Andecaliximab [Anti-matrix Metalloproteinase-9] induction therapy for ulcerative colitis: A randomised, double-blind, placebo-controlled, phase 2/3 study in patients with moderate to severe disease

William J. Sandborn, Bal R. Bhandari, Charles Randall, Ziad H. Younes, Tomasz Romanczyk, Yan Xin, Emily Wendt, Hao Chai, Matt McKevitt, Sally Zhao, John S. Sundy, Satish Keshav, Silvio Danese

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

Background and Aims Matrix metalloproteinase-9 [MMP9] is implicated in the pathogenesis of ulcerative colitis [UC] via disruption of intestinal barrier integrity and function. A phase 2/3 combined trial was designed to examine the efficacy, safety, and pharmacokinetics of the anti-MMP9 antibody, andecaliximab [formerly GS-5745], in patients with moderately to severely active UC. Methods Patients were randomised [1:1:1] to receive placebo, 150 mg andecaliximab every 2 weeks [Q2W], or 150 mg andecaliximab weekly [QW], via subcutaneous administration. The primary endpoint was endoscopy/bleeding/stool [EBS]-defined clinical remission [endoscopic subscore of 0 or 1, rectal bleeding subscore of 0, and at least a 1-point decrease from baseline in stool frequency to achieve a subscore of 0 or 1] at Week 8. The phase 2/3 trial met prespecified futility criteria and was terminated before completion. This study describes results from the 8-week induction phase. Results Neither 150 mg andecaliximab Q2W or QW resulted in a significant increase vs placebo in the proportion of patients achieving EBS clinical remission at Week 8. Remission rates [95% confidence intervals] were 7.3% [2.0%-17.6%], 7.4% [2.1%-17.9%], and 1.8% [0.0%-9.6%] in the placebo, andecaliximab Q2W, and andecaliximab QW groups, respectively. Similarly, Mayo Clinic Score response, endoscopic response, and mucosal [histological] healing did not differ among groups. Rates of adverse events were comparable among andecaliximab and placebo. Conclusions Eight weeks of induction treatment with 150 mg andecaliximab in patients with UC did not induce clinical remission or response. Andecaliximab was well tolerated and pharmacokinetic properties were consistent with those previously reported.

Original languageEnglish
Pages (from-to)1021-1029
Number of pages9
JournalJournal of Crohn's and Colitis
Volume12
Issue number9
DOIs
Publication statusPublished - Aug 29 2018

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Matrix Metalloproteinase 9
Ulcerative Colitis
Placebos
Hemorrhage
Endoscopy
Pharmacokinetics
Medical Futility
Therapeutics
Confidence Intervals
Safety
Antibodies

Keywords

  • inflammation
  • matrix metalloproteinase-9
  • Ulcerative colitis

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Andecaliximab [Anti-matrix Metalloproteinase-9] induction therapy for ulcerative colitis : A randomised, double-blind, placebo-controlled, phase 2/3 study in patients with moderate to severe disease. / Sandborn, William J.; Bhandari, Bal R.; Randall, Charles; Younes, Ziad H.; Romanczyk, Tomasz; Xin, Yan; Wendt, Emily; Chai, Hao; McKevitt, Matt; Zhao, Sally; Sundy, John S.; Keshav, Satish; Danese, Silvio.

In: Journal of Crohn's and Colitis, Vol. 12, No. 9, 29.08.2018, p. 1021-1029.

Research output: Contribution to journalArticle

Sandborn, William J. ; Bhandari, Bal R. ; Randall, Charles ; Younes, Ziad H. ; Romanczyk, Tomasz ; Xin, Yan ; Wendt, Emily ; Chai, Hao ; McKevitt, Matt ; Zhao, Sally ; Sundy, John S. ; Keshav, Satish ; Danese, Silvio. / Andecaliximab [Anti-matrix Metalloproteinase-9] induction therapy for ulcerative colitis : A randomised, double-blind, placebo-controlled, phase 2/3 study in patients with moderate to severe disease. In: Journal of Crohn's and Colitis. 2018 ; Vol. 12, No. 9. pp. 1021-1029.
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abstract = "Background and Aims Matrix metalloproteinase-9 [MMP9] is implicated in the pathogenesis of ulcerative colitis [UC] via disruption of intestinal barrier integrity and function. A phase 2/3 combined trial was designed to examine the efficacy, safety, and pharmacokinetics of the anti-MMP9 antibody, andecaliximab [formerly GS-5745], in patients with moderately to severely active UC. Methods Patients were randomised [1:1:1] to receive placebo, 150 mg andecaliximab every 2 weeks [Q2W], or 150 mg andecaliximab weekly [QW], via subcutaneous administration. The primary endpoint was endoscopy/bleeding/stool [EBS]-defined clinical remission [endoscopic subscore of 0 or 1, rectal bleeding subscore of 0, and at least a 1-point decrease from baseline in stool frequency to achieve a subscore of 0 or 1] at Week 8. The phase 2/3 trial met prespecified futility criteria and was terminated before completion. This study describes results from the 8-week induction phase. Results Neither 150 mg andecaliximab Q2W or QW resulted in a significant increase vs placebo in the proportion of patients achieving EBS clinical remission at Week 8. Remission rates [95{\%} confidence intervals] were 7.3{\%} [2.0{\%}-17.6{\%}], 7.4{\%} [2.1{\%}-17.9{\%}], and 1.8{\%} [0.0{\%}-9.6{\%}] in the placebo, andecaliximab Q2W, and andecaliximab QW groups, respectively. Similarly, Mayo Clinic Score response, endoscopic response, and mucosal [histological] healing did not differ among groups. Rates of adverse events were comparable among andecaliximab and placebo. Conclusions Eight weeks of induction treatment with 150 mg andecaliximab in patients with UC did not induce clinical remission or response. Andecaliximab was well tolerated and pharmacokinetic properties were consistent with those previously reported.",
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AU - Sandborn, William J.

AU - Bhandari, Bal R.

AU - Randall, Charles

AU - Younes, Ziad H.

AU - Romanczyk, Tomasz

AU - Xin, Yan

AU - Wendt, Emily

AU - Chai, Hao

AU - McKevitt, Matt

AU - Zhao, Sally

AU - Sundy, John S.

AU - Keshav, Satish

AU - Danese, Silvio

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N2 - Background and Aims Matrix metalloproteinase-9 [MMP9] is implicated in the pathogenesis of ulcerative colitis [UC] via disruption of intestinal barrier integrity and function. A phase 2/3 combined trial was designed to examine the efficacy, safety, and pharmacokinetics of the anti-MMP9 antibody, andecaliximab [formerly GS-5745], in patients with moderately to severely active UC. Methods Patients were randomised [1:1:1] to receive placebo, 150 mg andecaliximab every 2 weeks [Q2W], or 150 mg andecaliximab weekly [QW], via subcutaneous administration. The primary endpoint was endoscopy/bleeding/stool [EBS]-defined clinical remission [endoscopic subscore of 0 or 1, rectal bleeding subscore of 0, and at least a 1-point decrease from baseline in stool frequency to achieve a subscore of 0 or 1] at Week 8. The phase 2/3 trial met prespecified futility criteria and was terminated before completion. This study describes results from the 8-week induction phase. Results Neither 150 mg andecaliximab Q2W or QW resulted in a significant increase vs placebo in the proportion of patients achieving EBS clinical remission at Week 8. Remission rates [95% confidence intervals] were 7.3% [2.0%-17.6%], 7.4% [2.1%-17.9%], and 1.8% [0.0%-9.6%] in the placebo, andecaliximab Q2W, and andecaliximab QW groups, respectively. Similarly, Mayo Clinic Score response, endoscopic response, and mucosal [histological] healing did not differ among groups. Rates of adverse events were comparable among andecaliximab and placebo. Conclusions Eight weeks of induction treatment with 150 mg andecaliximab in patients with UC did not induce clinical remission or response. Andecaliximab was well tolerated and pharmacokinetic properties were consistent with those previously reported.

AB - Background and Aims Matrix metalloproteinase-9 [MMP9] is implicated in the pathogenesis of ulcerative colitis [UC] via disruption of intestinal barrier integrity and function. A phase 2/3 combined trial was designed to examine the efficacy, safety, and pharmacokinetics of the anti-MMP9 antibody, andecaliximab [formerly GS-5745], in patients with moderately to severely active UC. Methods Patients were randomised [1:1:1] to receive placebo, 150 mg andecaliximab every 2 weeks [Q2W], or 150 mg andecaliximab weekly [QW], via subcutaneous administration. The primary endpoint was endoscopy/bleeding/stool [EBS]-defined clinical remission [endoscopic subscore of 0 or 1, rectal bleeding subscore of 0, and at least a 1-point decrease from baseline in stool frequency to achieve a subscore of 0 or 1] at Week 8. The phase 2/3 trial met prespecified futility criteria and was terminated before completion. This study describes results from the 8-week induction phase. Results Neither 150 mg andecaliximab Q2W or QW resulted in a significant increase vs placebo in the proportion of patients achieving EBS clinical remission at Week 8. Remission rates [95% confidence intervals] were 7.3% [2.0%-17.6%], 7.4% [2.1%-17.9%], and 1.8% [0.0%-9.6%] in the placebo, andecaliximab Q2W, and andecaliximab QW groups, respectively. Similarly, Mayo Clinic Score response, endoscopic response, and mucosal [histological] healing did not differ among groups. Rates of adverse events were comparable among andecaliximab and placebo. Conclusions Eight weeks of induction treatment with 150 mg andecaliximab in patients with UC did not induce clinical remission or response. Andecaliximab was well tolerated and pharmacokinetic properties were consistent with those previously reported.

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