivo (including PKPD) studies. It is highly debatable that a comparative toxicology study should be conducted in such a scenario. The regulatory guidelines for biosimilars [25,26] indicate that the lack of a comparative (presumably in the situation described above) or any toxicology study with a biosimilar candidate (e.g. due to lack of relevant toxicology species) can be justified by sponsors developing biosimilars. Limited experience to date (based on personal communication) suggests that comparative toxicology studies do not detect any meaningful differences (beyond the natural or explainable variability) between biosimilar candidates and their reference products even when some degree of “dissimilarity” in other nonclinical characterization has been observed.
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Comparative Clinical Studies Clinical development of biosimilars, although abbreviated, is still fairly extensive. The clinical program should always include at least one human comparative study using the biosimilar and the reference product side by side. The number and type of additional studies with the biosimilar candidate to confirm the expected efficacy and safety in patients can vary based on the characteristics of the reference products. The clinical studies provide the ultimate data to support the evidence of similarity between the biosimilar candidate and the reference product. The comparative nature of clinical studies with a biosimilar is focused on bioequivalence and requires new clinical trial expertise compared to conventional clinical trials, in which efficacy and safety are measured against placebo controls. In addition, most clinical trial investigators, primarily researchers at university hospitals, are much more interested in studying novel drug candidates than evaluating copies of the existing medicines, as the latter does not satisfy their pursuit of advancing clinical sciences. In some cases, where competition for patient enrollment in certain diseases is very high, clinical investigators are deeply critical of trials with biosimilars, viewing them as “stealing” patients from “real” clinical trials. This point of view can be countered, however, by the fact that in a comparative trial with the biosimilar candidate and the reference product, all patients benefit from being treated by a pharmacologically active and efficacious agent with no chance of being exposed to a placebo control, which does not provide any therapeutic effect. On top of such disputes, the new regulatory guidelines for biosimilars, either finalized or drafted [25–27], outline stringent requirements for clinical trials that should include a dose–response comparison between the biosimilar and the reference product, testing the most sensitive patient population to detect potential differences, and long-term monitoring of immunogenicity both prior to registration and during the post-marketing period. Also, the guidelines recommend using drug product from a large-scale commercial manufacturing process that is fully defined prior to the start of clinical trials. While such a rigorous evaluation would minimize any uncertainties associated with the approval of biosimilars, it will also minimize incentives and justification for investments in the development of biosimilars in light of only small reduction in costs compared to the development of new biologic entities. Because of this conundrum, the regulatory requirements for clinical development of biosimilars are still evolving and incomplete.
BIOSIMILAR CANDIDATES BASED ON MODALITY AND THERAPEUTIC CLASS Biopharmaceuticals include many different types of molecular constructs and can be grouped in three major categories: (1) therapeutic proteins (e.g. enzymes, hormones, cytokines); (2) monoclonal antibodies (mAbs), and modifications thereof, such as, mAbs conjugated to chemicals or immunoglobulin fragments (e.g. Fab); and (3) fusion proteins involving the Fc portion of immunoglobulin linked to other recombinant proteins. Lists of marketed biologics in these three categories are presented in Tables 5.1 (A, B, C) and 5.2 (A, B, C). Another categorization of biopharmaceuticals can be based on therapeutic area and disease indication. The major classes of biopharmaceuticals include drugs for treatment of cancer,
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TABLE 5.1 Biopharmaceuticals Approved for Marketing (US) in 1983–2005 Generic name (brand name) Year
Target /ligand
Indication
Therapeutic area
Interferon α-2b (Intron A) 1983
Interferon alfa-2b
Leukemias, melanoma, hepatitis C, hepatitis B
Oncology, infectious diseases
Interferon α-2a (Roferon A) 1984
Interferon alfa-2a
Leukemias, hepatitis C
Oncology, infectious diseases
Somatropin (Humatrope) 1987
Growth hormone
Growth hormone deficiency
Endocrinology
Interferon α-N3 (Alferon) 1989
Interferon alfa-N3
Genital warts
Various
Filgrastin (Neupogen) 1991
Granulocyte colony-stimulating factor Neutropenia (G-CSF)
Oncology and others
Sargramostim (Leukine) 1991
Granulocyte macrophage colonystimulating factor (GM-CSF)
Oncology
Aldesleukin (Proleukin) 1992
Interleukin-2 (IL-2) receptor on T and Metastatic renal cell carcinoma NK cells
Oncology
Dornase alpha (Pulmozyne) 1993
DNase
Cystic fibrosis
Pulmonary diseases
Epoetin alpha (Epogen/Procrit) 1993
Erythropoietin
Anemia
Oncology and others
Imiglucerase (Cerezyme) 1994
Glucocerebrosidase
Gaucher’s disease
Enzyme replacement therapy
Asparaginase (Elspar) 1994
l-Asparaginase
Acute lymphocytic leukemia
Oncology
Pegasparagase (Oncaspar) 1994
Pegylated l-asparaginase
Acute lymphoblastic leukemia
Oncology
Somatropine (Genotropine) 1995
Growth hormone
Growth hormone deficiency
Endocrinology
Alteplase (Activase) 1996
Tissue plasminogen activator
Restoration of function of central venous access devices
Cardiovascular diseases
A. THERAPEUTIC PROTEINS
Interferon beta-1a
Multiple sclerosis
Inflammation/autoimmunity
Mutation of tissue plasminogen activator
Acute myocardial infarction
Cardiovascular diseases
Follitropin (Follistim) 1997
Follicle-stimulating hormone
Infertility
Reproductive system
Interferon alphacon (Intergen) 1997
Interferon type 1
Hepatitis C
Infectious diseases
149
Interferon β-1a (Avonex) 1996 Reteplase (Retavase) 1996
Biosimilar Candidates Based on Modality and Therapeutic Class
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Chemotherapy-related acute myelogenous leukemia
Continued
Generic name (brand name) Year
Target /ligand
150
TABLE 5.1 Biopharmaceuticals Approved for Marketing (US) in 1983–2005 (cont’d)
Indication
Therapeutic area
Interleukin-11 (IL-11)
Thrombocytopenia in chemotherapy
Oncology
Glucagon (Glucagen) 1998
Glucagon hormone
Hypoglycemic reactions in diabetic patients
Endocrinology
Interferon γ-1b (Actimune) 1999
Interferon gamma-1b
Infections with chronic granulomatous diseases, malignant osteoporosis
Infectious diseases, oncology
Insulin glargine (Lantus) 2000
Long-acting insulin
Diabetes
Endocrinology
Insulin aspart (Novolog) 2000
Rapid-acting insulin
Diabetes
Endocrinology
Tenecteplase (Tnkase) 2000
Tissue plasminogen activator
Myocardial infarction
Cardiovascular diseases
Darbepoetin alpha (Aranesp) 2001
Erythropoietin
Anemia
Oncology and others
Anakinra (Kineret) 2001
IL-1 receptor antagonist
Rheumatoid arthritis
Inflammation/autoimmunity
Drotrecogin alpha (Xigris) 2001
Activated protein C
Sepsis
Infectious diseases
PegInterferon α-2b (Peg-Intron) 2001
Interferon alfa-2b, pegylated
Hepatitis C
Infectious diseases
Interferon β-1a (Rebif) 2002
Interferon beta-1a, pegylated
Multiple sclerosis
Inflammation/autoimmunity
PegInterferon α-2a (Pegasys) 2002
Interferon alfa-2a, pegylated
Hepatitis C, hepatitis B
Infectious diseases
Pegfilgrastim (Neulasta) 2002
Pegylated G-CSF
Neutropenia
Oncology and others
Rasburicase (Elitek) 2002
Urate oxidase
Cancer-related hyperuricemia
Oncology
Teriparatide (Forteo) 2002
Parathyroid hormone
Osteoperosis
Bone diseases
Agalisdase beta (Fabrazyme) 2003
Alpha galactosidase
Fabry’s disease
Enzyme replacement therapy
Interferon β-1b (Betaseron) 2003
Interferon beta-1b
Multiple sclerosis
Inflammation/autoimmunity
Laronidase (Adlurazyme) 2003
α-l-iduronidase
Mucopolysaccharidosis I
Enzyme replacement therapy
Insulin glulisine (Apidra) 2004
Rapid-acting insulin
Diabetes
Endocrinology
Palifermin (Kepivance) 2004
Keratinocytes growth factor
Oral mucotitis in cancer
Oncology
5. OVERVIEW OF BIOSIMILAR THERAPEUTICS
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Oprelvekin (Neumega) 1997
Insulin (Levemir) 2005
Long-acting basal insulin
Diabetes
Endocrinology
Galsulfase (Naglazyme) 2005
N-Acetylgalactosamine 4-sulfase
Mucopolysaccharidosis VI
Enzyme replacement therapy
Mecasermin, (Increlex) 2005
Insulin growth factor-1 (IGF-1)
Growth failure secondary to severe primary IGF-1 deficiency
Endocrinology
Muromomab (Orthoclone OKT3) 1992
T-cell surface protein CD3 antagonist (murine antibody)
Rejection of transplanted organs
Organ transplant
Abciximab (Reopro) 1997
Platelet glycoprotein GpIIbIIIa receptor (Fab fragment) antagonist
Acute blood clot complications
Cardiovascular diseases
Daclizumab (Zenapax) 1997
IL-2 receptor (IL-2R, CD25) antagonist Rejection of transplanted organs
Organ transplant
Rituximab (Rituxan) 1997
B-cell surface protein CD20 antagonist
Non-Hodgkin’s lymphoma, rheumatoid arthritis
Oncology, inflammation/ autoimmunity
Trastuzumab (Herceptin) 1997
Human epidermal growth factor receptor 2 (HER2) antagonist
Breast cancer
Oncology
Infliximab (Remicade) 1998
Tumor necrosis factor (TNF) alpha antagonist
Rheumatoid arthritis, Crohn’s disease, psoriatic arthritis, ankylosing spondylitis, psoriaris
Inflammation/autoimmunity
Basiliximab (Simulect) 1998
IL-2R alpha chain (CD25) antagonist
Organ transplant
Immunology
Palivizumab (Synagis) 1998
F protein of respiratory syncytial virus (RSV) antagonist
Prophylaxis of serious lower respiratory tract disease
Infectious diseases
Gemtuzumab ozogamicin (Mylotarg) 2000
Anti-CD33 conjugated with calicheamicin
Acute myeloid leukemia
Oncology
Alemtuzumab (Campath) 2001
B-cell surface protein CD52 antagonist
B-cell chronic lymphocytic leukemia
Oncology
Adalimumab (Humira) 2002
TNF alpha antagonist
Rheumatoid arthritis, Crohn’s disease Inflammation/autoimmunity
Ibritumomab tiuxetan (Zevalin) 2002
Anti-CD20 linked to radioactive yttrium-90
Non-Hodgkin’s lymphoma
Oncology
131I-Tositumomab
Anti-CD20 linked to radioactive iodine-131
Non-Hodgkin’s lymphoma, chronic lymphocytic leukemia
Oncology
B. MONOCLONAL ANTIBODIES
151
Continued
Biosimilar Candidates Based on Modality and Therapeutic Class
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(Bexxar) 2003
152
TABLE 5.1 Biopharmaceuticals Approved for Marketing (US) in 1983–2005 (cont’d)
Target /ligand
Indication
Therapeutic area
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Efalizumab (Raptiva) 2003
Integrin lymphocyte functionassociated antigen-1 (CD11a) antagonist
Psoriasis
Inflammation/autoimmunity
Omalizumab (Xolair) 2003
IgE antagonist
Asthma
Pulmonary diseases
Bevacizumab (Avastin) 2004
Vascular endothelial growth factor (VEGF) antagonist
Colorectal cancer
Oncology
Cetuximab (Erbitux) 2004
Epidermal growth factor receptor (EGFR) antagonist
Colorectal cancer
Oncology
Etanercept (Enbrel) 1998
TNFalpha (TNFR:Fc) antagonist
Rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, psoriaris
Inflammation/autoimmunity
Alefacept (Amevive) 2003
Leukocyte function antigen-3 (LFA3:Fc) antagonist
Psoriasis
Inflammation/autoimmunity
C. FUSION PROTEINS
5. OVERVIEW OF BIOSIMILAR THERAPEUTICS
Generic name (brand name) Year
153
Biosimilar Candidates Based on Modality and Therapeutic Class
TABLE 5.2 Biopharmaceuticals Approved for Marketing (US) after 2005 Generic name (brand name) Date
Target/ligand
Indication
Therapeutic area
A. THERAPEUTIC PROTEINS Alglucosidase α (Myozyme) 2006
Alglucosidase alpha
Pompe diseases
Enzyme replacement therapy
Insulin (Exubera) 2006
Glucose metabolism
Type 1 or type 2 diabetes
Endocrinology
Idursulfase (Elaprase) 2006
Idursulfase
Hunter syndrome mucopolysaccharidosis II
Enzyme replacement therapy
Somatropine (Omnitrope) 2006
Sustained release of growth hormone
Growth failure
Endocrinology
PegEpo (Mircera) 2007
Methoxy polyethylene glycol-epoetin beta
Anemia associated with chronic renal failure
Various
Ecallantide (Kalbitor) 2009
Plasma kallikrein inhibitor
Hereditary angioedema
Genetic disorders
Pegloticase (Krystexxa) 2010
Pegylated uricase
Refractory chronic gout
Inflammation/ autoimmunity
B. MONOCLONAL ANTIBODIES Natalizumab (Tysabri) 2006
Integrin alpha4beta1 antagonist
Multiple sclerosis
Inflammation/ autoimmunity
Panitumumab (V Ectibix) 2006
EGFR1 antagonist
Colorectal cancer
Oncology
Ranibizumab (Lucentis) 2006
VEGF-R antagonist (antibody fragment)
Macular degeneration, agerelated, wet; Retinal vein occlusion; Edema
Ophthalmology
Eculizumab (Soliris) 2007
Complement factor C5 inhibitor
Hemolytic anemia, hemolytic uremic syndrome
Hematology
Certolizumab pegol (Cimzia) 2008
TNFalpha antagonist (pegylated Fab fragment)
Crohn’s disease, rheumatoid arthritis
Inflammation/ autoimmunity
Canakinumab (Ilaris) 2009
IL-1beta antagonist
Muckle–Wells syndrome, familial cold autoinflammatory syndrome, neonatal onset multisystem inflammatory disease
Inflammation/ autoimmunity
Golimumab (Simponi) 2009
TNFalpha antagonist
Rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis
Inflammation/ autoimmunity
Ofatumumab (Arzerra) 2009
B-cell CD20 antagonist
Chronic lymphocytic leukemia
Oncology
Ustekinumab (Stelara) 2009
IL-12/IL-23 antagonist
Psoriasis
Inflammation/ autoimmunity Continued
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154
5. OVERVIEW OF BIOSIMILAR THERAPEUTICS
TABLE 5.2 Biopharmaceuticals Approved for Marketing (US) after 2005 (cont’d) Generic name (brand name) Date
Target/ligand
Indication
Therapeutic area
Denosumab (Xgeva, Prolia) 2010
Receptor activator of nuclear factor kappa-B ligand (RANKL) antagonist
Osteoporosis, bone regeneration (cancer-related bone loss)
Bone diseases
Tocilizumab (Actemra) 2010
IL-6R antagonist
Castleman’s disease, rheumatoid arthritis, juvenile arthritis
Inflammation/ autoimmunity
Belimumab (Benlysta) 2011
BLyS (B-cell survival factor) antagonist
Systemic lupus erythematosus, rheumatoid arthritis
Inflammation/ autoimmunity
Brentuximab Vendotin (Adcetris) 2011
Anti-CD30 (cell surface protein) conjugated to monomethyl auristatin
Refractory Hodgkin lymphoma
Oncology
Ipilimumab (Yervoy) 2011
CTLA-4 (extracellular domain) antagonist
Melanoma
Oncology
Abatacept (Orencia) 2006
T-cell CD80/CD86 co-stimulation (CTLA4:Fc) inhibitor
Rheumatoid arthritis
Inflammation/ autoimmunity
Rilonacept (Arcalyst) 2008
IL-1 receptor (IL-1R:Fc) antagonist
Cryopyrin-associated periodic syndromes
Inflammation/ autoimmunity
Romiplastim (Nplate) 2008
Thrombopoietin (TPO:Fc) receptor agonist
Chronic immune thrombocytopenia
Inflammation/ autoimmunity
Aflibercept (Eylea) 2011
VEGF trap (specific domain of VEGFR1/ VEGFR2:Fc)_
Neovascular (wet) age-related Ophthalmology macular degeneration
Belatacept (Nulojix) 2011
Cytotoxic T-cell inhibitor via CD28: CD80/CB86 interaction (extracellular CTLA-4:Fc)
Kidney transplant rejection
C. FUSION PROTEINS
Organ transplant
inflammatory, and autoimmune diseases, metabolic disorders, enzyme and hormone deficiencies, and others (Tables 5.1 and 5.2). The tables include biologic products approved for marketing in the US as new biological entities (NBE) in chronological order, allowing for the appreciation of evolutionary changes in the range and types of biotechnology-derived medicines. Some of the changes are focused on improving convenience of biologic drug administration (e.g. by pegylation of recombinant proteins, their half-life has been prolonged and frequency of parenteral administration reduced). Other modifications are focused on expanding disease indications by changing target binding specificity through additional engineering
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Summary
155
of biologic constructs. Such modifications could be made by the same innovator or a competitor, but in each case a new application for approval as a NBE had to be filed and marketing authorization received. A number of marketed biologics, with the expired or imminent loss of patent protection, have been selected as targets for biosimilars based on high revenues. In contrast to the desired and deliberate modifications to improve biologic products that are already effective therapeutics, biosimilars can not intentionally be modified. The first wave of biosimilars approved in EU markets represents a class of therapeutic proteins and include growth hormone (somatotropin), erythropoietin (epoetin), and granulocyte colony-stimulating factor (filgrastim). Based on publication of specific guidance for biosimilars to insulin and interferon [28,29] one can assume that biosimilar candidates to marketed insulin products and interferon products may be in development. The “blockbuster” biologics include several mAbs to treat inflammatory diseases and cancer, and these drugs are expected to be targets for biosimilars upon their patent expiration. The mAbs that may face competition from the development of their biosimilars include TNFblocking products (e.g. adalimumab), anti-CD20 antibody (rituximab), anti-HER2 antibody (trastuzumab), and anti-VEGF (bavacizumab). Particulars related to the nonclinical development of biosimilars, mainly to selected marketed therapeutic proteins, are discussed in Chapter 3.
SUMMARY Global interest in access to lower cost biopharmaceuticals in the form of biosimilars aligns with the concept of generic medications for chemical pharmaceuticals. However, based on experience to date, development of biosimilars poses much greater challenges not only due to demanding requirements in clinical development, but also uncertainty in manufacturing and marketing capabilities. The development costs of a biosimilar, while lower than the cost of developing a novel biopharmaceutical, are still high. Manufacturing capabilities that require sophisticated facilities, technologies, and processes have proven to be elevated barriers to developing biosimilars. Interactions with physicians and healthcare providers require new resources in educational processes both prior to conduct of clinical trials and after obtaining marketing authorization. Sales teams need to acquire deeper medical and technical knowledge to explain why biosimilars are not generic substitutions of their original biopharmaceutical counterparts and yet should be trusted as equally safe and efficacious medicines. Likewise, investment in market strategies to meet required post-marketing surveillance is very significant. Lastly, slowly shaping regulatory framework, especially in the US, makes the investments quite risky. Nonetheless, growing interest in biosimilars in emerging markets, including India, China, and Brazil, where health authorities have published or drafted their own guidelines, will likely increase investments in biosimilars in those regions. In conclusion, the value proposition of biosimilars is complex and has to be addressed by the full range of stakeholders, including manufacturers, regulators, physicians, payers, and patients. If development, registration, and marketing of biosimilars become broadly successful, it will likely happen over the long term.
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