Treatment of Active Crohn's Disease With MLN0002, a Humanized Antibody to the α4β7 Integrin

Published:October 02, 2008DOI:

      Background & Aims

      Selective blockade of lymphocyte–vascular endothelium interactions in the gastrointestinal tract is a promising therapeutic strategy for inflammatory bowel disease. This randomized, double-blind, controlled trial assessed the efficacy and safety of MLN0002, a monoclonal antibody targeting the α4β7 integrin, in patients with active Crohn's disease.


      Patients were randomized to receive MLN0002 2.0 mg/kg (n = 65), MLN0002 0.5 mg/kg (n = 62), or placebo (n = 58) by intravenous infusion on days 1 and 29. The primary efficacy end point was clinical response (≥70-point decrement in the Crohn's Disease Activity Index [CDAI] score) on day 57. Secondary end points were the proportions of patients with clinical remission (CDAI score ≤150) and with an enhanced clinical response (≥100-point decrement in CDAI). Human anti-human antibody levels were measured.


      Clinical response rates at day 57 were 53%, 49%, and 41% in the MLN0002 2.0 mg/kg, MLN0002 0.5 mg/kg, and placebo groups. Clinical remission rates at day 57 were 37%, 30%, and 21%, respectively (P = .04 for the 2.0 mg/kg vs placebo comparison). At day 57, 12% and 34% of patients in the 2.0- and 0.5-mg/kg groups had clinically significant human anti-human antibody levels (titers > 1:125). There was one infusion-related hypersensitivity reaction. The most common serious adverse event was worsening of Crohn's disease.


      This phase 2 study was suggestive of a dose-dependent beneficial effect of MLN0002 therapy on clinical remission. MLN0002 was well tolerated in patients with active Crohn's disease.

      Abbreviations used in this paper:

      AE (adverse event), CDAI (Crohn's Disease Activity Index), HAHA (human anti-human antibodies), IBD (inflammatory bowel disease), IBDQ (Inflammatory Bowel Disease Questionnaire), PML (progressive multifocal leukoencephalopathy), SAE (serious adverse events)
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        • Gisbert J.P.
        • Gomollon F.
        • Mate J.
        • et al.
        Role of 5-aminosalicylic acid (5-ASA) in treatment of inflammatory bowel disease: a systematic review.
        Dig Dis Sci. 2002; 47: 471-488
        • Akobeng A.K.
        • Gardener E.
        Oral 5-aminosalicylic acid for maintenance of medically-induced remission in Crohn's Disease.
        Cochrane Database Syst Rev. 2005; 1: CD003715
        • Baumgart D.C.
        • Sandborn W.J.
        Inflammatory bowel disease: clinical aspects and established and evolving therapies.
        Lancet. 2007; 369: 1641-1657
        • Irving P.M.
        • Gearry R.B.
        • Sparrow M.P.
        • et al.
        Review article: appropriate use of corticosteroids in Crohn's disease.
        Aliment Pharmacol Ther. 2007; 26: 313-329
        • Steinhart A.H.
        • Ewe K.
        • Griffiths A.M.
        • et al.
        Corticosteroids for maintenance of remission in Crohn's disease.
        Cochrane Database Syst Rev. 2003; 4: CD000301
        • Sandborn W.J.
        • Lofberg R.
        • Feagan B.G.
        • et al.
        Budesonide for maintenance of remission in patients with Crohn's disease in medically induced remission: a predetermined pooled analysis of four randomized, double-blind, placebo-controlled trials.
        Am J Gastroenterol. 2005; 100: 1780-1787
        • Choi P.M.
        • Targan S.R.
        Immunomodulator therapy in inflammatory bowel disease.
        Dig Dis Sci. 1994; 39: 1885-1892
        • Kwon J.H.
        • Farrell R.J.
        The risk of lymphoma in the treatment of inflammatory bowel disease with immunosuppressive agents.
        Crit Rev Oncol Hematol. 2005; 56: 169-178
        • Kandiel A.
        • Fraser A.G.
        • Korelitz B.I.
        • et al.
        Increased risk of lymphoma among inflammatory bowel disease patients treated with azathioprine and 6-mercaptopurine.
        Gut. 2005; 54: 1121-1125
        • Gionchetti P.
        • Rizzello F.
        • Habal F.
        • et al.
        Standard treatment of ulcerative colitis.
        Dig Dis. 2003; 21: 157-167
        • Connell W.R.
        • Kamm M.A.
        • Ritchie J.K.
        • et al.
        Bone marrow toxicity caused by azathioprine in inflammatory bowel disease: 27 years of experience.
        Gut. 1993; 34: 1081-1085
        • Hanauer S.B.
        • Feagan B.G.
        • Lichtenstein G.R.
        • et al.
        Maintenance infliximab for Crohn's disease: the ACCENT I randomised trial.
        Lancet. 2002; 359: 1541-1549
        • Hanauer S.B.
        • Sandborn W.J.
        • Rutgeerts P.
        • et al.
        Human anti-tumor necrosis factor monoclonal antibody (adalimumab) in Crohn's disease: the CLASSIC-I trial.
        Gastroenterology. 2006; 130: 323-333
        • Colombel J.F.
        • Sandborn W.J.
        • Rutgeerts P.
        • et al.
        Adalimumab for maintenance of clinical response and remission in patients with Crohn's disease: the CHARM trial.
        Gastroenterology. 2007; 132: 52-65
        • Schreiber S.
        • Rutgeerts P.
        • Fedorak R.N.
        • et al.
        A randomized, placebo-controlled trial of certolizumab pegol (CDP870) for treatment of Crohn's disease.
        Gastroenterology. 2005; 129: 807-818
        • Keane J.
        • Gershon S.
        • Wise R.P.
        • et al.
        Tuberculosis associated with infliximab, a tumor necrosis factor alpha-neutralizing agent.
        N Engl J Med. 2001; 345: 1098-1104
      1. Centocor Inc. [email protected] (infliximab) for IV injection. Prescribing information. Malvern, PA, 2006.

        • Rosh J.R.
        • Gross T.
        • Mamula P.
        • et al.
        Hepatosplenic T-cell lymphoma in adolescents and young adults with Crohn's disease: a cautionary tale?.
        Inflamm Bowel Dis. 2007; 13: 1024-1030
        • von Andrian U.H.
        • Engelhardt B.
        Alpha4 integrins as therapeutic targets in autoimmune disease.
        N Engl J Med. 2003; 348: 68-72
        • Sandborn W.J.
        • Colombel J.F.
        • Enns R.
        • et al.
        Natalizumab induction and maintenance therapy for Crohn's disease.
        N Engl J Med. 2005; 353: 1912-1925
        • Targan S.
        • Feagan B.G.
        • Fedorak R.N.
        • et al.
        Natalizumab for the treatment of active Crohn's disease: results of the ENCORE trial.
        Gastroenterology. 2007; 132: 1672-1683
        • Hou J.
        • Major E.O.
        Progressive multifocal leukoencephalopathy: JC virus induced demyelination in the immune compromised host.
        J Neurovirol. 2000; 6: S98-S100
        • Berlin C.
        • Berg E.L.
        • Briskin M.J.
        • et al.
        Alpha 4 beta 7 integrin mediates lymphocyte binding to the mucosal vascular addressin MAdCAM-1.
        Cell. 1993; 74: 185-195
        • Briskin M.
        • Winsor-Hines D.
        • Shyjan A.
        • et al.
        Human mucosal addressin cell adhesion molecule-1 is preferentially expressed in intestinal tract and associated lymphoid tissue.
        Am J Pathol. 1997; 151: 97-110
        • Arihiro S.
        • Ohtani H.
        • Suzuki M.
        • et al.
        Differential expression of mucosal addressin cell adhesion molecule-1 (MAdCAM-1) in ulcerative colitis and Crohn's disease.
        Pathol Int. 2002; 52: 367-374
        • Feagan B.G.
        • Greenberg G.R.
        • Wild G.
        • et al.
        Treatment of ulcerative colitis with a humanized antibody to the alpha4beta7 integrin.
        N Engl J Med. 2005; 352: 2499-2507
        • Best W.R.
        • Becktel J.M.
        • Singleton J.W.
        • et al.
        Development of a Crohn's disease activity index.
        Gastroenterology. 1976; 70: 439-444
        • Guyatt G.
        • Mitchell A.
        • Irvine E.J.
        • et al.
        A new measure of health status for clinical trials in inflammatory bowel disease.
        Gastroenterology. 1989; 96: 804-810
        • MSSO–Maintenance and Support Services Organization
        Medical dictionary for regulatory activities (MedDRA).
        (Accessed 28 August 2008)
        • Seth P.
        • Diaz F.
        • Major E.O.
        Advances in the biology of JC virus and induction of progressive multifocal leukoencephalopathy.
        J Neurovirol. 2003; 9: 236-246
        • Manna P.
        • Scantlebury V.
        • Bryant K.
        • et al.
        JC viral disease in renal transplantation.
        Am J Transplant. 2004; 4: 142
        • Ghosh S.
        • Goldin E.
        • Gordon F.H.
        • et al.
        Natalizumab for active Crohn's disease.
        N Engl J Med. 2003; 348: 24-32
        • Su C.
        • Lichtenstein G.R.
        • Krok K.
        • et al.
        A meta-analysis of the placebo rates of remission and response in clinical trials of active Crohn's disease.
        Gastroenterology. 2004; 126: 1257-1269
        • Su C.
        • Lewis J.D.
        • Goldberg B.
        • et al.
        A meta-analysis of the placebo rates of remission and response in clinical trials of active ulcerative colitis.
        Gastroenterology. 2007; 132: 516-526
        • Buno S.A.
        • Torres Jimenez R.
        • Olveira A.
        • et al.
        Lithogenic risk factors for renal stones in patients with Crohn's disease.
        Arch Esp Urol. 2001; 54: 282-292
        • Yousry T.A.
        • Major E.O.
        • Ryschkewitsch C.
        • et al.
        Evaluation of patients treated with natalizumab for progressive multifocal leukoencephalopathy.
        N Engl J Med. 2006; 354: 924-933
        • Biogen Idec
        Biogen Idec and Elan provide update on utilization, safety and total patient exposure of Tysabri in patients with multiple sclerosis.
        • Panzara M.A.
        • Belcher G.
        • Kooijmans M.
        • et al.
        Use of natalizumab in patients with relapsing multiple sclerosis: updated safety results from TOUCH and TYGRIS.
        Mult Scler. 2007; 13: 565