Phase 2 Randomized Study of CP-690,550, an Oral Janus Kinase Inhibitor, in Active Crohn's Disease

Sandborn, William J.; Ghosh, Subrata; Panés, Julián; Vranić, Ivana; Spanton, J. A.; Niezychowski, Wojciech

doi:10.1016/s0016-5085(11)60503-9

Cited by 24 publications

(36 citation statements)

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“…A multicentre, double-blind, placebo controlled study with tofacitinib in patients with moderate to severe active CD showed no clinically significant response following 4 weeks of treatment compared with placebo, but in patients with moderate to severe UC it showed improvement in both clinical response and remission rates [258,259].…”

Section: New Avenues Against Pro-inflammatory Cytokines or Downstreammentioning

confidence: 99%

Gut Inflammation: Current Update on Pathophysiology, Molecular Mechanism and Pharmacological Treatment Modalities

Gyires¹,

Tóth²,

Zádori

2014

CPD

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Inflammatory bowel disease (IBD) is a chronic and relapsing inflammatory condition of the gastrointestinal tract. The two main forms of IBD are Crohn's disease and ulcerative colitis. According to the recent concept the disease is caused by a combination of factors, including genetics, immune dysregulation, barrier dysfunction and the change in microbial flora. Environmental factors, such as changes in diet, antibiotic use, smoking or improved domestic hygiene (e.g. eradication of intestinal helminths) probably contribute to the development and increased prevalence of IBD. Dysregulation of mucosal immunity in IBD causes an overproduction of inflammatory cytokines which resulted in uncontrolled intestinal inflammation. Based on extensive research over the last decade, besides the conventional therapy, there are several novel pathways and specific targets, on which focus new therapeutics. New therapeutics aim 1./ to correct genetic susceptibility by stimulating NOD2 expression, TLR3 signaling or inhibition of TLR4 pathway, 2./ to restore the immune dysregulation by inhibition of pro-inflammatory cytokines (TNF-, IL-6, IL-13, IL-17, IL-18, IL-21), Th1 polarisation (IL-2, IL-12, IL-23, IFN-), T-cell activation, leukocyte adhesion, as well as by immunostimulation (GM-CSF, G-CSF) and anti-inflammatory cytokines (IL-10, IL-11, IFN--1a), 3./ to restore mucosal barrier function and stimulate mucosal healing by different growth factors, such as GH, EGF, KGF, TGF-, VEGF, 4./ to restore the normal bacterial flora by antibiotics, probiotics. However, in spite of these numerous potential targets, the true value and clinical significance of most of the new biologics and molecules are not clear yet.

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Section: New Avenues Against Pro-inflammatory Cytokines or Downstreammentioning

confidence: 99%

Gut Inflammation: Current Update on Pathophysiology, Molecular Mechanism and Pharmacological Treatment Modalities

Gyires¹,

Tóth²,

Zádori

2014

CPD

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“…In a clinical phase II trial including 139 patients with moderate to severe CD that were randomized to receive one of three doses of tofacitinib or placebo, the primary end point, clinical response at week 4, was not achieved. However, there was a significant reduction in serum CRP levels and fecal calprotectin levels in patients receiving the highest dose of tofacitinib and the drug was in general well tolerated [181]. In a phase II trial including 194 patients with moderate to severe UC, that were randomized to receive one of four doses of tofacitinib or placebo, tofacitinib reached its primary endpoint, which was clinical response at week 8.…”

Section: New Drugs Directed Against Cytokine Signal Transductionmentioning

confidence: 99%

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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“…Indeed, small molecule inhibitor of Janus kinases (JAKs) specific for JAK1 and JAK3, namely, tofacitinib, inhibit the signaling of several cytokines such as IL 2, IL 4, IL 7, IL 9, IL 15, and IL 21. It has been shown that tofacitinib can suppress T cell differentiation and activation conferring beneficial effects in IBD, particularly in ulcerative colitis [86][87][88].…”

Section: Therapeutic Implicationsmentioning

confidence: 99%

Cytokines and Nitric Oxide in Immunopathogenesis of IBD and Potential Therapeutic Approaches

Soufli¹,

Toumi²,

Rafa³

et al. 2016

New Insights Into Inflammatory Bowel Disease

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Inflammatory bowel disease (IBD), which includes Crohn's disease (CD) and ulcerative colitis (UC), is a multi-factorial condition characterized by a chronic inflammation of the gastrointestinal tract. In IBD, the balance between pro/anti-inflammatory cytokines and immuno-regulatory cytokines is disturbed. An over-production of pro-inflammatory cytokines and nitric oxide characterizes the pathogenesis of IBD. In Crohn's disease the major cytokines are generated by Th1-and Th17-polarized T cells. In contract, UC is viewed more as an atypical Th2-type immune response characterized by the generation of high amount of IL-5, IL-4 and IL-13. Both Th1 and Th17 cytokines are involved in the up-regulation of iNOS expression in IBD and the production of high level of nitric oxide (NO). The latter, as an effect, causes tissue damages through the generation of reactive nitric oxygen species (RNOS). A better understanding of the pathogenesis of IBD has led to the development of new therapeutic strategies based on targeting cytokines and their receptors as well as NO modulation. Manipulation the microbiota with probiotics and helminthes may have potential use as anti-inflammatory agents in IBD by inducing anti-inflammatory cytokine pattern.

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Phase 2 Randomized Study of CP-690,550, an Oral Janus Kinase Inhibitor, in Active Crohn's Disease

Cited by 24 publications

References 0 publications

Gut Inflammation: Current Update on Pathophysiology, Molecular Mechanism and Pharmacological Treatment Modalities

Gut Inflammation: Current Update on Pathophysiology, Molecular Mechanism and Pharmacological Treatment Modalities

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

Cytokines and Nitric Oxide in Immunopathogenesis of IBD and Potential Therapeutic Approaches

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