Role of Biosimilars in the Treatment of Rheumatic Diseases
Role of Biosimilars in the Treatment of Rheumatic Diseases
Manufacturing processes of novel biological products are subject to iterative modification, to increase efficiency of production or accommodate manufacturing site changes. Such changes require extensive analysis of pre- and post-change products (comparability exercise), with subsequent approval by regulatory authorities; EMA/FDA, therefore, have extensive experience in regulating comparability exercises. In the USA, there is no public regulatory determination of comparability similar to the European Public Assessment Report, so physicians and patients may never know a manufacturing change has occurred. Clinical testing is, however, mandated when sufficient changes to the reference product occur. Importantly, these alterations are made with a knowledge of the original manufacturing process, which differs from biosimilar development where proprietary manufacturing data are unavailable. EMA and FDA, therefore, stipulate that studies comparing biosimilars to reference products be more extensive.
Manufacture of large, complex proteins utilises a living cell line cultured in highly controlled settings. Subtle changes in protein conformation may result in altered function, insolubility or immunogenicity, thus, amino acid sequences and higher-order structures must be reproduced.
Biological agents include protein mediators, such as hormones and growth factors, with a molecular weight of ~5000–50 000 Da. These exhibit well-characterised structural features that can be replicated reliably using recombinant techniques. By contrast, mAbs and Cepts are complex molecules, ~150 000 Da, which must be folded correctly to maintain conformational integrity. Post-translational modifications (eg, glycosylation, methylation, oxidation, deamidation) may influence tertiary and quaternary structures. Conformational integrity determines affinity, selectivity, functional activity and immunogenicity of mAbs and Cepts, yet can be inherently difficult to replicate: glycosylation patterns are not template driven, and are extremely sensitive to minor alterations in manufacturing conditions. Moreover, deglycosylated peptide motifs represent important sites of B-cell epitopes, thereby providing new or different immunogenic domains. While these issues have generally led to concerns regarding inferiority of biosimilars compared with reference products, it must be borne in mind that such alterations could potentially lead to superior efficacy and safety. However, according to regulations set forth by EMA and FDA, neither an 'inferior' nor a 'superior' product would qualify as a biosimilar, due to the potential for altered biological activity and/or safety. Biosimilars manufacturers must ensure sufficient analyses are performed to demonstrate a high degree of similarity between reference agents and biosimilars, prior to their entry into equivalence trials.
Importance of Conformational Structure for Biological Effect. Affinity is a key determinant of the pharmacokinetic (PK) and pharmacodynamic (PD) profile of mAbs and Cepts, potentially impacting their dosing regimen. Thus, it is important to determine plasma levels and obtain accurate PK and PD data for biosimilars. Antibody binding to target antigen is determined by affinity, but even when affinity is high, concentrations must be adequate to maintain effective binding. The importance of affinity for determining dosing regimens is highlighted by two human TNFi mAbs, adalimumab and golimumab, with similar in vivo half-lives and sizes. Both recognise the same target, albeit different epitopes, yet one is administered every 2 weeks and the other monthly. Higher binding affinity for golimumab appears to be the predominant difference, allowing efficacy to be maintained at lower serum concentrations. These data highlight the importance of binding affinity for biological efficacy, reflecting the need for close reproduction of conformational structure for biosimilar mAbs and Cepts.
Immunogenicity. All biological agents are immunogenic because they are non-self; even humanised and 'fully human' mAbs and Cepts can result in measurable immune responses. Many factors can influence immunogenicity, such as changes in glycosylation patterns that may expose or hide antigenic components, alter solubility or influence protein degradation. Importantly, experience has demonstrated that presence of aggregates, impurities or contaminants can provoke unwanted immune responses. Thus, alterations in manufacturing processes/storage conditions may result in altered immunogenicity of biosimilars compared with reference products.
The effects of antibiological antibodies include reduction in serum levels, adverse events and formation of neutralising antibodies. Anti-infliximab antibodies have been associated with infusion reactions in patients with Crohn's disease, while antiadalimumab antibodies may heighten the risk of rare thromboembolic events in patients with RA and psoriatic arthritis. Postmarketing surveillance of TNFi mAbs has identified a potential link between antibiological antibodies and treatment-related vasculitis, albeit very rare events. It is therefore important to implement clinical trials of sufficient size and duration to determine the safety of biosimilars and postmarketing surveillance to identify rare adverse events. This is also important for reference products that undergo iterative manufacturing process alterations resulting in consequences if significant changes occur.
Most commonly, immunogenicity contributes to loss of clinical efficacy, that is, tachyphylaxis. Loss of clinical responses to TNFi occur over time, and have been associated with the presence of antibiological antibodies in some patients. This is more common in those with Crohn's disease, where intermittent administration is more frequent and background medication less commonly utilised when compared with RA.
Route of administration and host-related factors also influence immunogenicity. Patients with autoimmune diseases more commonly develop antibiological antibodies, as well as naturally occurring anticytokine autoantibodies. Consideration of separate clinical trials for biosimilars in different therapeutic indications is therefore important.
Fc Effector Function. Activity of mAbs and Cepts depends not only upon interactions with target antigen, but also Fc receptor (FcγR) function. Mutations of just one amino acid are sufficient to impair Fc interactions, thereby altering complement activation and/or antibody-dependent cytotoxicity, and reducing the efficacy of therapeutic mAbs. For example, two anti-CD20 mAbs, ofatumumab and rituximab, display different levels of B cell depletion, potentially due to altered fucosylation patterns. Due to constraints in conformational changes, etanercept exhibits reduced complement binding compared with infliximab and adalimumab. Efficacy of mAbs can also be affected by individual patient characteristics: in patients with RA and psoriatic arthritis, FcγR polymorphisms result in different responses to TNFi. Biosimilars must, therefore, demonstrate highly similar efficacy and safety to the reference product in well-designed RCTs.
The key question for biosimilars is not whether differences exist compared with the reference, but whether differences are clinically relevant. Microheterogeneity is a feature of batch-to-batch variability for any biological agent, and sometimes major changes occur with alterations to manufacturing processes; the degree of variability is assessed with quality control of each batch. As manufacturing processes for biologicals become more efficient, batch sizes increase, and only one or two batches may account for the entire use of a reference product in the European Union (EU) or USA over a 1-year period. For biosimilars, it is necessary to establish 'acceptable variation' parameters for comparability with the reference product. If comparisons are to a single batch, then these parameters will be more narrow than the batch-to-batch variation of the reference product.
Given their inherent complexity, biosimilar mAbs and Cepts cannot be absolutely identical to the reference. However, certain fundamental features must be retained ( table 5 ). Even sophisticated comparability testing, in vitro assays and animal studies cannot fully predict the biological and clinical activity of a therapeutic mAb; the only way to sufficiently assess the efficacy and safety of biosimilars is via RCTs in patients with the disease in question. Concerns surrounding the immunogenicity of biological products have previously been compounded by the limited clinical relevance of standardised assays for antibiological antibodies. However, the emergence of biosimilars has encouraged development of more robust assays that can detect antibodies in the presence of higher circulating levels of mAbs and Cepts, which can be used in clinical settings.
Reference Biologicals versus Biosimilars: How Similar Must They Be?
Reference Agents: Are They Identical to the Initial Approved Product?
Manufacturing processes of novel biological products are subject to iterative modification, to increase efficiency of production or accommodate manufacturing site changes. Such changes require extensive analysis of pre- and post-change products (comparability exercise), with subsequent approval by regulatory authorities; EMA/FDA, therefore, have extensive experience in regulating comparability exercises. In the USA, there is no public regulatory determination of comparability similar to the European Public Assessment Report, so physicians and patients may never know a manufacturing change has occurred. Clinical testing is, however, mandated when sufficient changes to the reference product occur. Importantly, these alterations are made with a knowledge of the original manufacturing process, which differs from biosimilar development where proprietary manufacturing data are unavailable. EMA and FDA, therefore, stipulate that studies comparing biosimilars to reference products be more extensive.
Manufacturing and Functional Implications
Manufacture of large, complex proteins utilises a living cell line cultured in highly controlled settings. Subtle changes in protein conformation may result in altered function, insolubility or immunogenicity, thus, amino acid sequences and higher-order structures must be reproduced.
Biological agents include protein mediators, such as hormones and growth factors, with a molecular weight of ~5000–50 000 Da. These exhibit well-characterised structural features that can be replicated reliably using recombinant techniques. By contrast, mAbs and Cepts are complex molecules, ~150 000 Da, which must be folded correctly to maintain conformational integrity. Post-translational modifications (eg, glycosylation, methylation, oxidation, deamidation) may influence tertiary and quaternary structures. Conformational integrity determines affinity, selectivity, functional activity and immunogenicity of mAbs and Cepts, yet can be inherently difficult to replicate: glycosylation patterns are not template driven, and are extremely sensitive to minor alterations in manufacturing conditions. Moreover, deglycosylated peptide motifs represent important sites of B-cell epitopes, thereby providing new or different immunogenic domains. While these issues have generally led to concerns regarding inferiority of biosimilars compared with reference products, it must be borne in mind that such alterations could potentially lead to superior efficacy and safety. However, according to regulations set forth by EMA and FDA, neither an 'inferior' nor a 'superior' product would qualify as a biosimilar, due to the potential for altered biological activity and/or safety. Biosimilars manufacturers must ensure sufficient analyses are performed to demonstrate a high degree of similarity between reference agents and biosimilars, prior to their entry into equivalence trials.
Importance of Conformational Structure for Biological Effect. Affinity is a key determinant of the pharmacokinetic (PK) and pharmacodynamic (PD) profile of mAbs and Cepts, potentially impacting their dosing regimen. Thus, it is important to determine plasma levels and obtain accurate PK and PD data for biosimilars. Antibody binding to target antigen is determined by affinity, but even when affinity is high, concentrations must be adequate to maintain effective binding. The importance of affinity for determining dosing regimens is highlighted by two human TNFi mAbs, adalimumab and golimumab, with similar in vivo half-lives and sizes. Both recognise the same target, albeit different epitopes, yet one is administered every 2 weeks and the other monthly. Higher binding affinity for golimumab appears to be the predominant difference, allowing efficacy to be maintained at lower serum concentrations. These data highlight the importance of binding affinity for biological efficacy, reflecting the need for close reproduction of conformational structure for biosimilar mAbs and Cepts.
Immunogenicity. All biological agents are immunogenic because they are non-self; even humanised and 'fully human' mAbs and Cepts can result in measurable immune responses. Many factors can influence immunogenicity, such as changes in glycosylation patterns that may expose or hide antigenic components, alter solubility or influence protein degradation. Importantly, experience has demonstrated that presence of aggregates, impurities or contaminants can provoke unwanted immune responses. Thus, alterations in manufacturing processes/storage conditions may result in altered immunogenicity of biosimilars compared with reference products.
The effects of antibiological antibodies include reduction in serum levels, adverse events and formation of neutralising antibodies. Anti-infliximab antibodies have been associated with infusion reactions in patients with Crohn's disease, while antiadalimumab antibodies may heighten the risk of rare thromboembolic events in patients with RA and psoriatic arthritis. Postmarketing surveillance of TNFi mAbs has identified a potential link between antibiological antibodies and treatment-related vasculitis, albeit very rare events. It is therefore important to implement clinical trials of sufficient size and duration to determine the safety of biosimilars and postmarketing surveillance to identify rare adverse events. This is also important for reference products that undergo iterative manufacturing process alterations resulting in consequences if significant changes occur.
Most commonly, immunogenicity contributes to loss of clinical efficacy, that is, tachyphylaxis. Loss of clinical responses to TNFi occur over time, and have been associated with the presence of antibiological antibodies in some patients. This is more common in those with Crohn's disease, where intermittent administration is more frequent and background medication less commonly utilised when compared with RA.
Route of administration and host-related factors also influence immunogenicity. Patients with autoimmune diseases more commonly develop antibiological antibodies, as well as naturally occurring anticytokine autoantibodies. Consideration of separate clinical trials for biosimilars in different therapeutic indications is therefore important.
Fc Effector Function. Activity of mAbs and Cepts depends not only upon interactions with target antigen, but also Fc receptor (FcγR) function. Mutations of just one amino acid are sufficient to impair Fc interactions, thereby altering complement activation and/or antibody-dependent cytotoxicity, and reducing the efficacy of therapeutic mAbs. For example, two anti-CD20 mAbs, ofatumumab and rituximab, display different levels of B cell depletion, potentially due to altered fucosylation patterns. Due to constraints in conformational changes, etanercept exhibits reduced complement binding compared with infliximab and adalimumab. Efficacy of mAbs can also be affected by individual patient characteristics: in patients with RA and psoriatic arthritis, FcγR polymorphisms result in different responses to TNFi. Biosimilars must, therefore, demonstrate highly similar efficacy and safety to the reference product in well-designed RCTs.
Properties of Biosimilars: How Similar is Similar Enough?
The key question for biosimilars is not whether differences exist compared with the reference, but whether differences are clinically relevant. Microheterogeneity is a feature of batch-to-batch variability for any biological agent, and sometimes major changes occur with alterations to manufacturing processes; the degree of variability is assessed with quality control of each batch. As manufacturing processes for biologicals become more efficient, batch sizes increase, and only one or two batches may account for the entire use of a reference product in the European Union (EU) or USA over a 1-year period. For biosimilars, it is necessary to establish 'acceptable variation' parameters for comparability with the reference product. If comparisons are to a single batch, then these parameters will be more narrow than the batch-to-batch variation of the reference product.
Given their inherent complexity, biosimilar mAbs and Cepts cannot be absolutely identical to the reference. However, certain fundamental features must be retained ( table 5 ). Even sophisticated comparability testing, in vitro assays and animal studies cannot fully predict the biological and clinical activity of a therapeutic mAb; the only way to sufficiently assess the efficacy and safety of biosimilars is via RCTs in patients with the disease in question. Concerns surrounding the immunogenicity of biological products have previously been compounded by the limited clinical relevance of standardised assays for antibiological antibodies. However, the emergence of biosimilars has encouraged development of more robust assays that can detect antibodies in the presence of higher circulating levels of mAbs and Cepts, which can be used in clinical settings.
