Ustekinumab induced a clinical response in patients with moderate to severe Crohn’s disease that was resistant to tumor necrosis factor antagonists, in a phase IIb clinical trial published online Oct. 17 in the New England Journal of Medicine.
However, the agent did not improve remission rates, compared with placebo, said Dr. William J. Sandborn, professor of medicine and chief of the division of gastroenterology at the University of California San Diego, La Jolla, and his associates.
Dr. William J. Sandborn
"A sizable proportion" of patients with moderate to severe Crohn’s disease do not respond to TNF antagonists, have an unsustained response, or must discontinue the medications because of adverse effects. After ustekinumab showed efficacy in such patients in a phase IIa clinical study, Dr. Sandborn and his colleagues performed a 36-week double-blind phase II2b trial in 526 adults at 153 medical centers in 12 countries.
Ustekinumab, a human IgG monoclonal antibody that inhibits the receptors for interleukin-12 and interleukin-23 on T cells, natural killer cells, and antigen-presenting cells, has Food and Drug Administration approval for use in plaque psoriasis. This clinical trial was sponsored by an affiliate of the manufacturer, Janssen Biotech.
During an 8-week induction phase, the study subjects were randomly assigned to receive intravenous placebo (132 patients) or ustekinumab in 1-mg/kg (131 patients), 3-mg/kg (132 patients), or 6-mg/kg (131 patients) doses. Then, during weeks 8-36, the study subjects who showed a response to induction therapy and those who did not show a response were separately randomized to receive either subcutaneous ustekinumab (90 mg) or placebo at week 8 and week 16, as maintenance therapy.
Treatment efficacy was assessed at week 22, and patients were followed through week 36 for a safety analysis. A total of 36.1% of the subjects discontinued the study before week 36.
The primary end point was a clinical response, defined as a decrease of 100 points or more on the Crohn’s Disease Activity Index (CDAI) score.
A total of 39.7% of patients receiving the 6-mg induction dose showed a clinical response, which was significantly greater than the 23.5% of patients receiving placebo, the investigators said (New Engl. J. Med. 2012 [doi:10.1056/NEJMoa1203572]).
A greater number of patients receiving the lower doses of ustekinumab than receiving placebo showed a clinical response, but the differences between these low-dose groups and the placebo group did not reach statistical significance.
The 6-mg/kg dose was effective across most demographic and disease characteristics, judging from the findings of a subgroup analysis. It was consistently effective in patients who had failed on their first attempt at therapy with TNF antagonists, patients who had failed on two or more TNF antagonists, and patients who had only had a transient response to TNF antagonists.
However, rates of clinical remission did not differ significantly between patients receiving ustekinumab and those receiving placebo, Dr. Sandborn and his associates said.
At all follow-up visits, the proportion of patients who had a 70-point clinical response was significantly higher, the reductions in mean CDAI scores were significantly greater, and the reductions in C-reactive protein levels were significantly greater in patients receiving 6 mg per kg of ustekinumab than in the placebo group.
As a maintenance therapy, 90 mg of subcutaneous ustekinumab appeared to be effective in patients who responded to the induction dose of the agent. The proportion of patients who showed a clinical response at week 22 was 69.4% in those receiving maintenance ustekinumab, significantly greater than the 42.5% response rate among those receiving maintenance placebo.
Among patients who responded to induction-phase ustekinumab, 41.7% of those who also received maintenance ustekinumab achieved clinical remission at week 22, compared with only 27.4% of those who received maintenance placebo.
Similarly, among patients who showed a response to induction ustekinumab, reductions in both CDAI scores and CRP levels were sustained if they continued on maintenance ustekinumab but were not sustained if they continued on placebo for the maintenance period.
However, patients who did not show a response to induction ustekinumab also did not benefit from additional ustekinumab in the maintenance phase of the study.
The results of the safety analysis were "somewhat limited" by the small sample size and the short duration of treatment. No deaths, serious opportunistic infections, or major adverse cardiovascular events were reported, "but large studies of longer duration are needed to assess uncommon adverse events," the investigators said.
Of note, one patient receiving ustekinumab as both induction and maintenance therapy developed a basal cell carcinoma. Among patients taking ustekinumab in the induction phase of the study, six developed serious infections: Clostridium difficile, viral gastroenteritis, UTI, anal abscess, vaginal abscess, and a staph infection of a central catheter.
