A phase 1/2A Trial of STA 5326, an oral interleukin-12/23 inhibitor, in patients with active moderate to severe Crohnʼs disease

Burakoff, Robert; Barish, Charles F.; Riff, Dennis; Pruitt, Ronald E.; Chey, William Y.; Farraye, Francis A.; Shafran, Ira; Katz, Seymour; Krone, Charles L.; Vliet, Martha Vander; Stevens, Christopher; Sherman, Matthew L.; Jacobson, Eric; Bleday, Ronald

doi:10.1097/01.ibd.0000225337.14356.31

Cited by 98 publications

(56 citation statements)

References 27 publications

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“…The success of cytokine inhibition in rheumatoid arthritis is also paralleled in other inflammatory diseases, including psoriatic dermatitis and arthritis (93), with TNF inhibition having a demonstrated role, in addition to promising newer targets, such as IL-22 and IL-23 (94,95). Evidence for the value of cytokine inhibition exists in diseases other than inflammatory arthropathies, with efficacy demonstrated for TNF (96), as well as IL-12/23 (97,98), in inflammatory bowel disease. In this setting of proven efficacy for cytokine inhibition in other diseases of dysregulated immunity, further definition of the role of cytokines in the determination of GVHD severity is likely to translate rapidly into efficacious therapies for the transplant patient population.…”

Section: Translational Applicationmentioning

confidence: 99%

Cytokines in Graft-versus-Host Disease

Henden

Hill

2015

The Journal of Immunology

153

117

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Graft-versus-host disease (GVHD) is a complication of allogeneic bone marrow transplantation whereby transplanted naive and marrow-derived T cells damage recipient tissue through similar mechanisms to those that allow destruction of malignant cells, the therapeutic intent of bone marrow transplantation. The manifestations and severity of GVHD are highly variable and are influenced by the proportions of naive cells maturing along regulatory T cell, Th1, Th2, or Th17 phenotypes. This maturation is largely influenced by local cytokines, which, in turn, activate transcription factors and drive development toward a dominant phenotype. In addition, proinflammatory cytokines exert direct effects on GVHD target tissues. Our knowledge of the role that cytokines play in orchestrating GVHD is expanding rapidly and parallels other infective and inflammatory conditions in which a predominant T cell signature is causative of pathology. Because a broad spectrum of cytokine therapies is now routinely used in clinical practice, they are increasingly relevant to transplant medicine.

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Section: Translational Applicationmentioning

confidence: 99%

Cytokines in Graft-versus-Host Disease

Henden

Hill

2015

The Journal of Immunology

153

117

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“…An initial phase I/IIa trial in patients with moderate to severe CD showed a clinical activity of the agent [56]. However, a following placebo-controlled, randomized phase II trial in 220 patients with moderate to severe CD revealed that apilimod mesylate has no significant effect on the induction of a clinical response at day 29 when compared to placebo.…”

Section: Apilimod Mesylatementioning

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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“…However, clinical trials with various IL-12/IL-23 blockers in CD were quite disappointing. For example, apilimod mesylate, a small inhibitor of IL-12 and IL-23 transcription, was not superior to placebo in controlling disease activity in patients with CD [66,67]. Similarly, ustekinumab, a monoclonal antibody targeting p40 subunit was only partially effective in patients with active CD.…”

Section: Inhibitors Of T Cell Differentiation or T Cell-derived Cytokmentioning

confidence: 99%

Targeting T cells in Chronic Inflammatory Bowel Diseases

Caprioli¹,

Marafini²,

Facciotti³

et al. 2013

J Clin Cell Immunol

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The pathological process that causes tissue damage in Crohn's disease (CD) and ulcerative colitis, the major inflammatory bowel diseases (IBD) in humans, is supposed to be mediated by distinct subsets of effector T cells, which accumulate in inflamed intestine of patients as a result of multiple mechanisms. These include enhanced recruitment of T cells from the systemic circulation, increased cell cycling and resistance against apoptotic stimuli. Within the inflamed gut, effector T cells produce elevated levels of cytokines, which target multiple immune and nonimmune cell types thus contributing to amplify the detrimental inflammatory response. Strategies aimed at blocking T cell function in the gut have been employed with some success in patients with CD and patients with UC.

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A phase 1/2A Trial of STA 5326, an oral interleukin-12/23 inhibitor, in patients with active moderate to severe Crohnʼs disease

Abstract: Oral qd dosing of STA 5326 for 4 weeks was well tolerated in doses up to 70 mg qd in patients with active moderate to severe Crohn's disease. Clinical activity was observed at qd doses of 28 mg and above.

Cited by 98 publications

References 27 publications

Cytokines in Graft-versus-Host Disease

Cytokines in Graft-versus-Host Disease

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

Targeting T cells in Chronic Inflammatory Bowel Diseases

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