Tofacitinib was associated with greater clinical response and remission rates than was placebo in a double-blind, phase II trial of patients with moderately or severely active ulcerative colitis.
Current treatment of ulcerative colitis with mesalamine, glucocorticoids, azathioprine, and anti–tumor necrosis factor (anti-TNF) agents such as infliximab and adalimumab is not always effective, and may be associated with serious toxic effects (Gastroenterology 2006;130:940-87). Thus, "additional treatments are needed," said Dr. William J. Sandborn, chief of the division of gastroenterology and professor of medicine at the University of California, San Diego and his associates (N. Engl. J. Med. 2012;367:616-24).
Tofacitinib is a selective oral inhibitor of the Janus kinase (JAK) family of enzymes that includes JAK1 and JAK3, which mediate signal-transduction activity for multiple cytokines, including several that are integral to lymphocyte activation, function, and proliferation. Although the importance of the JAK family in the pathogenesis of ulcerative colitis is unclear, tofacitinib has shown efficacy against other immune-mediated conditions, including organ allograft rejection, rheumatoid arthritis, and psoriasis.
The 8-week trial was conducted at 51 centers in 17 countries from January 2009 through September 2010 with funding from Pfizer. Subjects had to be at least 18 years of age, with a confirmed diagnosis of ulcerative colitis of 3 months’ duration or longer, a score of 6-12 on the Mayo risk calculator for ulcerative colitis,and evidence on sigmoidoscopic examination of moderately or severely active disease. In most of the patients, the use of conventional therapy (mesalamine, glucocorticoids, immunosuppressants, or anti-TNF agents used as monotherapy or in some combination) had failed, according to the investigators.
During the study, patients could receive oral mesalamine or oral prednisone at a stable dosage of 30 mg or less per day. However, patients receiving azathioprine, 6-mercaptopurine, and methotrexate discontinued them immediately before initiating therapy with tofacitinib, and patients who had previously received anti-TNF therapy were required to discontinue it for at least 8 weeks before study entry.
Patients were randomly assigned to receive twice-daily oral tofacitinib doses of 0.5 mg, 3 mg, 10 mg, or 15 mg or placebo for 8 weeks, and were then followed for 4 weeks through 12 weeks. Of the 195 patients randomized, 194 received at least one dose of the study drug or placebo and 157 completed the full 8 weeks of treatment. Across all treatment groups, 131 patients (67.5%) received concomitant aminosalicylates, and 85 (43.8%) received concomitant glucocorticoids at some point during the study, they noted.
Clinical response was defined as a decrease from baseline in the total Mayo score (defined as an absolute decrease by at least 3 points and a relative decrease by at least 30%) with an accompanying decrease in the rectal bleeding subscore of at least 1 point or an absolute rectal bleeding subscore of 0 or 1.
The primary end point, clinical response at 8 weeks, occurred in 42% (20) of the patients who received placebo. The response was significantly greater than that seen only among the patients who received the highest doses of tofacitinib, 78% of those receiving 15 mg (P less than .001). For the lower doses, the clinical response rates were not significantly different from those with placebo (61%, 48% and 32%, respectively, for 10 mg, 3 mg and 0.5 mg).
Clinical remission, a secondary end point, was defined as a total Mayo score of 0-2, with no individual subscore exceeding 1. Clinical remission at 8 weeks occurred in 10% (5) of the placebo patients. Here, the difference from placebo with tofacitinib was significant for doses of 3 mg (33%; P = .01), 10 mg (48%; P less than .001), and 15 mg (41%; P less than .001).
Another secondary end point, endoscopic response, was defined as a decrease from baseline in the endoscopy subscore by at least 1.The secondary end point of endoscopic remission was defined as an endoscopy subscore of 0.
An endoscopic response at 8 weeks occurred in 46% with placebo, significantly lower than the responses with tofacitinib doses of 10 mg (67%; P = .07) and 15mg (78%; P = .001). Endoscopic remission at 8 weeks occurred in just 2% of the placebo group, vs. significantly greater proportions of 18% with 3 mg (P = .01), 30% with 10 mg (P less than .001), and 27% with 15 mg (P less than .001).
Rates of overall and serious adverse events, as well as adverse events from infection, were similar among the groups. Two patients receiving 10 mg of tofacitinib twice daily had serious adverse events from infection (a postoperative abscess in one and anal abscess in the other). There was a dose-dependent increase in both LDL and HDL cholesterol concentrations at 8 weeks with tofacitinib, which reversed after discontinuation of the study drug . During the study period, the absolute neutrophil count was less than 1,500 cells per cubic millimeter in three patients receiving tofacitinib, but was not less than 1,000 cells per cubic millimeter in any patient, Dr. Sandborn and his associates reported.