Ustekinumab Induction as Therapy for Crohn’s Disease

Crohn’s disease is a chronic inflammatory disease of the bowel. One third of patients with Crohn’s disease do not respond to initial treatment with tumor necrosis factor (TNF) antagonists; another one third have a transient response and require either dose escalation or a switch to another therapy. Patients in the first group are unlikely to have a positive response to another TNF antagonist and those in the second group, who switch to a second TNF antagonist, are less likely to have a response than patients who have not previously received a TNF antagonist.

In a previous study, ustekinumab was shown to have efficacy in patients with moderate-to-severe Crohn’s disease, particularly among patients who had received infliximab previously. Ustekinumab is currently approved to treat moderate-to-severe plaque psoriasis.

Researchers recently conducted a trial of ustekinumab to assess the efficacy of ustekinumab in patients with moderate-to-severe Crohn’s disease that was resistant to TNF antagonists. They reported trial results in the New England Journal of Medicine [2012;367(16):1519-1528].

The phase 2b trial was a 36-week, randomized, double-blind, placebo-controlled trial of ustekinumab comprising an 8-week induction phase and a 28-week maintenance phase. The researchers evaluated patients at 153 centers in 12 countries from October 2008 through December 2010. The primary end point was a clinical response at 6 weeks.

Inclusion criteria included being ≥18 years of age and having at least a 3-month history of Crohn’s disease with a score of 220 to 450 points on the Crohn’s Disease Activity Index (CDAI). Scores on the CDAI range from 0 to 600, with higher scores representing worse disease. A 50-point change indicates the minimal clinically important difference. All patients also met specified criteria for a primary nonresponse, a secondary nonresponse, or unacceptable side effects after receiving a TNF antagonist at an approved dose.

Exclusion criteria included undergoing bowel resection within 6 months prior to enrollment and those with the short-bowel syndrome, clinically significant stricture that could require surgery or preclude the use of the CDAI to assess the response to therapy, abscess, active tuberculosis, current infection, or other previous or current opportunistic infection or cancer.

During the induction phase of the trial, 526 patients were randomly assigned to receive intravenous (IV) ustekinumab at a dose of 1 mg per kilogram of body weight (n=131), 3 mg/kg (n=132), 6 mg/kg (n=131), or placebo (n=132). Demographic and disease baseline characteristics were similar across all 4 groups; however, median CDAI scores for the group receiving placebo and the group receiving 1 mg of ustekinumab per kilogram were somewhat lower compared with those receiving higher doses.

Among those in the placebo group, 113 proceeded to the maintenance phase, as did 364 of those receiving IV ustekinumab. During the maintenance phase, 145 patients who had a response to ustekinumab at 6 weeks underwent a second randomization to receive subcutaneous injections of ustekinumab (90 mg) or placebo at weeks 8 and 16.

The proportion of patients who had a clinical response was significantly greater among patients in the group receiving 6 mg of ustekinumab compared with those in the placebo group (P=.005). The proportions of those receiving 1 mg, 3 mg, and 6 mg reaching the primary end point were 36.6%, 34.1%, and 39.7%, respectively, compared with 23.5% for the placebo group.

There was no statistically significant difference in the rate of clinical remission with the 6-mg dose compared with placebo at 6 weeks.

During the maintenance phase, therapy with ustekinumab, compared with placebo, resulted in statistically significant increased rates of clinical remission (41.7% vs 27.4%; P=.03) and response (69.4% vs 42.5%; P<.001) at 22 weeks.

In conclusion, the researchers noted, “Patients with moderate-to-severe Crohn’s disease that was resistant to TNF antagonists had an increased rate of response to induction with ustekinumab, as compared with placebo. Patients with an initial response to ustekinumab had significantly increased rates of response and remission with ustekinumab as maintenance therapy.”