Tofacitinib, an Oral Janus Kinase Inhibitor, in Active Ulcerative Colitis
- 16 August 2012
- journal article
- research article
- Published by Massachusetts Medical Society in The New England Journal of Medicine
- Vol. 367 (7), 616-624
- https://doi.org/10.1056/nejmoa1112168
Abstract
Ulcerative colitis is a chronic inflammatory disease of the colon for which current treatments are not universally effective. One additional treatment may be tofacitinib (CP-690,550), an oral inhibitor of Janus kinases 1, 2, and 3 with in vitro functional specificity for kinases 1 and 3 over kinase 2, which is expected to block signaling involving gamma chain–containing cytokines including interleukins 2, 4, 7, 9, 15, and 21. These cytokines are integral to lymphocyte activation, function, and proliferation. In a double-blind, placebo-controlled, phase 2 trial, we evaluated the efficacy of tofacitinib in 194 adults with moderately to severely active ulcerative colitis. Patients were randomly assigned to receive tofacitinib at a dose of 0.5 mg, 3 mg, 10 mg, or 15 mg or placebo twice daily for 8 weeks. The primary outcome was a clinical response at 8 weeks, defined as an absolute decrease from baseline in the score on the Mayo scoring system for assessment of ulcerative colitis activity (possible score, 0 to 12, with higher scores indicating more severe disease) of 3 or more and a relative decrease from baseline of 30% or more with an accompanying decrease in the rectal bleeding subscore of 1 point or more or an absolute rectal bleeding subscore of 0 or 1. The primary outcome, clinical response at 8 weeks, occurred in 32%, 48%, 61%, and 78% of patients receiving tofacitinib at a dose of 0.5 mg (P=0.39), 3 mg (P=0.55), 10 mg (P=0.10), and 15 mg (P1) at 8 weeks occurred in 13%, 33%, 48%, and 41% of patients receiving tofacitinib at a dose of 0.5 mg (P=0.76), 3 mg (P=0.01), 10 mg (P<0.001), and 15 mg (P<0.001), respectively, as compared with 10% of patients receiving placebo. There was a dose-dependent increase in both low-density and high-density lipoprotein cholesterol. Three patients treated with tofacitinib had an absolute neutrophil count of less than 1500. Patients with moderately to severely active ulcerative colitis treated with tofacitinib were more likely to have clinical response and remission than those receiving placebo. (Funded by Pfizer; ClinicalTrials.gov number, NCT00787202.)Keywords
This publication has 23 references indexed in Scilit:
- Modulation of Innate and Adaptive Immune Responses by Tofacitinib (CP-690,550)The Journal of Immunology, 2011
- Adalimumab for induction of clinical remission in moderately to severely active ulcerative colitis: results of a randomised controlled trialGut, 2011
- Discovery of CP-690,550: A Potent and Selective Janus Kinase (JAK) Inhibitor for the Treatment of Autoimmune Diseases and Organ Transplant RejectionJournal of Medicinal Chemistry, 2010
- Ulcerative Colitis Practice Guidelines in Adults: American College of Gastroenterology, Practice Parameters CommitteeThe American Journal of Gastroenterology, 2010
- European evidence-based Consensus on the management of ulcerative colitis: Current managementJournal of Crohn's and Colitis, 2008
- The specificity of JAK3 kinase inhibitorsBlood, 2008
- Inflammatory bowel disease: clinical aspects and established and evolving therapiesThe Lancet, 2007
- Inflammatory bowel disease: cause and immunobiologyThe Lancet, 2007
- American Gastroenterological Association Institute Technical Review on Corticosteroids, Immunomodulators, and Infliximab in Inflammatory Bowel DiseaseGastroenterology, 2006
- Course of ulcerative colitis: Analysis of changes in disease activity over yearsGastroenterology, 1994