In a previous phase 2b trial, intravenous ustekinumab induction therapy in patients with Crohn’s disease that was refractory to treatment with tumor necrosis factor (TNF) antagonists showed a significant benefit in terms of clinical response but not remission, and subcutaneously administered maintenance doses of ustekinumab were efficacious during a period of 22 weeks. Feagan et al. randomly assigned patients to receive a single intravenous dose of ustekinumab (either 130 mg or approximately 6 mg per kilogram of body weight) or placebo in two induction trials. The UNITI-1 trial included 741 patients who met the criteria for primary or secondary nonresponse to TNF antagonists or had unacceptable side effects. The UNITI-2 trial included 628 patients in whom conventional therapy failed or unacceptable side effects occurred. Patients who completed these induction trials then participated in IM-UNITI, in which the 397 patients who had a response to ustekinumab were randomly assigned to receive subcutaneous maintenance injections of 90 mg of ustekinumab (either every 8 weeks or every 12 weeks) or placebo. The research is summarized in a new Original Article.
• What are some of the limitations of current therapies for Crohn’s disease?
Crohn’s disease is a chronic inflammatory disease of the gastrointestinal tract that is treated with glucocorticoids, immunosuppressants, TNF antagonists, or integrin inhibitors. The drawbacks of these agents include an increased risk of infection and cancer and limited efficacy.
• What is ustekinumab?
Ustekinumab is a monoclonal antibody to the p40 subunit of interleukin-12 and interleukin-23 that has been approved for use in the treatment of psoriasis and psoriatic arthritis. In previous trials involving patients with psoriasis in which ustekinumab was administered subcutaneously for up to 5 years, the drug was not associated with an increased risk of serious adverse events.
Morning Report Questions
Q: Is ustekinumab effective as induction and maintenance therapy in Crohn’s disease?
A: At week 0 in the trial by Feagan et al., patients in both induction trials were randomly assigned, in a 1:1:1 ratio, to receive a single intravenous infusion of 130 mg of ustekinumab, a weight-range–based dose that approximated 6 mg of ustekinumab per kilogram of body weight, or placebo. (The administration of 6 mg of ustekinumab per kilogram meant that patients weighing ≤55 kg received 260 mg, those weighing >55 kg and ≤85 kg received 390 mg, and those weighing >85 kg received 520 mg.) In the maintenance trial, patients who had a response to ustekinumab induction therapy at week 8 were randomly assigned, in a 1:1:1 ratio, to receive subcutaneous injections of 90 mg of ustekinumab every 8 weeks, 90 mg of ustekinumab every 12 weeks, or placebo through week 40. In both induction trials, the primary end point was clinical response at week 6, which was defined as a decrease from baseline in the Crohn’s Disease Activity Index (CDAI) score of at least 100 points or a total CDAI score less than 150. In the maintenance trial, the primary end point was clinical remission at week 44 (CDAI score <150). Both ustekinumab induction regimens showed consistent benefit over placebo, irrespective of previous treatment or response to a TNF antagonist. Ustekinumab was significantly better than placebo with respect to the primary and all major secondary end points for induction at both doses, with the highest rates of response and remission observed with the dose of 6 mg per kilogram. At week 44 of the maintenance trial, among those who had a response to ustekinumab during induction, both subcutaneous ustekinumab doses showed significantly higher efficacy than placebo.
Q: Did the trial by Feagan et al. raise new safety concerns regarding the use of ustekinumab in patients with Crohn’s disease?
A: In the trial by Feagan et al., there were no deaths, and rates of overall adverse events, serious adverse events, and adverse events within 1 hour after infusion occurred at similar rates across groups. The rates of adverse events were similar for subcutaneous maintenance therapy with ustekinumab and placebo, and there was no apparent relationship between dose and safety. The adverse events observed in these trials are consistent with 5 years of cumulative data acquired for patients with psoriasis (who received subcutaneous doses ≤90 mg) and 2 years of safety data for patients with psoriatic arthritis.