Interchangeability of Biosimilars: What Level of Clinical Evidence is Needed to Support the Interchangeability Designation in the United States

A biosimilar is a biologic drug that is highly similar to a reference (originator) product, with no clinically meaningful differences between the two products in safety, purity, and potency . Regulatory approval of a biosimilar is based on analytical, structural, and functional comparisons with the reference product, comparative nonclinical (in vivo) studies, clinical pharmacokinetics and/or pharmacodynamics, and immunogenicity. In addition, comparative clinical efficacy and safety assessments are usually conducted and, taken together, comprise the totality of the evidence supporting biosimilarity. For a biosimilar to meet the additional designation of interchangeability in the United States (US), the applicant must demonstrate that the biological drug can be expected to produce the same clinical result as the reference product in any given patient and if the biological drug is administered more than once to an individual, the risk in terms of safety or diminished efficacy of alternating or switching between the use of the biological drug and the reference product is no greater than the risk of using the reference product without such alternation or switch . The challenges faced in conducting clinical studies to support a designation of interchangeability, as defined in the final interchangeability guidance from the US Food and Drug Administration, are considered. Potential alternative approaches to generating adequate and sufficient clinical data to support a designation of interchangeability are also presented

Immunogenicity negatively influences the outcome of adalimumab treatment in Crohn's disease

Background: Adalimumab is an effective treatment in patients with Crohn's disease; as it is a humanized anti-tumour necrosis factor monoclonal antibody, immunogenicity is thought not to be of any significance. Aim: To assess whether antibodies to adalimumab (ATAs) affect adalimumab treatment outcome in patients with Crohn's disease previously treated with infliximab. Methods: A retrospective study was p

The effects of continuous venovenous hemofiltration on coagulation activation

INTRODUCTION: The mechanism of coagulation activation during continuous venovenous hemofiltration (CVVH) has not yet been elucidated. Insight into the mechanism(s) of hemostatic activation within the extracorporeal circuit could result in a more rational approach to anticoagulation. The aim of the present study was to investigate whether CVVH using cellulose triacetate filters causes activation of the contact factor pathway or of the tissue factor pathway of coagulation. In contrast to previous studies, CVVH was performed without anticoagulation. METHODS: Ten critically ill patients were studied prior to the start of CVVH and at 5, 15 and 30 minutes and 1, 2, 3 and 6 hours thereafter, for measurement of prothrombin fragment F1+2, soluble tissue factor, activated factor VII, tissue factor pathway inhibitor, kallikrein–C1-inhibitor and activated factor XII–C1-inhibitor complexes, tissue-type plasminogen activator, plasminogen activator inhibitor type I, plasmin–antiplasmin complexes, protein C and antithrombin. RESULTS: During the study period the prothrombin fragment F1+2 levels increased significantly in four patients (defined as group A) and did not change in six patients (defined as group B). Group A also showed a rapid increase in transmembrane pressure, indicating clotting within the filter. At baseline, the activated partial thromboplastin time, the prothrombin time and the kallikrein–C1-inhibitor complex and activated factor XII–C1-inhibitor complex levels were significantly higher in group B, whereas the platelet count was significantly lower in group B. For the other studied markers the differences between group A and group B at baseline were not statistically significant. During CVVH the difference in the time course between group A and group B was not statistically significant for the markers of the tissue factor system (soluble tissue factor, activated factor VII and tissue factor pathway inhibitor), for the markers of the contact system (kallikrein–C1-inhibitor and activated factor XII–C1-inhibitor complexes) and for the markers of the fibrinolytic system (plasmin–antiplasmin complexes, tissue-type plasminogen activator and plasminogen activator inhibitor type I). CONCLUSION: Early thrombin generation was detected in a minority of intensive care patients receiving CVVH without anticoagulation. Systemic concentrations of markers of the tissue factor system and of the contact system did not change during CVVH. To elucidate the mechanism of clot formation during CVVH we suggest that future studies are needed that investigate the activation of coagulation directly at the site of the filter. Early coagulation during CVVH may be related to lower baseline levels of markers of contact activation

Identification of Clinically and Pathophysiologically Relevant Rheumatoid Factor Epitopes by Engineered IgG Targets

Objective: Rheumatoid factors (RFs), which are anti-IgG autoantibodies strongly associated with rheumatoid arthritis (RA), are also found in other diseases and in healthy individuals. RFs bind to various epitopes in the constant (Fc-) domain of IgG. Therefore, disease-specific reactivity patterns may exist. This study was undertaken in order to develop a new approach to dissecting RF epitope binding patterns across different diseases. Methods: We analyzed RF reactivity patterns in serum from patients with seropositive arthralgia, patients with RA, and patients with primary Sjögren’s syndrome (SS) using bioengineered, natively folded IgG-Fc targets that demonstrated selective RF binding toward several distinct regions of the IgG-Fc domain. Results: Rheumatoid factor responses primarily bound the Fc Elbow region, with a smaller number of RFs binding the Fc Tail region, while the Fc receptor binding region was hardly targeted. A restricted reactivity against the IgG-Fc Tail region was associated with less positivity for anti–citrullinated protein antibodies (ACPAs) and less arthritis development in arthralgia, whereas combined reactivity toward IgG-Fc Tail and Elbow regions was associated with more arthritis development. Reactivity toward the IgG-Fc Tail region was observed far more frequently in RA than in primary SS. Conclusion: Bioengineered IgG targets enable serologic characterization of RF reactivity patterns, and use of this approach appears to reveal patterns associated with ACPA detection and arthritis development in patients with arthralgia. These patterns are able to distinguish RA patients from primary SS patients. This new methodology improves the clinical value of RFs and our understanding of their pathophysiologic processes

Association of response to TNF inhibitors in rheumatoid arthritis with quantitative trait loci for CD40 and CD39

This study was supported by Medical Research Council (MRC) MR/K015346/1 MATURA study. ARUK 20670 MATURA study. Publisher Copyright: © Author(s) (or their employer(s)) 2019.Objectives We sought to investigate whether genetic effects on response to TNF inhibitors (TNFi) in rheumatoid arthritis (RA) could be localised by considering known genetic susceptibility loci for relevant traits and to evaluate the usefulness of these genetic loci for stratifying drug response. Methods We studied the relation of TNFi response, quantified by change in swollen joint counts (ΔSJC) and erythrocyte sedimentation rate (ΔESR) with locus-specific scores constructed from genome-wide assocation study summary statistics in 2938 genotyped individuals: 37 scores for RA; scores for 19 immune cell traits; scores for expression or methylation of 93 genes with previously reported associations between transcript level and drug response. Multivariate associations were evaluated in penalised regression models by cross-validation. Results We detected a statistically significant association between ΔSJC and the RA score at the CD40 locus (p=0.0004) and an inverse association between ΔSJC and the score for expression of CD39 on CD4 T cells (p=0.00005). A previously reported association between CD39 expression on regulatory T cells and response to methotrexate was in the opposite direction. In stratified analysis by concomitant methotrexate treatment, the inverse association was stronger in the combination therapy group and dissipated in the TNFi monotherapy group. Overall, ability to predict TNFi response from genotypic scores was limited, with models explaining less than 1% of phenotypic variance. Conclusions The association with the CD39 trait is difficult to interpret because patients with RA are often prescribed TNFi after failing to respond to methotrexate. The CD39 and CD40 pathways could be relevant for targeting drug therapy.Peer reviewe

Association of response to TNF inhibitors in rheumatoid arthritis with quantitative trait loci for CD40 and CD39

We sought to investigate whether genetic effects on response to TNF inhibitors (TNFi) in rheumatoid arthritis (RA) could be localised by considering known genetic susceptibility loci for relevant traits and to evaluate the usefulness of these genetic loci for stratifying drug response. Methods: We studied the relation of TNFi response, quantified by change in swollen joint counts ("SJC) and erythrocyte sedimentation rate ("ESR) with locus-specific scores constructed from genome-wide assocation study summary statistics in 2938 genotyped individuals: 37 scores for RA; scores for 19 immune cell traits; scores for expression or methylation of 93 genes with previously reported associations between transcript level and drug response. Multivariate associations were evaluated in penalised regression models by cross-validation. Results: We detected a statistically significant association between "SJC and the RA score at the CD40 locus (p=0.0004) and an inverse association between "SJC and the score for expression of CD39 on CD4 T cells (p=0.00005). A previously reported association between CD39 expression on regulatory T cells and response to methotrexate was in the opposite direction. In stratified analysis by concomitant methotrexate treatment, the inverse association was stronger in the combination therapy group and dissipated in the TNFi monotherapy group. Overall, ability to predict TNFi response from genotypic scores was limited, with models explaining less than 1% of phenotypic variance. Conclusions: The association with the CD39 trait is difficult to interpret because patients with RA are often prescribed TNFi after failing to respond to methotrexate. The CD39 and CD40 pathways could be relevant for targeting drug therapy

Immunogenicity of biological therapeutics: from assay to patient

Purpose of review To give an overview of the current knowledge on assay techniques and clinical implications of immunogenicity of biological therapeutics. Recent findings Assay techniques for the measurement of immunogenicity have improved, expanding the understanding of the immune response against biological therapeutics. Knowledge on the clinical effect of immunogenicity enables the treatment of patients in a targeted fashion, as a step towards personalized medicine. Summary Biological medications are able to induce an antidrug immune response. Immunogenicity impairs clinical response and is associated with adverse events. Several confounding factors influence the measurement of immunogenicity, including drug interference and background problems. Concomitant administration of methotrexate lowers the frequency and amount of antibodies formed, whereby the efficacy of biologicals is improved. Algorithms for therapeutic drug monitoring could aid in adapting treatment strategies in a controlled settin

Immunogenicity of anti-tumor necrosis factor antibodies - toward improved methods of anti-antibody measurement

To date, millions of people have been treated with therapeutic monoclonal antibodies (TmAbs) for various indications. It is becoming increasingly clear that TmAbs can be immunogenic, which may reduce efficacy or induce adverse effects. Over the years, the importance of antibody formation has been questioned and sometimes minimized, as few antibody responses to TmAbs (HACA or HAHA) were reported. However, the methods to detect and quantify such antibodies used in the past have been problematic. Only recently, methods have been developed that have adequate sensitivity and are not seriously disturbed by false-positive reactions caused by rheumatoid factors, natural antibodies to Fab or F(ab')(2) fragments, or Fc interactions of IgG4. The large number of treated patients, in combination with these new assays, presents a unique opportunity to study the anti-antibody immune response in man, possibly allowing us to manipulate immunogenicity in the futur

Interchangeability of Biosimilars: What Level of Clinical Evidence is Needed to Support the Interchangeability Designation in the United States?

A biosimilar is a biologic drug that is “highly similar to a reference (originator) product, with no clinically meaningful differences between the two products in safety, purity, and potency”. Regulatory approval of a biosimilar is based on analytical, structural, and functional comparisons with the reference product, comparative nonclinical (in vivo) studies, clinical pharmacokinetics and/or pharmacodynamics, and immunogenicity. In addition, comparative clinical efficacy and safety assessments are usually conducted and, taken together, comprise the “totality of the evidence” supporting biosimilarity. For a biosimilar to meet the additional designation of interchangeability in the United States (US), the applicant must demonstrate that the biological drug can be expected to produce the “same clinical result as the reference product in any given patient” and “if the biological drug is administered more than once to an individual, the risk in terms of safety or diminished efficacy of alternating or switching between the use of the biological drug and the reference product is no greater than the risk of using the reference product without such alternation or switch”. The challenges faced in conducting clinical studies to support a designation of interchangeability, as defined in the final interchangeability guidance from the US Food and Drug Administration, are considered. Potential alternative approaches to generating adequate and sufficient clinical data to support a designation of interchangeability are also presented