Feb. 14, 2020
The Food and Drug Administration approved the use of anti-tumor necrosis factor and anti-integrin agents for the treatment of ulcerative colitis in 2005 (infliximab), 2012 (adalimumab) and 2014 (vedolizumab). Although previous trials established safety and efficacy data for these biologic agents, that earlier research did not provide head-to-head comparisons.
In an effort to address that information gap, a group of researchers recently conducted a phase IIIb, double-blind, randomized trial comparing vedolizumab with adalimumab in adults with moderately to severely active ulcerative colitis (UC). Results from that trial, also known as the VARSITY study, were published in the New England Journal of Medicine in September 2019. Edward V. Loftus Jr., M.D., one of the article's authors, is a gastroenterologist specializing in inflammatory bowel diseases at Mayo Clinic's campus in Rochester, Minnesota.
Methods
The VARSITY study was an industry-funded, double-blind, double-dummy, randomized, active-controlled trial involving 769 patients from 245 centers in 34 countries, including Mayo Clinic.
Study participants were randomly assigned to one of two groups:
- Vedolizumab group: 383 patients receiving intravenous infusions of 300 mg of vedolizumab on day 1 and at weeks 2, 6, 14, 22, 30, 38 and 46 (plus injections of placebo)
- Adalimumab group: 386 patients receiving 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 two weeks thereafter until week 50 (plus infusions of placebo)
Standard dosing of vedolizumab and adalimumab were used, with no dose escalation permitted in either group. Previous exposure to a tumor necrosis factor inhibitor other than adalimumab was allowed in up to 25% of study participants.
This trial's primary outcome was clinical remission at week 52. Researchers defined clinical remission as follows:
- Total score of ≤2 on the Mayo scale (range, 0 to 12, with higher scores indicating more severe disease)
- No subscore >1 (range, 0 to 3) on any of the four Mayo scale components
Researchers also analyzed efficacy outcomes with the use of a hierarchical testing procedure, ranking these variables in the following order: clinical remission, endoscopic improvement (subscore of 0 to 1 on the Mayo endoscopic component) and corticosteroid-free remission at week 52.
Results
In a head-to-head comparison between these two biologic agents, vedolizumab demonstrated superior efficacy in two of the three measures evaluated: achievement of clinical remission and endoscopic improvement. Adalimumab demonstrated superior performance in achieving corticosteroid-free clinical remission. At week 52, the trial produced these results:
- Clinical remission was observed in 31.3% of participants in the vedolizumab group and 22.5% in the adalimumab group, with a 95% confidence interval (CI) of 2.5 to 15.0; P = 0.006.
- Endoscopic improvement was observed in 39.7% of participants in the vedolizumab group and 27.7% in the adalimumab group, with a 95% CI of 5.3 to 18.5; P < 0.001.
- Corticosteroid-free clinical remission occurred in 12.6% of participants in the vedolizumab group and in 21.8% in the adalimumab group, with a 95% CI of -18.9 to 0.4.
- Exposure-adjusted incidence rates of infection were 23.4 and 34.6 events per 100 patient-years in the vedolizumab group and the adalimumab group, respectively, and corresponding rates for serious infection were 1.6 and 2.2 events per 100 patient-years.
Conclusions
According to Dr. Loftus, these results provide valuable new guidance for clinicians. "The totality of the evidence from this trial — including the primary endpoint of clinical remission, secondary endoscopic endpoint, reductions in CRP and fecal calprotectin, and histologic improvement — suggests that vedolizumab is slightly superior to adalimumab for moderately to severely active ulcerative colitis, and it should be considered a first line biologic for this disease," says Dr. Loftus. "We are hopeful that these results will accelerate the ability of providers who care for patients with UC to prescribe vedolizumab in biologic-naive patients by reducing resistance from third-party payers and other barriers."
Dr. Loftus explains that this trial had a number of limitations worth noting: "The biggest question raised by the trial was the fact that the steroid-free remission rate was numerically but not statistically significantly higher in the adalimumab-treated patients. On the other hand, the mean and median reductions in steroid dose from baseline were numerically higher in the participants who were treated with vedolizumab. A steroid taper during the trial was suggested but not mandated. However, all of the other results in the trial were in favor of vedolizumab."
Beyond this trial, Dr. Loftus and other Mayo Clinic researchers are pursuing additional research efforts to analyze the efficacy of these biologic agents. "We have been involved in other trials of vedolizumab, including a study of a subcutaneous version, which could be FDA approved soon," says Dr. Loftus, who also notes that Mayo Clinic researchers are involved in phase II and III clinical trials of multiple other investigational agents, including etrolizumab (an anti-beta-7-integrin agent), upadacitinib and filgotinib (Janus kinase inhibitors), risankizumab (an anti-interleukin-23 agent), ozanimod (a sphingosine-1-phosphate receptor modulator), and BMS-986165 (a tyrosine kinase 2 inhibitor).
For more information
Sands BE, et al. Vedolizumab versus adalimumab for moderate-to-severe ulcerative colitis. New England Journal of Medicine. 2019;381:1215.