Ustekinumab is emerging as an option for inflammatory bowel disease.  A study examining its effectiveness for TNF-refractory Crohn’s disease has been published (NEJM 2012; 367: 1519-28).

In this trial, members of CERTIFI (Crohn’s Evaluation of Response to Ustekinumab Anti-Interleukin-12/23 for Induction) from 153 centers in 12 countries assessed the efficacy of Ustekinumab in 526 adult patients.  The primary outcome was a clinical response (CDAI >100 point drop) at 6 weeks.

Ustekinumab (currently approved for plaque psoriasis) is a ‘fully human IgG1κ monoclonal antibody’ which blocks the activity of interleukin-12 (IL-12) and interleukin-23 (IL-23) by inhibiting receptors on T cells, natural killer cells, and antigen-presenting cells.  IL-12 and IL-23 have been implicated in the pathophysiology of Crohn’s disease.

This study of ustekinumab was a 36-week randomized, double-blind, placebo-controlled phase 2b trial.  The first 8 weeks were for induction.  After induction, based on response, patients were enrolled in a 28-week maintenance phase.  Initial dosing was 1, 3, or 6 mg/kg of intravenous ustekinumab or placebo.  Maintenance dose was 90 mg subcutaneously.

Patients were permitted to continue receiving stable doses of drugs.  However, entry requirements included a washout period for intravenous glucocorticoids (3 weeks), TNF antagonists (8 weeks), and natalizumab (12 months).

Results:

• 36.6%, 34.1% and 39.7% of ustekinumab patients (1, 3, and 6 mg/kg respectively) responded at 6 weeks compared with 23.5% of placebo.  The difference was statistically significant for 6 mg/kg/dose.
• Maintenance therapy (among responders) noted increased clinical remission with ustekinumab compared with placebo 41.7%  vs 27.4%.
• Overall rates of infection were similar. Serious infections were noted in 6 patients receiving ustekinumab compared with 1 placebo-treated patient.  Infusion reactions were uncommon.
• Patients who did not have a response to ustekinumab in the induction phase did not benefit from additional ustekinumab in the maintenance phase.

Overall, in this study, patients dosed at 6 mg/kg during induction were more likely to have a response but not more likely to have a remission.  Since all patients in this study had failed at least one TNF antagonist and 50% had failed at least two, the benefit of ustekinumab in other Crohn’s disease patients remains undefined.

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