There are definitely a lot of new therapies on the horizon for inflammatory bowel disease. One of these agents is likely to be tofacitinib which has shown efficacy for active ulcerative colitis (NEJM 2012; 367: 616-24).
Background: Tofacitinib is a selective oral inhibitor of Janus kinase (JAK) which mediates activity for multiple cytokines, including interleukins 2, 4, 7, 9, 15, and 21. Blockage of a common signaling molecule by these cytokines “should result in suppression of both T and B cells while maintaining regulatory T-cell function. It has shown efficacy for organ allograft rejection, rheumatoid arthritis, and psoriasis.” A previous small study by these investigators did not demonstrate efficacy in Crohn’s disease (Gastroenterology 2011; 140: Suppl: S124 Abstract).
Design: In this study which began as a double-blind, placebo-controlled, phase 2 trial, tofacitinib or placebo was given to 194 adult patients (from 51 centers in 17 countries) with moderate-to-severe active ulcerative colitis. Dosing for tofacitinib included groups receiving 0.5 mg, 3 mg, 10 mg, or 15 mg (all BID). “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.” Most of these patients had failed conventional therapy, including mesalamine, corticosteroids, immunosuppressants, and anti-TNF agents.
Results: At 8 weeks, the primary outcome with the highest doses (10 mg & 15 mg) of tofacitinib had clinical response rates of 61% (p=0.1) and 78% (p<0.001) respectively compared with a 42% placebo response. Clinical remission (Mayo score ≤ 2) occurred in 48% and 41% respectively (both p<0.001) compared with 10% in placebo group. Endoscopic remission was noted in 30% and 27% respectively (both p<0.001) compared with 2% of placebo group.
In addition, tofacitinib administration improved CRP values and fecal calprotectin concentrations (Figure 2 of article).
Potential adverse effects included the following
- neutropenia (ANC 1000-1500) observed in three treated patients
- two tofacitinib patients (10 mg group) developed abscesses
- mild increases in LDL and HDL were noted and dose-related (these changes have been seen in rheumatoid arthritis patients as well)
- N Engl J Med 2012; 367:495-507 | August 9, 2012. Tofacitinib for rheumatoid arthritis