Phase 2 Study of CP-690,550, an Oral Janus Kinase Inhibitor, in Active Ulcerative Colitis

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

doi:10.1016/s0016-5085(11)60445-9

Cited by 14 publications

(15 citation statements)

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“…5 In ulcerative colitis, treatment with tofacitinib was associated with dose-dependent improvement in clinical response and remission rates. 6 These results suggest that tofacitinib has the potential to be an important therapeutic option for patients diagnosed with these autoimmune disorders.The clearance mechanisms for tofacitinib in humans are approximately 70% non-renal (hepatic metabolism primarily via cytochrome P450 [CYP] 3A4, with a minor contribution from CYP2C19) and 30% renal excretion. …”

mentioning

confidence: 92%

The effect of mild and moderate hepatic impairment on the pharmacokinetics of tofacitinib, an orally active Janus kinase inhibitor

Lawendy

Lamba

Wang

et al. 2014

Clinical Pharm in Drug Dev

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Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis. We report here an evaluation of the pharmacokinetics of a single 10 mg dose of tofacitinib in healthy volunteers (n = 6) and subjects with mild (n = 6) or moderate (n = 6) hepatic impairment. Compared to healthy volunteers, tofacitinib area under the plasma concentration-time profile from time 0 to infinity (AUCinf ) and maximum observed concentration (Cmax ) in subjects with mild hepatic impairment were not altered. In subjects with moderate hepatic impairment, the geometric mean AUCinf and Cmax of tofacitinib were increased (90% confidence intervals of percentage increase) by approximately 65% (25%, 117%) and 49% (12%, 97%), respectively. A single dose of tofacitinib 10 mg resulted in two treatment-emergent adverse events (AE) in the mild hepatic impairment group, and one in the moderate hepatic impairment group; they were not considered related to study treatment. There were no deaths, serious AEs, discontinuations due to AEs, or dose reductions due to AEs. Data from this study were critical to deriving dose adjustments for subjects with hepatic impairment.

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mentioning

confidence: 92%

The effect of mild and moderate hepatic impairment on the pharmacokinetics of tofacitinib, an orally active Janus kinase inhibitor

Lawendy

Lamba

Wang

et al. 2014

Clinical Pharm in Drug Dev

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“…33 Tofacitinib was shown to have efficacy in psoriasis, 34 rheumatoid arthritis, 35 and ulcerative colitis, the last sharing pathomechanistical features with acute intestinal GVHD. 36 However, although tofacitinib is approved for patients with rheumatoid arthritis, it has not been used in patients with hematologic malignancies, and the broad JAK1,2,3 might affect the toxicity profile in those patients.…”

Section: Discussionmentioning

confidence: 99%

Activity of therapeutic JAK 1/2 blockade in graft-versus-host disease

Spoerl

Mathew²,

Bscheider

et al. 2014

Blood

356

296

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Key Points• We report that ruxolitinib reduces murine GVHD via increased Treg numbers.• We demonstrate the potent activity of ruxolitinib treatment in patients with corticosteroidrefractory GVHD.Graft-versus-host-disease (GVHD) is a severe complication of allogeneic hematopoietic cell transplantation (allo-HCT) characterized by the production of high levels of proinflammatory cytokines. Activated Janus kinases (JAKs) are required for T-effector cell responses in different inflammatory diseases, and their blockade could potently reduce acute GVHD. We observed that inhibition of JAK1/2 signaling resulted in reduced proliferation of effector T cells and suppression of proinflammatory cytokine production in response to alloantigen in mice. In vivo JAK 1/2 inhibition improved survival of mice developing acute GVHD and reduced histopathological GVHD grading, serum levels of proinflammatory cytokines, and expansion of alloreactive luc-transgenic T cells. Mechanistically, we could show that ruxolitinib impaired differentiation of CD4 1 T cells into IFN-g-and IL17A-producing cells, and that both T-cell phenotypes are linked to GVHD. Conversely, ruxolitinib treatment in allo-HCT recipients increased FoxP3 1 regulatory T cells, which are linked to immunologic tolerance. Based on these results, we treated 6 patients with steroid-refractory GVHD with ruxolitinib. All patients responded with respect to clinical GVHD symptoms and serum levels of proinflammatory cytokines. In summary, ruxolitinib represents a novel targeted approach in GVHD by suppression of proinflammatory signaling that mediates tissue damage and by promotion of tolerogenic Treg cells. (Blood. 2014;123(24):3832-3842)

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“…In trials both in CD and UC the overall incidences of adverse events were similar between patients administered tofacitinib and those given placebo. However, as has been seen to a lesser degree with tocilizumab, there was a dose-dependent increase in low-density lipoprotein cholesterol observed in patients treated with tofacitinib,62 63 which will require further investigation to determine the long-term effects.…”

Section: Targeting the Adaptive Immune Systemmentioning

confidence: 90%

“…Tofacitinib was, however, associated with a significant decrease in CRP and fecal calprotectin levels 62. In contrast, a study in patients with moderate to severe UC showed that 8 weeks of treatment with tofacitinib was associated with a dose-dependent improvement in both clinical response and remission rates 63. In trials both in CD and UC the overall incidences of adverse events were similar between patients administered tofacitinib and those given placebo.…”

Section: Targeting the Adaptive Immune Systemmentioning

confidence: 96%

New therapies for inflammatory bowel disease: from the bench to the bedside

Danese

2011

Gut

282

172

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The mechanisms underlying the chronic intestinal inflammation that is a hallmark of inflammatory bowel diseases (IBD) are complex. Components of the pathological response include the adaptive and innate immune systems, as well as the intestinal epithelium and endothelium. Advances in the understanding of the roles of each of these components have resulted in the development of multiple biological agents that all represent an alternative to the use of current therapies in patients with refractory Crohn's disease or ulcerative colitis. This study systematically reviews the mechanisms of action, efficacy and safety of new and emerging therapies that are currently in clinical trials and discusses future directions in the treatment of IBD.

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Phase 2 Study of CP-690,550, an Oral Janus Kinase Inhibitor, in Active Ulcerative Colitis

Cited by 14 publications

References 0 publications

The effect of mild and moderate hepatic impairment on the pharmacokinetics of tofacitinib, an orally active Janus kinase inhibitor

The effect of mild and moderate hepatic impairment on the pharmacokinetics of tofacitinib, an orally active Janus kinase inhibitor

Activity of therapeutic JAK 1/2 blockade in graft-versus-host disease

New therapies for inflammatory bowel disease: from the bench to the bedside

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