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      Pharmacokinetic equivalence, comparable safety, and immunogenicity of an adalimumab biosimilar product (M923) to Humira in healthy subjects

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          Abstract

          The aims of this randomized, double‐blind, three‐arm, single‐dose study were to demonstrate pharmacokinetic (PK) equivalence of the adalimumab biosimilar M923 (hereafter referred to as “M923”) to each of 2 reference products, and to assess M923's safety and immunogenicity. Primary PK endpoints were maximum observed concentration ( C max), area under the curve (AUC) from time 0 extrapolated to infinity (AUC 0‐inf), and AUC from time 0 to 336 hours (AUC 0‐336). Secondary endpoints included safety and immunogenicity assessments. Healthy subjects were randomized 1:1:1 to receive a 40‐mg dose of M923 (n = 107); adalimumab US Humira (n = 105), hereafter referred to as “US Humira”; or adalimumab EU Humira (n = 103), hereafter referred to as “EU Humira.” PK equivalence was demonstrated for all primary PK endpoints . Geometric least squares means ratios (GMRs) for C max, AUC 0‐inf, and AUC 0‐336 were 99.4, 100.9, and 100.5, respectively, between the M923 and EU Humira arms and 102.6, 104.2, and 102.9 between the M923 and US Humira arms. The 90% confidence intervals of the GMRs for all PK endpoints were within prespecified confidence bounds of 80%‐125%. Adverse event rates were similar across the M923 (47.7%), US Humira (50.9%), and EU Humira (53.3%) arms and were generally mild (73.7%) or moderate (22.0%). The proportion of subjects with a confirmed antidrug antibody (ADA) response was similar across study arms. This study demonstrated bioequivalent PK among M923, US Humira, and EU Humira and demonstrated that the PK parameters were consistent with similar safety and tolerability profile and ADA response rates.

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          Adalimumab for maintenance of clinical response and remission in patients with Crohn's disease: the CHARM trial.

          This study evaluated the efficacy and safety of adalimumab, a fully human, anti-tumor necrosis factor monoclonal antibody administered subcutaneously, in the maintenance of response and remission in patients with moderate to severe Crohn's disease (CD). Patients received open-label induction therapy with adalimumab 80 mg (week 0) followed by 40 mg (week 2). At week 4, patients were stratified by response (decrease in Crohn's Disease Activity Index > or =70 points from baseline) and randomized to double-blind treatment with placebo, adalimumab 40 mg every other week (eow), or adalimumab 40 mg weekly through week 56. Co-primary end points were the percentages of randomized responders who achieved clinical remission (Crohn's Disease Activity Index score <150) at weeks 26 and 56. The percentage of randomized responders in remission was significantly greater in the adalimumab 40-mg eow and 40-mg weekly groups versus placebo at week 26 (40%, 47%, and 17%, respectively; P < .001) and week 56 (36%, 41%, and 12%, respectively; P < .001). No significant differences in efficacy between adalimumab eow and weekly were observed. More patients receiving placebo discontinued treatment because of an adverse event (13.4%) than those receiving adalimumab (6.9% and 4.7% in the 40-mg eow and 40-mg weekly groups, respectively). Among patients who responded to adalimumab, both adalimumab eow and weekly were significantly more effective than placebo in maintaining remission in moderate to severe CD through 56 weeks. Adalimumab was well-tolerated, with a safety profile consistent with previous experience with the drug.
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            Immunogenicity to Biotherapeutics – The Role of Anti-drug Immune Complexes

            Biological molecules are increasingly becoming a part of the therapeutics portfolio that has been either recently approved for marketing or those that are in the pipeline of several biotech and pharmaceutical companies. This is largely based on their ability to be highly specific relative to small molecules. However, by virtue of being a large protein, and having a complex structure with structural variability arising from production using recombinant gene technology in cell lines, such therapeutics run the risk of being recognized as foreign by a host immune system. In the context of immune-mediated adverse effects that have been documented to biological drugs thus far, including infusion reactions, and the evolving therapeutic platforms in the pipeline that engineer different functional modules in a biotherapeutic, it is critical to understand the interplay of the adaptive and innate immune responses, the pathophysiology of immunogenicity to biological drugs in instances where there have been immune-mediated adverse clinical sequelae and address technical approaches for their laboratory evaluation. The current paradigm in immunogenicity evaluation has a tiered approach to the detection and characterization of anti-drug antibodies (ADAs) elicited in vivo to a biotherapeutic; alongside with the structural, biophysical, and molecular information of the therapeutic, these analytical assessments form the core of the immunogenicity risk assessment. However, many of the immune-mediated adverse effects attributed to ADAs require the formation of a drug/ADA immune complex (IC) intermediate that can have a variety of downstream effects. This review will focus on the activation of potential immunopathological pathways arising as a consequence of circulating as well as cell surface bound drug bearing ICs, risk factors that are intrinsic either to the therapeutic molecule or to the host that might predispose to IC-mediated effects, and review the recent literature on prevalence and intensity of established examples of type II and III hypersensitivity reactions that follow the administration of a biotherapeutic. Additionally, we propose methods for the study of immune parameters specific to the biology of ICs that could be of use in conjunction with the detection of ADAs in circulation.
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              Comparative Immunogenicity of TNF Inhibitors: Impact on Clinical Efficacy and Tolerability in the Management of Autoimmune Diseases. A Systematic Review and Meta-Analysis.

              Tumor necrosis factor (TNF) inhibitors are a mainstay in the treatment of rheumatoid arthritis (RA), as well as in the management of spondyloarthritis (SpA) and inflammatory bowel diseases (IBD). Unfortunately, a portion of patients taking these drugs require escalating doses within the approved label to achieve response, while others lose response altogether. This may be due to the development of antibodies against TNFi agents.
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                Author and article information

                Contributors
                tganguly@momentapharma.com
                Journal
                Pharmacol Res Perspect
                Pharmacol Res Perspect
                10.1002/(ISSN)2052-1707
                PRP2
                Pharmacology Research & Perspectives
                John Wiley and Sons Inc. (Hoboken )
                2052-1707
                08 January 2018
                February 2018
                : 6
                : 1 ( doiID: 10.1002/prp2.2018.6.issue-1 )
                : e00380
                Affiliations
                [ 1 ] ChemoCentryx Mountain View CA USA
                [ 2 ] QuintilesIMS Reading UK
                [ 3 ] NuCana plc Newton MA USA
                [ 4 ] Momenta Pharmaceuticals, Inc. Cambridge MA USA
                [ 5 ] Shire Cambridge MA USA
                [ 6 ] Shire Vienna Austria
                [ 7 ] QuintilesIMS Durham NC USA
                [ 8 ] QuintilesIMS Overland Park KS USA
                [ 9 ] Biologics Development Services Tampa FL USA
                Author notes
                [*] [* ] Correspondence

                Tanmoy Ganguly, Momenta Pharmaceuticals, Inc., Cambridge, MA, USA.

                Email: tganguly@ 123456momentapharma.com

                [†]

                At the time of this study Jan Hillson and Molly Rosano were employees of Momenta Pharmaceuticals, Inc., Cambridge, MA, USA.

                [‡]

                At the time of this study Paul Rhyne was an employee of QuintilesIMS, Durham, NC, USA.

                [§]

                At the time of this study James Roach was SVP, Development, and Chief Medical Officer, Momenta Pharmaceuticals, Inc., Cambridge, MA, USA.

                Author information
                http://orcid.org/0000-0003-0681-4737
                Article
                PRP2380
                10.1002/prp2.380
                5817835
                29417761
                9065f2a8-4a8d-4db7-a7f4-a3149206fe15
                © 2018 The Authors. Pharmacology Research & Perspectives published by John Wiley & Sons Ltd, British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics.

                This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.

                History
                : 11 October 2017
                : 27 November 2017
                Page count
                Figures: 4, Tables: 5, Pages: 11, Words: 7634
                Funding
                Funded by: Baxalta US Inc., now part of Shire
                Categories
                Original Article
                Original Articles
                Custom metadata
                2.0
                prp2380
                February 2018
                Converter:WILEY_ML3GV2_TO_NLMPMC version:version=5.3.2.2 mode:remove_FC converted:19.02.2018

                biologicals,monoclonal antibodies,pharmacokinetics
                biologicals, monoclonal antibodies, pharmacokinetics

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