A Randomized, Placebo-Controlled Trial of MDX-1100, an Anti-IP-10 Antibody, for Moderately to Severely Active Ulcerative Colitis

Mayer, Lloyd; Sandborn, William J.; Stepanov, Yu.М.; Maccarone, Judith; Tao, Xiaolu; Lu, Lian Wei; Gujrathi, Sheila; Aranda, Richard; Luo, Allison

doi:10.1053/j.gastro.2010.05.065

Cited by 8 publications

(7 citation statements)

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“…In a placebo-controlled trial in patients with moderate to severe UC, MDX-1100 did not show a significant clinical benefit when compared to placebo in the overall population [105]. However, when data were stratified according to MDX-1100 trough serum levels, there were increasing rates for response, remission and mucosal healing with increasing MDX serum levels.…”

Section: Anti-c-x-c Motif Chemokine 10 (Cxcl10) Strategiesmentioning

confidence: 91%

Review: New Anti-Cytokines for IBD: What is in the Pipeline?

Scharl

Vavricka²,

Rogler

2013

CDT

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Significant advances have been achieved in the understanding of the pathogenesis of inflammatory bowel disease (IBD). A number of susceptibility genes have been detected by large genome wide screening-approaches. New therapeutic concepts emerge from these insights. The most important progress in recent years certainly is the introduction of biologics in the therapy of IBD. TNF blockers have been shown to be very effective for the control of complicated disease courses. Currently, in addition to the three already established anti-TNF antibodies, new anti-TNF molecules, for example Golimumab, are in clinical trials and also reveal promising results. However, not all of the patients respond to anti-TNF treatment and many patients lose their response. Therefore, additional therapeutic approaches are urgently needed. Attractive therapy targets are cytokines as well as their receptors and signaling pathways. At the moment a large number of biologicals and inhibitors are tested in clinical trials and some of them provide very promising results for the treatment of IBD patients. In particular, inhibition of IL-12p40 by specific antibodies as well as of the janus kinase (JAK)3 by a small molecule promise to be very effective approaches. Though antibodies targeting for example IL-6, IL-6R, IL-13 or CCR9 are only in the early steps of clinical development, they have already demonstrated to be a possible treatment option which needs to be confirmed in further trials. Taken together a large number of new therapeutic anti-cytokine approaches are currently tested in clinical trials in IBD patients. In this review, the new therapeutic approaches for cytokine inhibition in IBD patients are discussed. Taken together a large number of new therapeutic anti-cytokine approaches are currently tested in clinical trials in IBD patients. In this review, the new therapeutic approaches for cytokine inhibition in IBD patients are discussed.

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Section: Anti-c-x-c Motif Chemokine 10 (Cxcl10) Strategiesmentioning

confidence: 91%

Review: New Anti-Cytokines for IBD: What is in the Pipeline?

Scharl

Vavricka²,

Rogler

2013

CDT

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“…BMS-936557 binds to IP-10 with high affinity (∼1 nM) and specifically blocks its interaction with CXCR3 18. As a result, BMS-936557 is a potent inhibitor of IP-10-induced chemotaxis of activated T cells (EC 50 ∼0.8 nM) 18.…”

Section: Introductionmentioning

confidence: 99%

“…As a result, BMS-936557 is a potent inhibitor of IP-10-induced chemotaxis of activated T cells (EC 50 ∼0.8 nM) 18. BMS-936557 does not bind to either Mig (CXCL9) or ITAC (CXCL11), the other ligands for CXCR3,18 and so is only expected to modulate IP-10-mediated functions. Phase I studies have evaluated the pharmacodynamic, pharmacokinetic and safety profile of BMS-936557 at doses of up to 10 mg/kg in healthy volunteers, in addition to demonstrating safety in patients with UC 19 20.…”

Section: Introductionmentioning

confidence: 99%

Anti-IP-10 antibody (BMS-936557) for ulcerative colitis: a phase II randomised study

Mayer

Sandborn

Stepanov

et al. 2013

Gut

Self Cite

177

103

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ObjectiveInterferon-γ-inducible protein-10 (IP-10 or CXCL10) plays a role in inflammatory cell migration and epithelial cell survival and migration. It is expressed in higher levels in the colonic tissue and plasma of patients with ulcerative colitis (UC). This phase II study assessed the efficacy and safety of BMS-936557, a fully human, monoclonal antibody to IP-10, in the treatment of moderately-to-severely active UC.DesignIn this 8-week, phase II, double-blind, multicentre, randomised study, patients with active UC received placebo or BMS-936557 (10 mg/kg) intravenously every other week. The primary endpoint was the rate of clinical response at Day 57; clinical remission and mucosal healing rates were secondary endpoints. Post hoc analyses evaluated the drug exposure–response relationship and histological improvement.Results109 patients were included (BMS-936557: n=55; placebo: n=54). Prespecified primary and secondary endpoints were not met; clinical response rate at Day 57 was 52.7% versus 35.2% for BMS-936557 versus placebo (p=0.083), and clinical remission and mucosal healing rates were 18.2% versus 16.7% (p=1.00) and 41.8% versus 35.2% (p=0.556), respectively. However, higher BMS-936557 steady-state trough concentration (Cminss) was associated with increased clinical response (87.5% vs 37.0% (p<0.001) for patients with Cminss 108–235 μg/ml vs placebo) and histological improvements (73.0% vs 41.0%; p=0.004). Infections occurred in 7 (12.7%) BMS-936557-treated patients and 3 (5.8%) placebo-treated patients. 2 (3.6%) BMS-936557 patients discontinued due to adverse events.ConclusionsAnti-IP-10 antibody, BMS-936557, is a potentially effective therapy for moderately-to-severely active UC. Higher drug exposure correlated with increasing clinical response and histological improvement. Further dose–response studies are warranted.Clinical Trial Registration Number:ClinicalTrials.gov NCT00656890.

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“…Response, remission and mucosal healing rates in patients in the tertile with the highest serum concentrations were 88%, 44% and 69% compared with 35%, 17% and 35% in the placebo group, respectively. The authors reported that new trials with higher drug doses will be performed .…”

Section: Therapeutics Regulating Leucocyte Recruitment In Ibdmentioning

confidence: 73%

“…In a Phase II trial in 109 patients with moderate to severe and treatment refractory UC, MDX‐1100 did not show statistically significant differences in efficacy compared with placebo. After 8 weeks of active treatment, 53% of patients had a clinical response versus 35% in the placebo group ( P = 0.08) . However, when patients were stratified according to serum drug concentration, a clear dose–response relationship emerged.…”

Section: Therapeutics Regulating Leucocyte Recruitment In Ibdmentioning

confidence: 99%