Patients with Crohn's disease who have failed to respond adequately to anti-tumor necrosis factor (anti-TNF) treatment may benefit from the monoclonal antibody ustekinumab, results of a double-blind, placebo-controlled trial suggest.
Indeed, around 42% of patients achieved full clinical remission at 22 weeks after ustekinumab induction and maintenance.
"A sizable proportion of patients with moderate-to-severe Crohn's disease do not have a response to treatment with TNF antagonists, and among patients who do have a response, it is often not sustained or side effects require discontinuation of therapy," study co-author William Sandborn (University of California San Diego, La Jolla, USA) and colleagues comment.
Noting that preclinical studies have implicated interleukin-12 and -23 in the pathophysiology of Crohn's disease, they performed a clinical trial of a corresponding antagonistic human monoclonal antibody, ustekinumab.
The phase II clinical trial involved in 658 patients with moderate-to-severe Crohn's disease that was resistant to TNF treatment. During the induction phase, 526 patients were randomly assigned to receive intravenous ustekinumab (at a dose of 1, 3, or 6 mg/kg) and 132 to receive placebo.
At 6 weeks of follow up, the proportion of patients who achieved a clinical response (≥100-point reduction in Crohn's Disease Activity Index [CDAI]) was 36.6%, 34.1%, and 39.7% for 1, 3, and 6 mg ustekinumab/kg, respectively, compared with 23.5% for placebo.
However, the rate of clinical remission (CDAI<150) with ustekinumab did not differ significantly from the rate with placebo at 6 weeks.
A maintenance phase was then initiated among 145 patients who responded to ustekinumab at 6 weeks, of whom 72 were randomized to receive subcutaneous injections of ustekinumab (90 mg) and 73 placebo at weeks 8 and 16.
Compared with placebo, maintenance therapy with ustekinumab resulted in significantly increased rates of clinical remission (41.7 vs 27.4%) and response (69.4 vs 42.5%) at 22 weeks.
Seven patients (six receiving ustekinumab) developed serious infections during induction, as did 11 (four receiving ustekinumab) during maintenance therapy. One patient, who was receiving ustekinumab, developed basal-cell carcinoma.
"Whether our findings in patients with disease that was resistant to TNF antagonists can be extrapolated to the broader Crohn's disease population is unclear," Sandborn et al comment in The New England Journal of Medicine.
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