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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

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 randomi...

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Autores principales: Boedigheimer, Michael J, Martin, David A, Amoura, Zahir, Sánchez-Guerrero, Jorge, Romero-Diaz, Juanita, Kivitz, Alan, Aranow, Cynthia, Chan, Tak Mao, Chong, Yip Boon, Chiu, Kit, Wang, Christine, Sohn, Winnie, Arnold, Gregory E, Damore, Michael A, Welcher, Andrew A, Sullivan, Barbara A, Kotzin, Brian L, Chung, James B
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BMJ Publishing Group 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5604705/
https://www.ncbi.nlm.nih.gov/pubmed/29018537
http://dx.doi.org/10.1136/lupus-2017-000226
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author Boedigheimer, Michael J
Martin, David A
Amoura, Zahir
Sánchez-Guerrero, Jorge
Romero-Diaz, Juanita
Kivitz, Alan
Aranow, Cynthia
Chan, Tak Mao
Chong, Yip Boon
Chiu, Kit
Wang, Christine
Sohn, Winnie
Arnold, Gregory E
Damore, Michael A
Welcher, Andrew A
Sullivan, Barbara A
Kotzin, Brian L
Chung, James B
author_facet Boedigheimer, Michael J
Martin, David A
Amoura, Zahir
Sánchez-Guerrero, Jorge
Romero-Diaz, Juanita
Kivitz, Alan
Aranow, Cynthia
Chan, Tak Mao
Chong, Yip Boon
Chiu, Kit
Wang, Christine
Sohn, Winnie
Arnold, Gregory E
Damore, Michael A
Welcher, Andrew A
Sullivan, Barbara A
Kotzin, Brian L
Chung, James B
author_sort Boedigheimer, Michael J
collection PubMed
description 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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spelling pubmed-56047052017-10-10 Safety, pharmacokinetics and pharmacodynamics of AMG 811, an anti-interferon-γ monoclonal antibody, in SLE subjects without or with lupus nephritis Boedigheimer, Michael J Martin, David A Amoura, Zahir Sánchez-Guerrero, Jorge Romero-Diaz, Juanita Kivitz, Alan Aranow, Cynthia Chan, Tak Mao Chong, Yip Boon Chiu, Kit Wang, Christine Sohn, Winnie Arnold, Gregory E Damore, Michael A Welcher, Andrew A Sullivan, Barbara A Kotzin, Brian L Chung, James B Lupus Sci Med Lupus Nephritis 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. BMJ Publishing Group 2017-09-14 /pmc/articles/PMC5604705/ /pubmed/29018537 http://dx.doi.org/10.1136/lupus-2017-000226 Text en © 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/
spellingShingle Lupus Nephritis
Boedigheimer, Michael J
Martin, David A
Amoura, Zahir
Sánchez-Guerrero, Jorge
Romero-Diaz, Juanita
Kivitz, Alan
Aranow, Cynthia
Chan, Tak Mao
Chong, Yip Boon
Chiu, Kit
Wang, Christine
Sohn, Winnie
Arnold, Gregory E
Damore, Michael A
Welcher, Andrew A
Sullivan, Barbara A
Kotzin, Brian L
Chung, James B
Safety, pharmacokinetics and pharmacodynamics of AMG 811, an anti-interferon-γ monoclonal antibody, in SLE subjects without or with lupus nephritis
title Safety, pharmacokinetics and pharmacodynamics of AMG 811, an anti-interferon-γ monoclonal antibody, in SLE subjects without or with lupus nephritis
title_full Safety, pharmacokinetics and pharmacodynamics of AMG 811, an anti-interferon-γ monoclonal antibody, in SLE subjects without or with lupus nephritis
title_fullStr Safety, pharmacokinetics and pharmacodynamics of AMG 811, an anti-interferon-γ monoclonal antibody, in SLE subjects without or with lupus nephritis
title_full_unstemmed Safety, pharmacokinetics and pharmacodynamics of AMG 811, an anti-interferon-γ monoclonal antibody, in SLE subjects without or with lupus nephritis
title_short Safety, pharmacokinetics and pharmacodynamics of AMG 811, an anti-interferon-γ monoclonal antibody, in SLE subjects without or with lupus nephritis
title_sort safety, pharmacokinetics and pharmacodynamics of amg 811, an anti-interferon-γ monoclonal antibody, in sle subjects without or with lupus nephritis
topic Lupus Nephritis
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5604705/
https://www.ncbi.nlm.nih.gov/pubmed/29018537
http://dx.doi.org/10.1136/lupus-2017-000226
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