Tofacitinib, an Oral Janus Kinase Inhibitor, in Active Ulcerative Colitis

N Engl J Med. 2012 Aug 16;367(7):616-24. doi: 10.1056/NEJMoa1112168.

Abstract

Background: 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.

Methods: 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.

Results: 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 (P<0.001), respectively, as compared with 42% of patients receiving placebo. Clinical remission (defined as a Mayo score ≤2, with no subscore >1) 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.

Conclusions: 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.).

Publication types

  • Clinical Trial, Phase II
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Adult
  • Colitis, Ulcerative / drug therapy*
  • Dose-Response Relationship, Drug
  • Double-Blind Method
  • Female
  • Humans
  • Janus Kinases / antagonists & inhibitors*
  • Lipoproteins, HDL / blood
  • Lipoproteins, LDL / blood
  • Male
  • Middle Aged
  • Piperidines
  • Protein Kinase Inhibitors / administration & dosage*
  • Protein Kinase Inhibitors / adverse effects
  • Protein Kinase Inhibitors / therapeutic use
  • Pyrimidines / administration & dosage*
  • Pyrimidines / adverse effects
  • Pyrimidines / therapeutic use
  • Pyrroles / administration & dosage*
  • Pyrroles / adverse effects
  • Pyrroles / therapeutic use
  • Remission Induction

Substances

  • Lipoproteins, HDL
  • Lipoproteins, LDL
  • Piperidines
  • Protein Kinase Inhibitors
  • Pyrimidines
  • Pyrroles
  • tofacitinib
  • Janus Kinases

Associated data

  • ClinicalTrials.gov/NCT00787202