By Nancy Walsh, Staff Writer, MedPage TodayPublished: October 17, 2012Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco
Patients with Crohn’s disease who are not helped by treatment with tumor necrosis factor (TNF) inhibitors may respond to a different type of biologic agent currently used for plaque psoriasis, a multicenter phase IIb trial suggested.
Among patients with refractory Crohn’s disease, 39.7% of patients receiving ustekinumab (Stelara) had a clinical response at week 6, compared with 23.5% of patients randomized to placebo, according to William J. Sandborn, MD, of the University of California San Diego, and colleagues.
Approximately one-third of patients with Crohn’s disease fail to respond to anti-TNF treatment, and an additional third lose their response. Previous experience has suggested that nonresponding patients are less likely to benefit from switching to a second TNF blocker.
Because the inflammatory IL-12/23 pathway has been implicated in the pathogenesis of this inflammatory bowel disorder, a phase IIa trial evaluating ustekinumab was performed and suggested clinical benefits.
To further explore the suitability of this treatment, Sandborn and colleagues enrolled 526 patients with mild-to-moderate disease and who had failed one or more TNF inhibitors, assigning them to receive 1, 3, or 6 mg/kg of intravenous ustekinumab or placebo as induction therapy.
Patients’ mean age was 39, and mean disease duration was 12 years. More than half were women.
Participants were granted to continue receiving conventional Crohn’s disease therapies such as glucocorticoids, immunomodulators, and mesalamine.
Clinical response was classified as a decrease of at least 100 points from baseline on the Crohn’s Disease Activity Index (CDAI), while remission was defined as achieving a CDAI score below 150 points.
Mean CDAI scores at baseline ranged from 312 to 338.
At weeks 6 and 8, the rate of remission did not differ between patients receiving the 6 mg/kg and those receiving placebo.
Among the possible reasons for the lack of remission early in treatment were the long duration and refractory disease in these patients, and the high baseline CDAI scores, according to the investigators.
Nonetheless, during the induction phase, significantly greater numbers of patients in the 6 mg/kg ustekinumab group had decreases of 70 points on the CDAI and had reductions in C-reactive protein levels.
Following the 6-week induction phase, patients were again randomized to placebo or to subcutaneous injections of ustekinumab in doses of 90 mg at weeks 8 and 16, respectively.
Efficacy was assessed at week 22, and safety through week 36.
At week 22, 69.4% of patients in the active treatment group had a clinical response, compared with 42.5% of those in the placebo group, for a difference of 26.9 percentage points (95% CI 11.5 to 42.5, P<0.001), the researchers reported.
In addition, among patients who had responded to ustekinumab during induction, 41.7% of those continuing on the active treatment were in remission compared with 27.4% of those given placebo, a difference of 14.3 percentage points (95% CI 2 to 27.1, P=0.03).
Sustained clinical responses, defined as a good response at each visit during maintenance, were seen in 55.6% of the ustekinumab group compared with 32.9% of the placebo group (P=0.005).
Among patients who had achieved clinical remission by week 6, 78.6% of those receiving the active treatment remained in remission at week 22 compared with 53.3% of those on placebo (P=0.06).
In addition, 30.6% of patients receiving ustekinumab who were in remission were no longer taking steroids compared with 17.8% of those receiving placebo (P=0.048).
For patients who did not respond to ustekinumab during induction, 20.2% and 18.2% of those who went on to receive the active treatment or placebo, respectively, had clinical responses during the maintenance phase (P=0.71).
“Patients who did not have a response to ustekinumab in the induction phase did not benefit from additional ustekinumab therapy in the maintenance phase,” the investigators observed.
During the induction phase of the study, five patients receiving the 6 mg/kg dose had serious infections, as did one patient on the 1 mg/kg dose and one receiving placebo.
In the maintenance phase, adverse events were similar in the active treatment and placebo groups, and no opportunistic infections, serious cardiac events, or deaths occurred.
One patient on ustekinumab developed a basal cell carcinoma, and antibodies to ustekinumab developed in 0.7% of patients.
Longer follow-up and bigger numbers of patients will be needed to more fully assess the safety of ustekinumab and to provide further evidence of efficacy, the investigators cautioned. It also remains unclear if this treatment is suitable for patients with Crohn’s disease who have not previously been treated with TNF inhibitors.
The study was funded by Janssen Research and Development.
Sandborn and several co-investigators reported consultancies and allows from multiple companies, including Janssen, Johnson and Johnson, Pfizer, Lilly, GSK, Boehringer Ingelheim, UCB, Abbott, and Prometheus. Sandborn also holds patents on drug formulations for inflammatory bowel disease.
Several co-authors are employees of Johnson & Johnson.
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