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Randomised clinical trial: a phase 1, dose‐ranging study of the anti‐matrix metalloproteinase‐9 monoclonal antibody GS‐5745 versus placebo for ulcerative colitis
BACKGROUND: Matrix metalloproteinase‐9 is a proteolytic enzyme whose expression is increased in ulcerative colitis. AIM: To evaluate the safety and efficacy of GS‐5745, a fully humanised anti‐matrix metalloproteinase‐9 monoclonal antibody, in moderately‐to‐severely active ulcerative colitis. METHODS...
Autores principales: | , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5089609/ https://www.ncbi.nlm.nih.gov/pubmed/27218676 http://dx.doi.org/10.1111/apt.13653 |
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author | Sandborn, W. J. Bhandari, B. R. Fogel, R. Onken, J. Yen, E. Zhao, X. Jiang, Z. Ge, D. Xin, Y. Ye, Z. French, D. Silverman, J. A. Kanwar, B. Subramanian, G. M. McHutchison, J. G. Lee, S. D. Shackelton, L. M. Pai, R. K. Levesque, B. G. Feagan, B. G. |
author_facet | Sandborn, W. J. Bhandari, B. R. Fogel, R. Onken, J. Yen, E. Zhao, X. Jiang, Z. Ge, D. Xin, Y. Ye, Z. French, D. Silverman, J. A. Kanwar, B. Subramanian, G. M. McHutchison, J. G. Lee, S. D. Shackelton, L. M. Pai, R. K. Levesque, B. G. Feagan, B. G. |
author_sort | Sandborn, W. J. |
collection | PubMed |
description | BACKGROUND: Matrix metalloproteinase‐9 is a proteolytic enzyme whose expression is increased in ulcerative colitis. AIM: To evaluate the safety and efficacy of GS‐5745, a fully humanised anti‐matrix metalloproteinase‐9 monoclonal antibody, in moderately‐to‐severely active ulcerative colitis. METHODS: We randomised 74 patients with ulcerative colitis to treatment with single or multiple ascending intravenous or subcutaneous doses of GS‐5745 or placebo. Multiple‐dose cohorts received either IV infusions (0.3, 1.0, 2.5 or 5.0 mg/kg GS‐5745 or placebo) every 2 weeks (three total IV infusions) or five weekly SC injections (150 mg GS‐5745 or placebo). The primary outcomes were the safety, tolerability and pharmacokinetics of escalating single and multiple doses of GS‐5745. Exploratory analyses in the multiple‐dose cohorts included clinical response (≥3 points or 30% decrease from baseline in Mayo Clinic score and ≥1 point decrease in the rectal bleeding subscore or a rectal bleeding subscore ≤1) and clinical remission (a complete Mayo Clinic score ≤2 with no subscore >1) at Day 36. Biological effects associated with a clinical response to GS‐5745 were explored using histological and molecular approaches. RESULTS: Twenty‐three of the 42 patients (55%) receiving multiple doses of GS‐5745 had adverse events, compared with 5/8 patients (63%) receiving placebo. GS‐5745 showed target‐mediated drug disposition, approximately dose‐proportional increases in maximum plasma concentration and more than dose‐proportional increases in the area under the plasma drug concentration‐time curve. Clinical response occurred in 18/42 patients (43%) receiving GS‐5745 compared with 1/8 patients (13%) receiving placebo. Clinical remission occurred in 6/42 patients (14%) receiving GS‐5745 and 0/8 (0%) receiving placebo. Patients with a clinical response to GS‐5745 had reductions in matrix metalloproteinase‐9 tissue levels (mean 48.9% decrease from baseline compared with a mean 18.5% increase in nonresponders, P = 0.008) significant improvements in histopathology scores (confirmed with three separate histological disease activity indices), as well as changes in colonic gene expression that were consistent with reduced inflammation. CONCLUSION: This phase 1 trial provides preliminary evidence for the safety and therapeutic potential of GS‐5745 in the treatment of ulcerative colitis. |
format | Online Article Text |
id | pubmed-5089609 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-50896092016-11-09 Randomised clinical trial: a phase 1, dose‐ranging study of the anti‐matrix metalloproteinase‐9 monoclonal antibody GS‐5745 versus placebo for ulcerative colitis Sandborn, W. J. Bhandari, B. R. Fogel, R. Onken, J. Yen, E. Zhao, X. Jiang, Z. Ge, D. Xin, Y. Ye, Z. French, D. Silverman, J. A. Kanwar, B. Subramanian, G. M. McHutchison, J. G. Lee, S. D. Shackelton, L. M. Pai, R. K. Levesque, B. G. Feagan, B. G. Aliment Pharmacol Ther Randomised Clinical Trial BACKGROUND: Matrix metalloproteinase‐9 is a proteolytic enzyme whose expression is increased in ulcerative colitis. AIM: To evaluate the safety and efficacy of GS‐5745, a fully humanised anti‐matrix metalloproteinase‐9 monoclonal antibody, in moderately‐to‐severely active ulcerative colitis. METHODS: We randomised 74 patients with ulcerative colitis to treatment with single or multiple ascending intravenous or subcutaneous doses of GS‐5745 or placebo. Multiple‐dose cohorts received either IV infusions (0.3, 1.0, 2.5 or 5.0 mg/kg GS‐5745 or placebo) every 2 weeks (three total IV infusions) or five weekly SC injections (150 mg GS‐5745 or placebo). The primary outcomes were the safety, tolerability and pharmacokinetics of escalating single and multiple doses of GS‐5745. Exploratory analyses in the multiple‐dose cohorts included clinical response (≥3 points or 30% decrease from baseline in Mayo Clinic score and ≥1 point decrease in the rectal bleeding subscore or a rectal bleeding subscore ≤1) and clinical remission (a complete Mayo Clinic score ≤2 with no subscore >1) at Day 36. Biological effects associated with a clinical response to GS‐5745 were explored using histological and molecular approaches. RESULTS: Twenty‐three of the 42 patients (55%) receiving multiple doses of GS‐5745 had adverse events, compared with 5/8 patients (63%) receiving placebo. GS‐5745 showed target‐mediated drug disposition, approximately dose‐proportional increases in maximum plasma concentration and more than dose‐proportional increases in the area under the plasma drug concentration‐time curve. Clinical response occurred in 18/42 patients (43%) receiving GS‐5745 compared with 1/8 patients (13%) receiving placebo. Clinical remission occurred in 6/42 patients (14%) receiving GS‐5745 and 0/8 (0%) receiving placebo. Patients with a clinical response to GS‐5745 had reductions in matrix metalloproteinase‐9 tissue levels (mean 48.9% decrease from baseline compared with a mean 18.5% increase in nonresponders, P = 0.008) significant improvements in histopathology scores (confirmed with three separate histological disease activity indices), as well as changes in colonic gene expression that were consistent with reduced inflammation. CONCLUSION: This phase 1 trial provides preliminary evidence for the safety and therapeutic potential of GS‐5745 in the treatment of ulcerative colitis. John Wiley and Sons Inc. 2016-05-24 2016-07 /pmc/articles/PMC5089609/ /pubmed/27218676 http://dx.doi.org/10.1111/apt.13653 Text en © 2016 The Authors. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd. This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial (http://creativecommons.org/licenses/by-nc/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. |
spellingShingle | Randomised Clinical Trial Sandborn, W. J. Bhandari, B. R. Fogel, R. Onken, J. Yen, E. Zhao, X. Jiang, Z. Ge, D. Xin, Y. Ye, Z. French, D. Silverman, J. A. Kanwar, B. Subramanian, G. M. McHutchison, J. G. Lee, S. D. Shackelton, L. M. Pai, R. K. Levesque, B. G. Feagan, B. G. Randomised clinical trial: a phase 1, dose‐ranging study of the anti‐matrix metalloproteinase‐9 monoclonal antibody GS‐5745 versus placebo for ulcerative colitis |
title | Randomised clinical trial: a phase 1, dose‐ranging study of the anti‐matrix metalloproteinase‐9 monoclonal antibody GS‐5745 versus placebo for ulcerative colitis |
title_full | Randomised clinical trial: a phase 1, dose‐ranging study of the anti‐matrix metalloproteinase‐9 monoclonal antibody GS‐5745 versus placebo for ulcerative colitis |
title_fullStr | Randomised clinical trial: a phase 1, dose‐ranging study of the anti‐matrix metalloproteinase‐9 monoclonal antibody GS‐5745 versus placebo for ulcerative colitis |
title_full_unstemmed | Randomised clinical trial: a phase 1, dose‐ranging study of the anti‐matrix metalloproteinase‐9 monoclonal antibody GS‐5745 versus placebo for ulcerative colitis |
title_short | Randomised clinical trial: a phase 1, dose‐ranging study of the anti‐matrix metalloproteinase‐9 monoclonal antibody GS‐5745 versus placebo for ulcerative colitis |
title_sort | randomised clinical trial: a phase 1, dose‐ranging study of the anti‐matrix metalloproteinase‐9 monoclonal antibody gs‐5745 versus placebo for ulcerative colitis |
topic | Randomised Clinical Trial |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5089609/ https://www.ncbi.nlm.nih.gov/pubmed/27218676 http://dx.doi.org/10.1111/apt.13653 |
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