Natalizumab for the Treatment of Active Crohn’s Disease: Results of the ENCORE Trial

Gastrointestinal Research Group, The University of Calgary, Calgary, Alberta, Canada
Gastroenterology (Impact Factor: 16.72). 06/2007; 132(5):1672-83. DOI: 10.1053/j.gastro.2007.03.024
Source: PubMed


A randomized placebo-controlled trial evaluated the efficacy of natalizumab induction therapy in patients with Crohn's disease.
Patients (N = 509) with moderately to severely active Crohn's disease and active inflammation characterized by elevated C-reactive protein concentrations were randomized (1:1) to receive natalizumab 300 mg or placebo intravenously at Weeks 0, 4, and 8. The primary end point was induction of response (> or =70-point decrease from baseline in the Crohn's Disease Activity Index score at Week 8 sustained through Week 12). Additional efficacy end points included the proportion of patients with sustained remission (Crohn's Disease Activity Index score <150 points) and response or remission over time.
Response at Week 8 sustained through Week 12 occurred in 48% of natalizumab-treated patients and 32% of patients receiving placebo (P < .001). Sustained remission occurred in 26% of natalizumab-treated patients and 16% of patients receiving placebo (P = .002). Week 4 response rates were 51% for natalizumab and 37% for placebo (P = .001). Responses remained significantly higher at subsequent assessments (P < .001) in natalizumab-treated patients. Natalizumab-treated patients also had significantly higher remission rates at Weeks 4, 8, and 12 (P < or = .009). The frequency and types of adverse events were similar between treatment groups.
Natalizumab induced response and remission at Week 8 that was sustained through Week 12. Response and remission rates for natalizumab were superior to those for placebo at Weeks 4, 8, and 12, demonstrating the early and sustained efficacy of natalizumab as induction therapy in patients with elevated C-reactive protein and active Crohn's disease. Natalizumab was well tolerated in this study.

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Available from: William J Sandborn, Feb 10, 2014
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    • "Natalizumab, a humanized anti-α4-integrin monoclonal antibody, is effective in the treatment of moderately to severely active CD patients, but it is not approved in Europe because it has been associated with an increased risk of multifocal leukoencephalopathy (one case/10,000 patients).64,65 Vedolizumab is a humanized immunoglobulin G1 mAb against α4β7 integrin that has been shown to be superior to placebo in inducing and maintaining clinical and endoscopic remission in UC patients.66 "
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    ABSTRACT: Dovepress 359 R E v i E w open access to scientific and medical research Open Access Full Text Article Abstract: Infliximab (IFX) is an effective treatment for inducing and maintaining response in Crohn's disease and ulcerative colitis patients. Some patients present lack of response or loss of response to IFX during maintenance therapy. Empirical management with combination therapy with an immunomodulator, IFX dose escalation, or switching IFX for another antitumor necrosis factor-α drug, mainly adalimumab, is common in clinical practice. Selecting the best choice with the help of serum drug concentrations and trough IFX antibody concentrations could be a very interesting approach. In addition to surgery, a broad spectrum of new drugs has been tested and could expand treatment options in the near future.
    Clinical and Experimental Gastroenterology 09/2014; 7. DOI:10.2147/CEG.S45297
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    • "Given that expression of mucosal adhesion molecules MAdCAM-1, intercellular adhesion molecule-1, and vascular cell adhesion molecule-1 have been described in mucosal tissues from patients with either CD or UC, Abs to these molecules and their corresponding receptors were deemed favorable targets as novel therapies for IBD (Figure 5).77 Natalizumab, a monoclonal antibody to α4 integrin, was approved in 2008 by the US Food and Drug Administration (FDA) for severe, refractory CD after efficacy was documented.78,79 However, its use is highly limited due to the risk of progressive multifocal leukoencephalopathy, a potentially fatal demyelinating disease, given its interference with leukocyte homing to the central nervous system through blockade of α4β1 signaling. "
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    ABSTRACT: The specific pathogenesis underlying inflammatory bowel disease is complex, and it is even more difficult to decipher the pathophysiology to explain for the similarities and differences between two of its major subtypes, Crohn's disease and ulcerative colitis (UC). Animal models are indispensable to pry into mechanistic details that will facilitate better preclinical drug/therapy design to target specific components involved in the disease pathogenesis. This review focuses on common animal models that are particularly useful for the study of UC and its therapeutic strategy. Recent reports of the latest compounds, therapeutic strategies, and approaches tested on UC animal models are also discussed.
    Drug Design, Development and Therapy 11/2013; 7:1341-1357. DOI:10.2147/DDDT.S40107 · 3.03 Impact Factor
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    • "These results indicate major differences in pathogenesis between UC/CD patients and MC patients, where the latter would likely not benefit from treatment with antibodies blocking homing to the intestinal mucosa, where, for example, Natalizumab has shown good responses in CD patients [18]. This also shows clearly that it is indeed a local mucosal antigen triggering the T cell activation in MC pathology, possibly by one or several microbiota-derived antigens or by drugs that may aggravate MC in some patients [19]. "
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    ABSTRACT: Dysregulated T cell responses in the intestine may lead to chronic bowel inflammation such as collagenous colitis (CC) and lymphocytic colitis (LC), together known as microscopic colitis (MC). Having demonstrated increased local T cell responses in the intestinal mucosa of MC patients, we investigated the recent thymic emigrants by measuring T cell receptor excision circle (TREC) levels in the colonic biopsies from CC (n = 8), LC (n = 5), and CC or LC patients in histopathological remission (CC-HR, n = 3) (LC-HR, n = 6), non-inflamed diarrhoea patients (n = 17), and controls (n = 10) by real-time PCR. We observed lower median TREC levels in both CC and LC patients as well as in LC-HR patients compared to controls. In contrast to MC patients, non-inflamed diarrhoea patients presented with enhanced TREC levels compared to controls. None of the recorded differences did, however, reach statistical significance. A trend towards increased relative expression of CD3 was noted in all MC subgroups examined and reached statistical significance in LC patients compared to controls. In conclusion, reduced TRECs level in the colonic mucosa, together with our previously demonstrated enhanced expression of Ki67(+) T cells, suggests local expansion of resident T lymphocytes in the inflamed mucosa of MC patients.
    07/2013; 2013:408638. DOI:10.1155/2013/408638
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