Ustekinumab induces and maintains remission in Crohn's disease

Last Updated: 2016-11-22

By Will Boggs MD

NEW YORK (Reuters Health) - Ustekinumab improves response rates and sustains remission in patients with moderately to severely active Crohn's disease, according to results from three clinical trials with up to 52 weeks of therapy.

"Ustekinumab is effective for induction and maintenance treatment in patients with Crohn's disease who are naïve to anti-TNF therapy or who have failed anti-TNF therapy," Dr. William J. Sandborn from University of California, San Diego in La Jolla told Reuters Health by email. "It has a favorable safety profile, and the patient self-administered subcutaneous (SQ) maintenance therapy once every 8 weeks is convenient for patients."

Ustekinumab, a monoclonal antibody to the p40 subunit of interleukin-12 and interleukin-23, was first approved for the treatment of psoriasis and psoriatic arthritis, and a previous phase 2b trial found it to be effective for inducing clinical responses (but not remission) in Crohn's disease refractory to treatment with TNF antagonists.

Dr. Sandborn and colleagues in the UNITI-IM-UNITI Study Group evaluated ustekinumab as an intravenous induction therapy and subcutaneous maintenance therapy in patients with moderately to severely active Crohn's disease.

In UNITI-1 and UNITI-2, the percentages of patients who had a response at week 6 were significantly higher in patients who received ustekinumab (33.7% to 55.5%) than in those who received placebo (21.5% to 28.7%), according to the November 17th report in The New England Journal of Medicine.

In both trials, the efficacy of ustekinumab was consistent across prespecified subgroups, and the rates at which patients met the criteria for major secondary efficacy endpoints were significantly higher in the ustekinumab groups than in the placebo groups.

In the maintenance study, the percentage of patients who were in remission at week 44 was significantly higher in the groups that received 90 mg ustekinumab every 8 weeks (53.1%) or every 12 weeks (48.8%) than in the placebo group (35.9%).

More than 40% of patients in the ustekinumab groups remained in sustained clinical remission at weeks 36, 40, and 44, compared with only 26.0% of patients in the placebo group.

Adverse event rates were similar across treatment groups.

Although statistical testing was not planned or performed, the dose of 6 mg/kg appeared to offer higher blood levels of ustekinumab and greater efficacy for most of the outcomes, compared with the dose of 130 mg.

"The fact that ustekinumab was effective in both anti-TNF failure patients and anti-TNF naïve patients was very important," Dr. Sandborn said. "The efficacy for induction treatment in patients who have failed anti-TNF agents appears to be more robust than switching to another anti-TNF agent or to other mechanisms of action. The efficacy in patients who have not failed anti-TNF drugs looks comparable to the results of anti-TNF drugs in patients who are naïve to biologic therapy. And the safety is quite favorable, with no statistically significant increases in serious infections or malignancy."

In email to Reuters Health, co-author Dr. Brian G. Feagan from Western University, London, Ontario, Canada referred to "the separation from placebo at week 3 indicating an early induction of remission effect and the sparing of corticosteroids (prednisone) in the maintenance phase," noting that "the latter is particularly important to patients."

Dr. Sandborn said, "Certainly it will play a major role in the care of patients who have failed one or more anti-TNF agents. It can also be used as a first-line biologic agent, and that may be particularly useful in patients where safety considerations are greater."

"First-line becomes attractive as the experience with safety is confirmed in the Crohn's disease population," Dr. Feagan added.

Dr. Uri Kopylov from Sheba Medical Center, Tel Hashomer, Israel told Reuters Health by email, "Ustekinumab is a long-awaited new compound for treatment of Crohn's disease that was recently approved by FDA based on the results of the study by Feagan et al. in the New England Journal of Medicine."

"Ustekinumab will provide a viable therapeutic option for Crohn's disease patients requiring biologic therapy, both as a first-line treatment and as a rescue therapy for those failing previous biologic therapy," he said. "It may be especially useful when safety concerns about use of anti-TNFs arise (although long-term follow-up registry studies are required to confirm the long-term safety of this drug) and probably for treatment of extraintestinal manifestations."

"The utility of therapeutic drug monitoring with ustekinumab should be explored in further studies," Dr. Kopylov said. "Endoscopic response data (that will be made available in further publications), as well as efficacy in perianal disease, would be of great interest."

Janssen Research and Development funded this research, employed nine of the 27 authors, and had various relationships with other authors.

SOURCE: http://bit.ly/2gjcdhf

N Engl J Med 2016.