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      Safety, pharmacokinetics and pharmacodynamics of AMG 811, an anti-interferon-γ monoclonal antibody, in SLE subjects without or with lupus nephritis

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          Abstract

          Objective

          To evaluate safety, pharmacokinetics and pharmacodynamics of anti-interferon (IFN)-γ monoclonal antibody AMG 811 in subjects with SLE without or with lupus nephritis (LN).

          Methods

          In this phase Ib, randomised, multiple-dose escalation study (NCT00818948), subjects without LN were randomised to subcutaneous AMG 811 (6, 20 or 60 mg) or placebo and subjects with LN were randomised to subcutaneous AMG 811 (20, 60 or 120 mg) or placebo every four weeks for three total doses. Outcomes included incidence of adverse events (AEs); pharmacokinetics; levels of serum proteins (CXCL-10, interleukin 18, monocyte chemotactic protein-1); changes in gene transcript profiles and clinical parameters (Safety of Estrogen in Lupus Erythematosus National Assessment-Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) scores, proteinuria, anti-double-stranded DNA (anti-dsDNA) antibodies, C3 complement, C4 complement).

          Results

          Fifty-six subjects enrolled (28 SLE without LN; 28 with LN). Baseline mean SELENA-SLEDAI scores were 2.2 and 12.0 for SLE subjects without and with LN, respectively. Most subjects reported an AE; no meaningful imbalances were observed between AMG 811 and placebo. Pharmacokinetic profiles were similar and mostly dose-proportional in subjects without or with LN. AMG 811 treatment reduced CXCL-10 protein levels and blood-based RNA IFN-γ Blockade Signature compared with placebo. Reductions were less pronounced and not sustained in subjects with LN, even at the highest dose tested, compared with subjects without LN. No effect on SELENA-SLEDAI scores, proteinuria, C3 or C4 complement levels, or anti-dsDNA antibodies was observed.

          Conclusion

          AMG 811 demonstrated favourable pharmacokinetics and acceptable safety profile but no evidence of clinical impact. IFN-γ-associated biomarkers decreased with AMG 811; effects were less pronounced and not sustained in LN subjects.

          Trial registration number

          NCT00818948; results.

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          Most cited references22

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          Mycophenolate mofetil versus cyclophosphamide for induction treatment of lupus nephritis.

          Recent studies have suggested that mycophenolate mofetil (MMF) may offer advantages over intravenous cyclophosphamide (IVC) for the treatment of lupus nephritis, but these therapies have not been compared in an international randomized, controlled trial. Here, we report the comparison of MMF and IVC as induction treatment for active lupus nephritis in a multinational, two-phase (induction and maintenance) study. We randomly assigned 370 patients with classes III through V lupus nephritis to open-label MMF (target dosage 3 g/d) or IVC (0.5 to 1.0 g/m(2) in monthly pulses) in a 24-wk induction study. Both groups received prednisone, tapered from a maximum starting dosage of 60 mg/d. The primary end point was a prespecified decrease in urine protein/creatinine ratio and stabilization or improvement in serum creatinine. Secondary end points included complete renal remission, systemic disease activity and damage, and safety. Overall, we did not detect a significantly different response rate between the two groups: 104 (56.2%) of 185 patients responded to MMF compared with 98 (53.0%) of 185 to IVC. Secondary end points were also similar between treatment groups. There were nine deaths in the MMF group and five in the IVC group. We did not detect significant differences between the MMF and IVC groups with regard to rates of adverse events, serious adverse events, or infections. Although most patients in both treatment groups experienced clinical improvement, the study did not meet its primary objective of showing that MMF was superior to IVC as induction treatment for lupus nephritis.
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            Adult-Onset Immunodeficiency in Thailand and Taiwan

            New England Journal of Medicine, 367(8), 725-734
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              Murine models of systemic lupus erythematosus.

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                Author and article information

                Journal
                Lupus Sci Med
                Lupus Sci Med
                lupusscimed
                lupus
                Lupus Science & Medicine
                BMJ Publishing Group (BMA House, Tavistock Square, London, WC1H 9JR )
                2053-8790
                2017
                14 September 2017
                : 4
                : 1
                : e000226
                Affiliations
                [1 ]Amgen Inc. , Thousand Oaks, California, USA
                [2 ]Amgen Inc. , Seattle, Washington, USA
                [3 ]French National Reference Center for SLE, Hôpital Pitié-Salpêtrière , Paris, France
                [4 ]Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán , Mexico City, Mexico
                [5 ]Altoona Center for Clinical Research , Duncansville, Pennsylvania, USA
                [6 ]Feinstein Institute for Medical Research , Manhasset, USA
                [7 ]Queen Mary Hospital, University of Hong Kong , Hong Kong
                [8 ]University Malaya Medical Centre , Kuala Lumpur, Malaysia
                Author notes
                [Correspondence to ] Dr James B Chung; chung@ 123456amgen.com
                Article
                lupus-2017-000226
                10.1136/lupus-2017-000226
                5604705
                29018537
                5664c882-8de0-4550-80a0-5fb4d03dcff3
                © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

                This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/

                History
                : 20 April 2017
                : 21 June 2017
                : 24 June 2017
                Funding
                Funded by: Amgen Inc.;
                Categories
                Lupus Nephritis
                1506
                Original research article
                Custom metadata
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