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European Journal of Gastroenterology & Hepatology:
doi: 10.1097/MEG.0000000000000098
Review article

Biosimilars in the therapy of inflammatory bowel diseases

Hlavaty, Tibor; Letkovsky, Juraj

Free Access
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Author Information

Department of Internal Medicine, Division of Gastroenterology and Hepatology, University Hospital, Bratislava, Slovakia

Correspondence to Tibor Hlavaty, MD, PhD, Department of Internal Medicine, Division of Gastroenterology and Hepatology, University Hospital Bratislava, Ruzinovska 6, SK-82606 Bratislava, Slovakia Tel: +421 917 752 297; fax: +421 248 234 905; e-mail: tibor.hlavaty2@gmail.com

Received January 29, 2014

Accepted March 13, 2014

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Abstract

A biosimilar is a copy of an approved biological medicine whose patent protections have expired. Biosimilars of antibodies to tumour necrosis factor α (TNFα) are becoming important in the treatment of inflammatory bowel diseases (IBD). The first one introduced commercially is an infliximab biosimilar. The aim of this study was to provide an overview of anti-TNFα biosimilars. The literature on biosimilars of monoclonal anti-TNFα antibodies was reviewed, including their manufacture and approval pathways, concerns about efficacy, safety, immunogenicity, extrapolation, switching and labelling. Previous experience with biosimilars of epoetin and other growth factors was also reviewed. The infliximab biosimilar CT-P13 was the first biosimilar monoclonal antibody registered for the treatment of IBD. The major advantage of biosimilars is the reduced cost of therapy. Concerns have arisen, however, about the efficacy and safety of CT-P13 in IBD, the extrapolation of results from rheumatologic trials to IBD and the free interchangeability of CT-P13 with infliximab. Experience with simple peptide biosimilars, such as epoetins and growth factors, has generally been positive, with these biosimilars having similar efficacy and safety as the original products, although immunogenicity remains a major concern. Upcoming postregistration studies will address concerns on biosimilars in IBD, including their efficacy, safety, immunogenicity, switching and interchangeability. Biosimilars active against the same epitopes, but with improved pharmacokinetic properties that enhance their efficacy and/or safety, may be the next stage in the development of biosimilars. Anti-TNFα biosimilars represent promising new treatment options for patients with IBD. However, data on their efficacy and safety in IBD are needed.
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Introduction

Inflammatory bowel diseases (IBD), which include ulcerative colitis (UC) and Crohn’s disease (CD), are idiopathic chronic relapsing inflammatory conditions of the gastrointestinal tract. Their natural course varies from an indolent chronic form to progressive devastating disease and, if treated inadequately, moderate to severe IBD often results in reduced quality of life, major abdominal surgery and/or disability.

Biological therapy with monoclonal antibodies to tumour necrosis factor α (TNFα), such as infliximab (IFX) and adalimumab, first introduced in the 1990s, was shown in large clinical trials to be effective in inducing and maintaining remission in patients with both CD and UC 1–5. IFX, the first anti-TNFα biological in use, has shown significant success in treating paediatric and adult patients with moderate to severe luminal and fistulizing CD, severe UC and several extraintestinal complications 1–3,6–9. IFX has also been used to treat patients with rheumatoid arthritis (RA), ankylosing spondylitis (AS) and psoriasis 10.

IFX has a favourable efficacy/safety profile when compared with other medications used in the treatment of IBD, such as corticosteroids, azathioprine and other immunomodulators. However, high treatment cost represents a major concern, preventing IFX’s wide reimbursement in many countries. The introduction of cheaper IFX generics, namely biosimilars, could overcome this major drawback. This review will therefore discuss current knowledge on biosimilars, including their specific properties, clinical experience with their use and their registration status, as well as their safety, efficacy, bioequivalence, extrapolation across indications and labelling. This review will also focus on IFX biosimilars introduced recently for the treatment of IBD.

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Biosimilars

Biopharmaceuticals are protein-based medicinal products developed using recombinant DNA technology. Biosimilar is a new term introduced by the European Medicinal Agency (EMA) to denote a copy of an original biopharmaceutical with similar biologic activity, physicochemical characteristics, efficacy and safety 11. Biosimilars are known as follow-on biologics in the USA and as subsequent entry biologics in Canada.

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Manufacturing of biosimilars

The manufacture of biosimilars is more complex than the production of small molecules. It requires several steps, including the determination and growth of a vector, the host cell expression system, the cell expansion procedure, the protein recovery mechanism (e.g. filtration and centrifugation), the purification process and the formulation of the therapeutic protein into a drug 12. Although the protein sequence of the biosimilar is identical to that of the original biopharmaceutical, companies that manufacture biosimilars do not have access to the later steps involved in the manufacturing of the original biopharmaceutical because these are trade secrets.

Currently, analytical tools are limited in their ability to show that biological products are completely identical. Accordingly, the absence of detectable differences does not mean equivalence 13, which means demonstrating that a biosimilar is ‘similar’ to its original molecule is very challenging. Despite guidance from the EMA and the US Food and Drug Administration (FDA), uncertainties remain in terms of the requirements for bioanalytical testing of biosimilars and innovator biologics 14.

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Registration of biosimilars

The complexity of the manufacturing process and the heterogeneity of biopharmaceuticals have been reflected in the registration process specific for biosimilars in the European Union (EU) 15. Evidence of full comparability in the quality of manufacturing and in testing at the preclinical and clinical levels is required to register a biosimilar. In the USA, the Biologics Price Competition and Innovation Act defines an abbreviated licensing pathway for biosimilars 16,17, but the most stringent criteria for the registration of biosimilars are those of Health Canada. Although the EMA and the US FDA allow extrapolation of efficacy data from clinical trials in one indication to other indications, Health Canada does not. By contrast, India has demonstrated very high acceptance of biosimilars; there, biosimilars are prescribed immediately after their launch and interchangeability among brands is common.

Since the implementation of a biosimilar approval pathway in 2005, 19 biosimilars of epoetin-α and epoetin-ζ, filgrastim and somatropine have been evaluated and 14 have been approved by the EMA 18. A recent review authored by members and experts of the Working Party on Similar Biological Medicinal Products of the EMA concluded that approved biosimilars can be considered therapeutic alternatives to their reference products 19.

Because of the recent or approaching expiration of patents for monoclonal antibody biologics, the first biosimilars to monoclonal antibodies have been submitted for approval 11,20. The first biosimilar of a monoclonal antibody that has been registered in Europe and the USA is the IFX biosimilar CT-P13 (Remsima; Celltrion Inc., Incheon, Korea and Inflectra; Hospira, Lake Forest, Illinois, USA) 21. It has been approved and is currently in clinical use in South Korea since 2012. Moreover, more than 35 biosimilar antibodies and Fc-fusion proteins are currently being evaluated in clinical trials in the EU; these include biosimilars of rituximab, trastuzumab, bevacizumab, cetuximab, adalimumab and etanercept (Table 1) 22–24.

Table 1
Table 1
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The benefits of biosimilars

Biological agents, including IFX and adalimumab, are seven of the 10 top grossing drugs in the world 12. The sales of IFX in 2013 were four billion USD in USA and 2.2 billion USD in EU 25. Historically, generics of small-molecule drugs has resulted in price reductions of up to 80% compared with their original molecules 26, but because of their higher development and manufacturing costs, the savings for biosimilars are expected to be only ∼25–30%. Nevertheless, this should still increase access to biological drugs for patients in need 20.

Another possible benefit is the development of antibodies that target the same validated epitope as the original monoclonal, but have been genetically modified to enhance their pharmacokinetic properties – for example, optimization of glycosylation profiles to enhance effector functions or exchanging of Fc domains to increase serum half-life or antibody-dependent cellular cytotoxicity 27. These molecules have been called biobetter, biosuperior and next-generation biologics.

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Infliximab biosimilar

On 27 June 2013, CT-P13 became the first biosimilar monoclonal antibody to be positively evaluated by the EMA Committee for Medicinal Products for use in adults and children with CD and UC, as well as for patients with RA, AS, psoriatic arthritis and plaque psoriasis. The committee also suggested implementing a pharmacovigilance plan as part of the marketing authorization 28.

CT-P13 is an IFX biosimilar produced in the same type of cell line (Sp2/0-AG14, cat no. CRL-1581), and with an amino acid sequence identical to that of the original molecule. CT-P13 is manufactured using the same human/mouse cell hybrid clone technology as IFX 29.

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Pharmacodynamic data of infliximab biosimilar

Tests of the in-vitro primary pharmacodynamic properties of CT-P13 and IFX have resulted in comparable parameters 30. CT-P13 and IFX showed comparable binding affinities to monomeric and trimeric forms of human TNFα (hTNFα) and transgenic mouse hTNFα (tmhTNFα) expressed by Jurkat cells, and to Fcγ receptors and FcRn. Moreover, both CT-P13 and IFX showed comparable hTNFα-neutralizing activity against a TNFα-sensitive mouse sarcoma cell line (WEHI-164).

CT-P13 could not bind to hTNFβ and TNFα from a range of species that did not bind IFX. The two molecules also had similar binding affinities to complement protein C1q, a similar ability to induce complement dependent cytotoxicity and similar apoptotic effects against a Jurkat T cell line expressing tmhTNFα. In addition, biotinylated CT-P13 and biotinylated IFX showed comparable cross reactivity with human tissues.

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Clinical studies with infliximab biosimilar

CT-P13 was studied in two randomized-controlled clinical trials. The first head-to-head trial comparing CT-P13 and IFX was the phase 1 PLANETAS trial, which involved 250 patients with AS 31. This study was not a conventional dose-finding phase 1 clinical trial, but a biosimilarity study designed to show pharmacokinetic equivalence and comparable efficacy and safety of CT-P13 and IFX. The two molecules had similar steady-state pharmacokinetic endpoints (area under the curve and Cmax), as well as a range of secondary pharmacokinetic endpoints. Their clinical efficacy endpoints, including ASAS20 and ASAS40 responses, were also similar. ASAS20 responses at weeks 14 and 30 were achieved by 62.6 and 70.5%, respectively, of patients treated with CT-P13 and by 64.8 and 72.4%, respectively, of patients treated with IFX. Antibodies to IFX in patients with active AS treated with CT-P13 and IFX were detected in 9.1 and 11.0%, respectively, at week 14 and in 27.4 and 22.5%, respectively, at week 30. Infusion-related reactions occurred in 3.9% of patients treated with CT-P13 compared with 4.9% of patients treated with IFX. CT-P13 was generally well tolerated, with a safety profile comparable with that of IFX up to week 30.

The initial findings of PLANETAS were confirmed in a large phase III randomized, double-blind, multicentre, trial in patients with RA with active disease despite methotrexate (MTX) treatment (PLANETRA) 30. The patients received 3 mg/kg of CT-P13 (n=302) or IFX (n=304), along with MTX (12.5–25 mg/week) and folic acid. The clinical efficacy of CT-P13 was equivalent to that of IFX, and the two antibody preparations had comparable pharmacokinetic profile, safety and immunogenicity. Of the patients in the CT-P13 and IFX groups, 60.9 and 58.6%, respectively, achieved the primary endpoint, ACR20 response at week 30. Moreover, 85.8 and 87.1%, respectively, showed good or moderate EULAR responses (C-reactive protein) at week 30. Overall treatment-emergent adverse events were reported in 181 (60.1%) CT-P13-treated patients and 183 (60.8%) IFX-treated patients, with most of these adverse events being mild to moderate in intensity. Of the patients in the CT-P13 and IFX groups, 25.4 and 25.8%, respectively, were positive for antibodies to IFX at week 14 and 48.4 and 48.2%, respectively, were positive at week 30. Infusion-related reactions occurred in 6.6 and 8.3% of these patients, respectively. Pharmacokinetic parameters, including mean and peak serum concentrations (Cmax), in the two groups were similar after each of the first six doses, as were the overall ranges of geometric means across all doses.

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Drawbacks to the use of biosimilars in inflammatory bowel diseases

Biologics are products produced by a living system, resulting in an inherent variability in the manufacturing process. Biosimilars, as well as various batches of a biological medicine, will show a certain degree of heterogeneity 20,32.

Even small changes in protein folding can manifest as clinically meaningful differences in efficacy and/or toxicity 13. The glycosylation pattern of a biological, which is sensitive to various conditions, including culture pH and concentrations of nutrients or hormones, is especially important for its activity 33.

Although the amino acid sequence of a biosimilar is identical to that of the original biopharmaceutical, there may be subtle differences in manufacturing processes – for example, during the expansion, filtration and purification steps 34. Although most of these differences have no clinical significance, there are exceptions, as discussed below.

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Experience from changes in the innovator manufacturing process

Frequent changes have occurred during the manufacturing process of registered innovator biologics 35. Biopharmaceuticals often undergo process improvements and changes during the life cycle of the drug, and these changes trigger comparability exercises that must be reviewed and accepted by regulatory authorities 21. The peer-reviewed literature includes many examples of acceptable differences between premanufacturing and postmanufacturing properties of leading recombinant biopharmaceuticals, such as epoetins, etanercept and rituximab 36,37. Switching individual patients from one batch to another during their course of treatment or between products synthesized before and after changes in manufacturing protocols has not led to problems in clinical practice.

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Experience from peptide biosimilars

Since 2005, the EMA has approved 14 biosimilars of epoetin-α and epoetin-ζ, filgrastim and somatropine. In addition to the studies presented for the registration of these products, several postauthorization interventional and observational studies and quality comparisons have been published. These studies highlighted several clinical issues related to the pharmacokinetics and immunogenicity of biosimilars.

Most head-to-head comparisons of biosimilar and original epoetins have shown comparable terms of efficacy and safety 38–41. Differences in dosing were observed in two studies with the epoetin-α biosimilar SB309 40,42. The mean weekly dosage of epoetin-α per kg body weight was ∼10% higher with SB309 than with the original epoetin-α. However, another cross-over trial showed that the two had equivalent efficacy 43. Studies have noted small differences in the structures of these two epoetins, with the amounts of undesired N-glycolyl and acetylated forms of neuraminic acid higher in the original epoetin-α than in the biosimilar SB309 44. To date, however, this difference has not had clinical consequences 45.

The filgrastim biosimilar is widely accepted for clinical use in patients with oncology. A pooled analysis of five postapproval studies of this filgrastim biosimilar [granulocyte colony stimulating factor (G-CSF)] included 1302 adult patients who received at least one cycle of chemotherapy with G-CSF support for the prevention of neutropenia 46. The occurrence of severe or febrile neutropenia with the biosimilar was within the range observed with the original G-CSF. Moreover, the safety profile of the biosimilar was consistent with that of the original G-CSF. The most recent EORTC clinical guidelines recommend both biosimilar and the original filgrastim for the prevention of chemotherapy-induced neutropenia on the basis of the choice of the clinician 47.

By contrast, several studies from India, where the regulatory requirements are less stringent, have shown significant differences in the structure, level of purity and glycosylation of several biosimilars and their innovator products 48,49. The degree of purity for some brands was below the standards of the Indian pharmacopoeia.

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Immunogenicity

Immunogenicity is one of the most important clinical issues associated with the use of biologics. The production of antibodies against an endogenous protein may reduce its therapeutic efficacy or induce autoimmunity to endogenous molecules or systemic immune reactions.

The development of antidrug antibodies is influenced by patient characteristics and concomitant immunosuppressive therapy as well as product-related factors. The interplay of these factors for a given product cannot be predicted in the laboratory. Furthermore, immunogenicity may emerge only after long-term exposure, underscoring the need for effective pharmacovigilance 38. Immunogenicity may be addressed by noninferiority trials lasting at least 6 months 12.

To date, the prevailing body of evidence with both innovator biologics and biosimilars suggests that postregistration manufacturing changes do not alter their level of immunogenicity.

There are, however, significant caveats from epoetin use. Immunogenicity to epoetin is clinically very dangerous because it can lead to a pure red cell aplasia (PRCA). Pharmacovigilance data suggested that the background rate of PRCA during epoetin therapy was ∼1/100 000 patient-years. Following a manufacturing change of subcutaneously administered original epoetin, however, there was a marked increase in the incidence of PRCA, with more than 200 patients treated for chronic kidney failure experiencing PRCA from 1998 to 2003 50. This epidemic was later attributed to the replacement of human serum albumin as a stabilizer with the synthetic detergent polysorbate 80 and glycine 51. These substances acted as an adjuvant, resulting in an immune response against membrane-bound erythroblasts in the bone marrow, causing red cell aplasia.

Neutralizing antibodies to erythropoietin were also induced by the biosimilar HX575 in two patients with chronic kidney disease enrolled in a clinical trial comparing subcutaneously administered HX575 with original epoetin 52. Recent analysis suggested that this increase in immunogenicity may have been because of tungsten contamination during the manufacture of the syringes, which caused protein denaturation and aggregation of HX575 batches 53. Because of this unexpected finding, the epoetin biosimilar HX575 has not received EMA authorization for subcutaneous administration in patients with chronic kidney disease.

Another small study from Thailand reported PRCA and neutralizing antiepoetin antibodies in the sera of 23 out of 30 patients subcutaneously administered a biosimilar to recombinant human erythropoetin A, accompanied by a sudden loss of efficacy in these patients 54.

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Extrapolation of biosimilars across indications

It remains unclear whether data from clinical trials in patients with a given condition should be extrapolated to those with other conditions. To date, registration authorities have not issued guidelines as to whether, and how, biosimilars can be interchanged with the original biopharmaceuticals.

Approval of the biosimilar G-CSF was based primarily on studies testing whether it can prevent chemotherapy-induced neutropenia. However, approval was later extrapolated to other indications, including peripheral blood stem cell mobilization and neutrophil recovery after stem cell transplantation. Initial clinical studies report that the biosimilar G-CSF had similar efficacy and safety as the original in these indications 55.

Many physicians who treat patients with IBD oppose extrapolation from other indications. For example, the ECCO position statement states that a biosimilar proven effective and safe for one indication may not necessarily be effective and safe for a second indication in which the reference biological was shown to be safe and effective 56. ECCO advocates the need for specific evidence in patients with IBD to establish its efficacy and safety for this condition. The Spanish Society of Gastroenterology task force also stated that results obtained from studies in patients with RA should not be extrapolated to patients with IBD 57. Several medications found to be effective in RA, such as etanercept or abatacept, were not effective in IBD 58,59. Moreover, the IFX dose used to treat IBD (5 mg/kg) is higher than that used to treat RA (3 mg/kg). In addition, IFX is more often used as monotherapy in IBD, whereas it is used routinely in combination with MTX in RA, and immunosuppression reduces the risk of developing anti-TNFα antibodies 7. Furthermore, the exact mechanisms of action of anti-TNF medication in various diseases have not been determined and may differ considerably.

By contrast, the proponents of free extrapolation argue that, on the basis of findings showing that the active moieties of biosimilar and innovator biopharmaceuticals are ‘highly similar’, the only unknown in the use of biosimilars is their possible immunogenicity because clinical outcomes will otherwise be the same 32. Furthermore, they have stated that, to date, there has been no need for additional clinical trials after changes in manufacturing processes. Moreover, extrapolations among all indications and interchangeability for each indication have been based on the results of previous studies. Thus, clinical studies following changes in the manufacture of a biologic, or following the development of a biosimilar, should focus on its immunogenicity. Subsequent postmarketing surveillance provides confirmation and is equally important for all medicines 32.

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Interchangeability of a biosimilar and original agent

The US FDA defines interchangeable as follows: ‘that the biological product may be substituted for the reference product without the intervention of the healthcare provider who prescribed the reference product’. For biologics that are administered more than once to a patient, the safety and efficacy of alternating or switching between a reference product and a biosimilar must be equal to the safety and efficacy of using only the reference product 16,17. However, methods of studying switching or alternating of these products have not yet been defined.

Most clinicians argue against the interchangeability of biosimilars 12,38,56,57. For example, a review of 5 years of experience with epoetins suggested that switching between an original reference erythropoetin A and a biosimilar should be considered as a change in clinical management and that clinicians should be involved in making such decisions 38. In a head-to-head comparison cross-over clinical trial, switching from epoetin-α to the epoetin biosimilar SB309 resulted in, approximately, a 10–15% increase in the dose required and transiently decreased the haemoglobin concentration by ∼5% 40. Switching back from SB309 to epoetin-α reduced the dose required by almost 10% and increased haemoglobin levels by ∼10%.

Although switching between biological medicines raises potential safety concerns, a review of 58 clinical trials that collectively included 12 039 patients found that safety was not compromised 60.

The proponents of interchangeability argue that changes, to date, in the manufacturing process did not preclude full interchangeability 32. Indeed, most clinicians were not aware of these changes in manufacturing.

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Labelling of biosimilars

Traceability refers to the ability to identify individual medical products and is essential for accurate pharmacovigilance. The official name of a pharmaceutical substance is its international nonproprietary name (INN), given by the WHO. Generally, generic versions of chemical medicines are assigned the same name because they are considered fully identical copies of the reference products. However, because biosimilars are not considered to be fully identical, it has been suggested that not just their brand names but also their INNs should be unique 12,56. Confusion among names, however, would require that the safety and efficacy of the innovator and biosimilar be collected separately. In the EU, however, biosimilars generally have the same INN as the original product.

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Conclusion

Biosimilars of innovator anti-TNFα are becoming important in the treatment of patients with IBD, with the first one, the IFX biosimilar CT-P13, approved recently for clinical use. Clinicians should become familiar with the benefits and concerns regarding the rapidly evolving concept of biosimilars. The major benefit of biosimilars in patients with IBD will be the reduced cost of treatment, which will result in better access to biological therapy. However, there are concerns about the efficacy and safety of biosimilars in IBD, as well as the extrapolation of results from patients with RA to those with IBD, and the free interchangeability of biosimilars and original biopharmaceuticals. Experience with peptide biosimilars, such as epoetins and growth factors, has been generally positive, suggesting that the efficacy and safety profiles of biosimilars and original products are comparable, although immunogenicity remains a major concern. Ongoing postregistration studies will address these concerns about the use of biosimilars in IBD and will assess their efficacy, safety, immunogenicity, switching and interchangeability. In addition, biobetter biosimilars of present biologics, which react with the same epitope but have improved pharmacokinetic properties, may have enhanced efficacy and/or safety and may be the next stage in the development of biosimilars.

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Acknowledgements

Conflicts of interest

In the last 5 years, Tibor Hlavaty has served as speaker, consultant or advisory board member for MSD, Abbvie, Hospira, Alfa Wasserman, ProMed CS and Pfizer. He has received a scientific grant from Ferring Pharmaceuticals and unrestricted educational grants from MSD and Abbvie. Juraj Letkovsky has no conflicts of interest.

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Keywords:

biosimilars; Crohn’s disease; immunogenicity; inflammatory bowel diseases; infliximab; safety; ulcerative colitis

© 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins

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