FROM THE NEW ENGLAND JOURNAL OF MEDICINE
Intravenous induction of the monoclonal antibody ustekinumab induced significantly higher 6-week clinical response rates in patients with moderately to severely active Crohn’s disease, compared with those who received placebo.
In addition, among those who had achieved clinical response to induction therapy, subcutaneous administration of ustekinumab led to high 44-week remission rates.
These results are based on a phase III development program that included two 8-week induction trials, UNITI-1 and UNITI-2, and one 44-week maintenance trial, IM-UNITI. Together, the trials represented 52 weeks of continuous therapy, explained lead investigators Brian Feagan, MD, of the Robarts Research Institute, Western University, London, Ont., and William Sandborn, MD, of the University of California in San Diego and their associates (N Engl J Med. 2016 Nov 16. doi: 10.1056/NEJMoa1602773).
All three trials were global, multisite, double-blind, placebo-controlled studies involving adults who had Crohn’s Disease Activity Index (CDAI) scores ranging from 220 to 450 out of 600, with higher scores indicating more severe disease.
“At week 0, 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,” Dr. Feagan, Dr. Sandborn, and their associates wrote.
A total of 741 patients participated in UNITI-1, while 628 patients participated in the UNITI-2 trial. Baseline and disease characteristics were similar among all groups, according to the researchers.
In UNITI-1, the percentage of patients who achieved the study’s primary endpoint of 6-week clinical response (defined as a 100-point decrease from baseline CDAI score or total CDAI score less than 150) was significantly higher in the groups that received ustekinumab at a dose of either 130 mg or 6 mg/kg (34.3% and 33.7%, respectively) than in the placebo group (21.5%).
The absolute difference between the 130-mg ustekinumab group and the placebo group was 12.8 percentage points (95% confidence interval, 5.0-20.7; P = .002), and the absolute difference between the 6-mg/kg ustekinumab dose and placebo was 12.3 percentage points (95% CI, 4.5-20.1; P = .003), the investigators reported.
Similarly, in UNITI-2, the percentages of patients who achieved 6-week clinical response also were significantly higher in the groups that received ustekinumab at a dose of either 130 mg or 6-mg/kg (51.7% and 55.5%, respectively), compared with the placebo group (28.7%).
The absolute difference between the 130-mg ustekinumab dose and placebo was 23.0 percentage points (95% CI, 13.8-32.1; P less than .001). Between the 6-mg/kg ustekinumab dose and placebo, the absolute difference was 26.8 percentage points (95% CI, 17.7-35.9; P less than .001).
“In the induction trials, both doses of ustekinumab were associated with greater reductions in and normalization of serum [C-reactive protein] levels than was placebo. The differences between ustekinumab and placebo were nominally significant and were observed as early as week 3 and persisted through week 8. Similar effects were observed for fecal calprotectin levels at week 6,” the investigators summarized.
In the maintenance trial IM-UNITI, patients from UNITI-1 and UNITI-2 (n = 1,281) 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 general, participants who received maintenance therapy with ustekinumab had significantly higher 44-week remission rates, compared with those who received placebo (53.1% for 8-week group, 48.8% for 12-week group, 35.9% for placebo).
“The rate of remission at week 44 was significantly higher among patients who entered maintenance in remission and who received treatment every 8 weeks – but not those who received treatment every 12 weeks – than among those who received placebo,” Dr. Feagan, Dr. Sandborn and their associates added.
Janssen Research and Development supported this study. Dr. Feagan, Dr. Sandborn, and 24 other investigators reported receiving financial compensation from various pharmaceutical companies, including Janssen. Nine of the investigators are employees of Janssen.
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