Anti-IP-10 antibody (BMS-936557) for ulcerative colitis: a phase II randomised study
Lloyd Mayer, William J Sandborn, Yuriy Stepanov, Karel Geboes, Robert Hardi, Michael Yellin, Xiaolu Tao, Li An Xu, Luisa Salter-Cid, Sheila Gujrathi, Richard Aranda, Allison Y Luo, Lloyd Mayer, William J Sandborn, Yuriy Stepanov, Karel Geboes, Robert Hardi, Michael Yellin, Xiaolu Tao, Li An Xu, Luisa Salter-Cid, Sheila Gujrathi, Richard Aranda, Allison Y Luo
Abstract
Objective: Interferon-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.
Design: In 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.
Results: 109 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.
Conclusions: Anti-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.
Keywords: Antibody Targeted Therapy; Ulcerative Colitis.
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References
- Ordas I, Eckmann L, Talimini M, et al. Ulcerative colitis. Lancet 2012;380:1606–19
- Kornbluth A, Sachar DB. Ulcerative colitis practice guidelines in adults: American College Of Gastroenterology, Practice Parameters Committee. Am J Gastroenterol 2010;105:501–23; quiz 24
- Travis SP, Stange EF, Lemann M, et al. European evidence-based Consensus on the management of ulcerative colitis: current management. J Crohns Colitis 2008;2:24–62
- Lichtenstein GR, Abreu MT, Cohen R, et al. American Gastroenterological Association Institute technical review on corticosteroids, immunomodulators, and infliximab in inflammatory bowel disease. Gastroenterology 2006;130:940–87
- Kuhne MPB, Wallace S, Chen S, et al. MDX-1100, a fully human anti-CXCL 10 (IP-10) antibody, is a high affinity, neutralizing antibody that has rntered phase I clinical trials for the treatment of Ulcerative Colitis (UC). J Immunol 2007;178:20
- Kabashima H, Yoneda M, Nagata K, et al. The presence of chemokine (MCP-1, MIP-1(alpha), MIP-1(beta), IP-10, RANTES)-positive cells and chemokine receptor (CCR5, CXCR3)-positive cells in inflamed human gingival tissues. Cytokine 2002;20:70–7
- Molesworth-Kenyon S, Mates A, Yin R, et al. CXCR3, IP-10, and Mig are required for CD4+ T cell recruitment during the DTH response to HSV-1 yet are independent of the mechanism for viral clearance. Virology 2005;333:1–9
- Romagnani P, Maggi L, Mazzinghi B, et al. CXCR3-mediated opposite effects of CXCL10 and CXCL4 on TH1 or TH2 cytokine production. J Allergy Clin Immunol 2005;116:1372–9
- Suzuki K, Kawauchi Y, Palaniyandi SS, et al. Blockade of interferon-gamma-inducible protein-10 attenuates chronic experimental colitis by blocking cellular trafficking and protecting intestinal epithelial cells. Pathol Int 2007;57: 413–20
- Soejima K, Rollins BJ. A functional IFN-gamma-inducible protein-10/CXCL10-specific receptor expressed by epithelial and endothelial cells that is neither CXCR3 nor glycosaminoglycan. J Immunol 2001;167:6576–82
- Schulthess FT, Paroni F, Sauter NS, et al. CXCL10 impairs beta cell function and viability in diabetes through TLR4 signaling. Cell Metab 2009;9:125–39
- Luster AD, Greenberg SM, Leder P. The IP-10 chemokine binds to a specific cell surface heparan sulfate site shared with platelet factor 4 and inhibits endothelial cell proliferation. J Exp Med 1995;182:219–31
- Uguccioni M, Gionchetti P, Robbiani DF, et al. Increased expression of IP-10, IL-8, MCP-1, and MCP-3 in ulcerative colitis. Am J Pathol 1999;155:331–6
- Witte A, Kuhne MR, Preston BT, et al. W1170 CXCL10 expression and biological activities in inflammatory bowel disease. Gastroenterology 2008;134:A-648
- Sasaki S, Yoneyama H, Suzuki K, et al. Blockade of CXCL10 protects mice from acute colitis and enhances crypt cell survival. Eur J Immunol 2002;32:3197–205
- Singh UP, Singh S, Taub DD, et al. Inhibition of IFN-gamma-inducible protein-10 abrogates colitis in IL-10−/− mice. J Immunol 2003;171:1401–6
- Hyun JG, Lee G, Brown JB, et al. Anti-interferon-inducible chemokine, CXCL10, reduces colitis by impairing T helper-1 induction and recruitment in mice. Inflamm Bowel Dis 2005;11:799–805
- Mayer L, Sandborn WJ, Stepanov Y, et al. A randomized placebo-controlled trial of MDX-1100, an anti-IP-10 antibody, for moderately-to-severely active ulcerative colitis. Oral presentation at DDW (Abstract 711a) 2010
- Hardi R, Mayer L, Targan SR, et al. A phase 1 open-label, single-dose, dose-escalation study of MDX-1100, a high-affinity, neutralizing, fully human Igg1(kappa) anti-CXCL10 (Ip10) monoclonal antibody, in ulcerative colitis. Gastroenterology 2008;134:A-99–100
- Yellin M, Paliienko I, Balanescu A, et al. A phase II, randomized, double-blind, placebo-controlled study evaluating the efficacy and safety of MDX-1100, a fully human anti-CXCL10 monoclonal antibody, in combination with methotrexate in patients with rheumatoid arthritis. Arthritis Rheum 2011;64:1730–9
- D'Haens G, Sandborn WJ, Feagan BG, et al. A review of activity indices and efficacy end points for clinical trials of medical therapy in adults with ulcerative colitis. Gastroenterology 2007;132:763–86
- Schroeder KW, Tremaine WJ, Ilstrup DM. Coated oral 5-aminosalicylic acid therapy for mildly to moderately active ulcerative colitis. A randomized study. N Engl J Med 1987;317:1625–9
- Geboes K, Riddell R, Ost A, et al. A reproducible grading scale for histological assessment of inflammation in ulcerative colitis. Gut 2000;47:404–9
- Geboes K, Olson A, Marano C. Infliximab results in reduction of inflammation and inflammatory markers in the mucosa of ulcerative colitis patients: the ACT 1 trial (Abstract). Am J Gastroenterol 2005;100:S292–3
- Yellin M, Paliienko I, Balanescu A, et al. A phase 2, multi-dose, double-blind, placebo-controlled, randomized, multicenter study of MDX-1100 (anti-CXCL10 Human Monoclonal Antibody) in combination with methotrexate in patients with active rheumatoid arthritis. Arthritis Rheum 2009;60:414
- Afif W, Leighton JA, Hanauer SB, et al. Open-label study of adalimumab in patients with ulcerative colitis including those with prior loss of response or intolerance to infliximab. Inflamm Bowel Dis 2009;15:1302–7
- Baumgart DC, Targan SR, Dignass AU, et al. Prospective randomized open-label multicenter phase I/II dose escalation trial of visilizumab (HuM291) in severe steroid-refractory ulcerative colitis. Inflamm Bowel Dis 2010;16:620–9
- Rutgeerts P, Sandborn WJ, Feagan BG, et al. Infliximab for induction and maintenance therapy for ulcerative colitis. N Engl J Med 2005;353:2462–76
- Sandborn W, Colombel J-F, Hanauer S, et al. A randomized placebo-controlled trial of abatacept for moderately-to-severely active ulcerative colitis. DDW abstract 2010
Source: PubMed