A phase 2 study of tofacitinib, an oral Janus kinase inhibitor, in patients with Crohn's disease.
OBJECTIVE
Tofacitinib, an orally administered Janus kinase inhibitor, blocks signaling through γ-chain-containing cytokines (interleukins 2, 4, 7, 9, 15, and 21). We performed a phase 2 trial to measure its efficacy in patients with moderate-to-severe active Crohn's disease.


METHODS
Patients (N = 139; age, ≥18 y) with moderate-to-severe active Crohn's disease were assigned randomly to groups given 1 mg (n = 36), 5 mg (n = 34), or 15 mg (n = 35) tofacitinib or placebo (n = 34), twice daily for 4 weeks, at 48 centers in 12 countries. The primary end point was the proportion of clinical responders at week 4 (decrease from baseline in the Crohn's Disease Activity Index score of ≥70 points [Response-70]). Secondary end points included clinical remission (Crohn's Disease Activity Index score of <150 points) at week 4.


RESULTS
A clinical response was observed in 36% (P = .467), 58% (P = .466), and 46% (P ≥ .999) of patients given the 1-, 5-, and 15-mg doses of tofacitinib, compared with 47% of patients given placebo. Clinical remission was observed in 31% (P = .417), 24% (P = .776), and 14% (P = .540) of patients given the 1-, 5-, and 15-mg doses of tofacitinib, compared with 21% of patients given placebo. The 15-mg dose of tofacitinib reduced levels of C-reactive protein and fecal calprotectin from baseline. Adverse and serious adverse events were similar among groups. Dose-dependent increases in low- and high-density lipoprotein cholesterol were observed in patients given the 5- or 15-mg doses of tofacitinib.


CONCLUSIONS
There were no significant differences in the percentage of patients with moderate-to-severe active Crohn's disease who achieved clinical responses (Response-70) or clinical remission after 4 weeks' administration of tofacitinib (1, 5, or 15 mg) or placebo twice daily. However, a large percentage of patients given placebo achieved Response-70 or remission. Reductions in C-reactive protein and fecal calprotectin levels among patients given the 15-mg dose of tofacitinib indicate its biologic activity. ClinicalTrials.gov number: NCT00615199.
Division of Gastroenterology, University of California San Diego, La Jolla, California. Electronic address: wsandborn@ucsd.edu.
William J
WJ
Sandborn
Department of Medicine, University of Calgary, Calgary, Alberta, Canada.
Subrata
S
Ghosh
Gastroenterology Department, Hospital Clinic de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red (CIBERehd), Barcelona, Spain.
Julian
J
Panes
Global Medicine Development, Pfizer Inc, Sandwich, United Kingdom.
Ivana
I
Vranic
Global Innovative Pharma Division, Pfizer Inc, Collegeville, Pennsylvania.
Wenjin
W
Wang
Global Medicine Development, Pfizer Inc, Collegeville, Pennsylvania.
Wojciech
W
Niezychowski
D000328:Adult; D000818:Animals; D001774:Blood Chemical Analysis; D002097:C-Reactive Protein / Q000032:analysis; D003424:Crohn Disease / Q000188:drug therapy*; D005243:Feces / Q000737:chemistry; D005260:Female; D006801:Humans; D053612:Janus Kinases / Q000037:antagonists & inhibitors*; D039841:Leukocyte L1 Antigen Complex / Q000032:analysis; D008297:Male; D008875:Middle Aged; D010880:Piperidines / Q000627:therapeutic use*; D010919:Placebos / Q000008:administration & dosage; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011743:Pyrimidines / Q000627:therapeutic use*; D011758:Pyrroles / Q000627:therapeutic use*; D016896:Treatment Outcome
D039841:Leukocyte L1 Antigen Complex; D010880:Piperidines; D010919:Placebos; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011758:Pyrroles; C479163:tofacitinib; D002097:C-Reactive Protein; D053612:Janus Kinases
CP-690,550; Crohn’s Disease; Randomized Control Trial; Tofacitinib