In one of two such trials published in The New England Journal of Medicine on Sept. 26, 2019, researchers led by, of the Icahn School of Medicine at Mount Sinai, New York, and associates evaluated ustekinumab as an 8-week induction therapy and a 44-week maintenance therapy in patients with moderate to severe ulcerative colitis (N Engl J Med 2019 Sep 25 doi: 10/1056/NEJMoa1900750). For the phase 3 trial, known as UNIFI, researchers randomly assigned 961 patients to receive an intravenous induction dose of ustekinumab over the course of 8 weeks (320 to a dose of 130 mg and 322 to a weight-range–based dose that approximated 6 mg per kilogram of body weight), while the remaining 319 received placebo. Patients who responded to induction therapy were randomly assigned to a 44-week maintenance phase in which they received subcutaneous maintenance injections of 90 mg of ustekinumab (172 to injections every 12 weeks, 176 to injections every 8 weeks, and 175 to placebo). The primary endpoint for both phases of the trial was clinical remission, defined as a total score of 2 or lower on the Mayo scale, and no subscore greater than 1 on any of the four Mayo scale components.
Dr. Sands and his colleagues found that at week 8, clinical remission was achieved in 15.6% of patients in the 130-mg ustekinumab infusion group, compared with 15.5% in the 6-mg per kg of body weight group, and 5.3% of those in the placebo group. “The percentages of patients who met major secondary endpoints or had histo-endoscopic mucosal healing were significantly higher in both ustekinumab groups than in the placebo group,” the researchers wrote. “Through week 8, the median changes from baseline in the IBDQ [Inflammatory Bowel Disease Questionnaire] score were significantly greater in both ustekinumab groups than in the placebo group.”
Meanwhile, at week 44, clinical remission was achieved in 38.4% of patients in the group receiving 90-mg subcutaneous ustekinumab every 12 weeks, compared with 43.8% of those in the group receiving 90 mg every 8 weeks, and 24% of those in the placebo group. “The percentages of patients with maintenance of clinical response through week 44, endoscopic improvement at week 44, or corticosteroid-free clinical remission (with either definition of clinical remission) at week 44 were significantly higher in both ustekinumab groups than in the placebo group,” the researchers wrote.
When they evaluated other endpoints, Dr. Sands and his colleagues observed that improvements in partial Mayo scores and reductions in serum and fecal concentrations of inflammatory biomarkers that occurred with induction were sustained through week 44. “Although our findings suggest that ustekinumab was effective in patients with or without previous treatment failure with biologics for both induction and maintenance therapy, the percentages of patients in whom each endpoint was achieved were lower across groups with previous treatment failure with biologics,” they wrote.
In the second study, known as VARSITY, researchers led by Dr. Sands conducted a randomized, phase 3b, head-to-head trial comparing vedolizumab with adalimumab in 769 adults with moderate to severe ulcerative colitis, in an effort to determine if vedolizumab is superior after 52 weeks of treatment (N Engl J Med 2019 Sep 25. doi: 10/1056/NEJMoa1905725). They assigned patients to receive IV infusions of 300 mg of vedolizumab on day 1 and at weeks 2, 6, 14, 22, 30, 38, and 46 (plus injections of placebo) or subcutaneous injections of 40 mg of adalimumab, with a total dose of 160 mg at week 1, 80 mg at week 2, and 40 mg every 2 weeks thereafter until week 50 (plus infusions of placebo). The primary endpoint was clinical remission, defined as a total score of 2 or lower on the Mayo scale, and no subscore greater than 1 on any of the four Mayo scale components.
At week 52, the researchers found that 31.3% of patients in the vedolizumab group achieved clinical remission, compared with 22.5% of those in the adalimumab group, while a higher percentage of patients in the vedolizumab group demonstrated endoscopic involvement (the first secondary outcome), compared with their counterparts in the adalimumab group (39.7% vs. 27.7%, respectively). Treatment effects were more pronounced in patients who had not previously used a TNF inhibitor.
In contrast, Dr. Sands and colleagues reported that at week 52, corticosteroid-free clinical remission was observed in 12.6% of patients in the vedolizumab group, compared with 21.8% of their counterparts in the adalimumab group. “It is difficult to explain the inconsistency of the results between this secondary remission outcome and the primary remission outcome,” they wrote. “The trial did not require a specific schedule for corticosteroid tapering, which can vary among practitioners. However, this limitation should not have resulted in differential effects in the two treatment groups.”
They noted that dosing regimens used in VARSITY were based on a conservative approach and use according to U.S. labels. “Real-world studies have shown improved efficacy outcomes after dose intensification in both adalimumab and vedolizumab therapies,” they wrote. “Data from ongoing trials of adalimumab () and vedolizumab ( ) may further characterize the effect of higher doses on efficacy outcomes.”
UNIFI was funded by Janssen Research and Development. Dr. Sands disclosed that the Icahn School of Medicine received an institutional grant from Janssen to conduct the study. VARSITY was funded with support from Takeda. Dr. Sands reported that he received grant support and consulting fees from Takeda. Dr. Sands and coauthors reported having financial ties to many other companies in the pharmaceutical and biotechnology industries.
SOURCE: Sands B et al. N Engl J Med. 2019 Sep 25 doi: 10/1056/NEJMoa1900750; N Engl J Med. 2019 Sep 25 doi:.10/1056/NEJMoa1905725.