Randomised clinical trial: A phase 1, dose-ranging study of the anti-matrix metalloproteinase-9 monoclonal antibody GS-5745 versus placebo for ulcerative colitis

W. J. Sandborn, B. R. Bhandari, R. Fogel, J. Onken, E. Yen, X. Zhao, Z. Jiang, D. Ge, Y. Xin, Z. Ye, D. French, J. A. Silverman, B. Kanwar, G. M. Subramanian, J. G. McHutchison, S. D. Lee, L. M. Shackelton, Rish Pai, B. G. Levesque, B. G. Feagan

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)157-169
Number of pages13
JournalAlimentary Pharmacology and Therapeutics
Volume44
Issue number2
DOIs
StatePublished - Jul 1 2016

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Matrix Metalloproteinase 9
Ulcerative Colitis
Randomized Controlled Trials
Monoclonal Antibodies
Placebos
Safety
Hemorrhage
Pharmaceutical Preparations
Peptide Hydrolases
Therapeutics
Pharmacokinetics
Inflammation
Gene Expression
Injections

ASJC Scopus subject areas

  • Pharmacology (medical)

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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. / 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, Rish; Levesque, B. G.; Feagan, B. G.

In: Alimentary Pharmacology and Therapeutics, Vol. 44, No. 2, 01.07.2016, p. 157-169.

Research output: Contribution to journalArticle

Sandborn, WJ, Bhandari, BR, Fogel, R, Onken, J, Yen, E, Zhao, X, Jiang, Z, Ge, D, Xin, Y, Ye, Z, French, D, Silverman, JA, Kanwar, B, Subramanian, GM, McHutchison, JG, Lee, SD, Shackelton, LM, Pai, R, Levesque, BG & Feagan, BG 2016, 'Randomised clinical trial: A phase 1, dose-ranging study of the anti-matrix metalloproteinase-9 monoclonal antibody GS-5745 versus placebo for ulcerative colitis', Alimentary Pharmacology and Therapeutics, vol. 44, no. 2, pp. 157-169. https://doi.org/10.1111/apt.13653
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, Rish ; 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. In: Alimentary Pharmacology and Therapeutics. 2016 ; Vol. 44, No. 2. pp. 157-169.
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abstract = "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.",
author = "Sandborn, {W. J.} and Bhandari, {B. R.} and R. Fogel and J. Onken and E. Yen and X. Zhao and Z. Jiang and D. Ge and Y. Xin and Z. Ye and D. French and Silverman, {J. A.} and B. Kanwar and Subramanian, {G. M.} and McHutchison, {J. G.} and Lee, {S. D.} and Shackelton, {L. M.} and Rish Pai and Levesque, {B. G.} and Feagan, {B. G.}",
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T1 - Randomised clinical trial

T2 - A phase 1, dose-ranging study of the anti-matrix metalloproteinase-9 monoclonal antibody GS-5745 versus placebo for ulcerative colitis

AU - Sandborn, W. J.

AU - Bhandari, B. R.

AU - Fogel, R.

AU - Onken, J.

AU - Yen, E.

AU - Zhao, X.

AU - Jiang, Z.

AU - Ge, D.

AU - Xin, Y.

AU - Ye, Z.

AU - French, D.

AU - Silverman, J. A.

AU - Kanwar, B.

AU - Subramanian, G. M.

AU - McHutchison, J. G.

AU - Lee, S. D.

AU - Shackelton, L. M.

AU - Pai, Rish

AU - Levesque, B. G.

AU - Feagan, B. G.

PY - 2016/7/1

Y1 - 2016/7/1

N2 - 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.

AB - 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.

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