A pair of studies appearing in The New England Journal of Medicine report on 2 separate studies of biologics in patients with moderate-to-severe ulcerative colitis: One study confirms top-line results seen earlier this year in a head-to-head study of vedolizumab and adalimumab, and the other reports on the results of a single intravenous infusion of ustekinumab followed by subcutaneous maintenance injections.
A pair of studies appearing in The New England Journal of Medicine report on 2 separate studies of biologics in patients with moderate-to-severe ulcerative colitis (UC): One study confirms top-line results seen earlier this year in a head-to-head study of vedolizumab and adalimumab, and the other reports on the results of a single intravenous infusion of ustekinumab followed by subcutaneous maintenance injections.
Vedolizumab, sold as Entyvio by Takeda, is approved by the FDA for the treatment of moderate-to-severe Crohn disease (CD) or UC, forms of inflammatory bowel disease (IBD), in those who have had an inadequate response or loss of response to immunomodulators, anti—tumor necrosis factor (anti-TNF) therapies, or corticosteroid therapy.
Head-to-head trials of agents are more common in rheumatic disease but less often in gastrointestinal disorders, the authors note.
The VARSITY trial, a double-blind, double-dummy, randomized, controlled trial, compared intravenous infusions of vedolizumab with subcutaneous injections of reference adalimumab, sold as Humira by AbbVie. Results show that vedolizumab was superior to adalimumab in terms of clinical remission and endoscopic improvement but not corticosteroid-free clinical remission.1
A total of 769 patients received at least 1 dose of vedolizumab (383 patients) or adalimumab (386 patients). At week 52, clinical remission was seen in a higher percentage of patients in the vedolizumab group than in the adalimumab group (31.3% vs 22.5%; difference, 8.8 percentage points; 95% CI, 2.5 to 15.0; P = .006). Endoscopic improvement saw a difference of 11.9 percentage points (39.7% vs 27.7%; 95% CI, 5.3 to 18.5; P <.001).
However, corticosteroid-free clinical remission occurred in 12.6% of the patients in the vedolizumab group, compared with 21.8% in the adalimumab group (difference, −9.3 percentage points; 95% CI, −18.9 to 0.4). The authors write that they could not explain the inconsistency of the results between clinical remission and corticosteroid-free clinical remission.
The other study, the phase 3 UNIFI trial, detailed the findings of a single intravenous infusion of ustekinumab followed by subcutaneous maintenance injections.2 The biologic, the first available therapy that targets the interleukin-12 and -23 pathway, is sold under the name Stelara by Janssen, a unit of Johnson & Johnson. In the United States, ustekinumab is approved for psoriasis, psoriatic arthritis and Crohn disease; earlier this month, it was cleared by the European Commission for moderate-to-severe UC.
Results showed that ustekinumab was more effective than placebo for inducing and maintaining remission, even in patients who had current or previous treatment with conventional or biologic therapy.
A total of 961 patients received an intravenous induction dose of ustekinumab (either 130 mg [320 patients] or a dose based on body weight, approximately 6 mg per kilogram [322 patients]) or placebo (319 patients). Patients who responded to induction therapy 8 weeks after administration of intravenous ustekinumab were randomly assigned again to receive subcutaneous maintenance injections of 90 mg of ustekinumab (either every 12 weeks [172 patients] or every 8 weeks [176 [patients]) or placebo (175 patients).
The primary end point in the induction trial by week 8 and the maintenance trial by week 44 was clinical remission (defined as a total score of 2 or less on the Mayo scale [range, 0-12, with higher scores indicating more severe disease] and no subscore greater than 1 [range, 0 to 3] on any of the 4 Mayo scale components).
The percentage of patients who had clinical remission at week 8 among patients who received intravenous ustekinumab at a dose of 130 mg (15.6%) or 6 mg per kilogram (15.5%) was significantly higher than that among patients who received placebo (5.3%) (P <.001 for both comparisons).
Among patients who had a response to induction therapy with ustekinumab and underwent a second randomization, the percentage of patients who had clinical remission at week 44 was significantly higher among patients assigned to 90 mg of subcutaneous ustekinumab every 12 weeks (38.4%) or every 8 weeks (43.8%) than among those assigned to placebo (24.0%) (P = .002 and P <.001, respectively). The incidence of serious adverse events with ustekinumab was similar to that with placebo.
Through 52 weeks of exposure, there were 2 deaths and 7 cases of cancer (1 each of prostate, colon, renal papillary, and rectal cancer, and 3 nonmelanoma skin cancers) among 825 patients who received ustekinumab; Among the 319 patients who received placebo, there were no deaths and 1 case of testicular cancer.
Writing in an accompanying editorial, Richard J. Farrell, MD, notes that biologic therapies have revolutionized the management of UC, with a shift in focus to achieving sustained corticosteroid-free remission.3 However, 50% of patients with UC do not respond to anti-TNF therapies or lose response eventually. In addition, anti-TNF agents and immunosuppressive drugs carry a risk of infections and some malignancies, and rates of colectomy for UC have not fallen over a 10-year period.
Farrell cautiones that any claims of superiority for vedolizumab “should be balanced against the significant cost advantages of a subcutaneous regimen of adalimumab. In many respects, the ideal trial to assess whether vedolizumab should supplant anti-TNF therapies would involve a head-to-head comparison of infliximab infusions with vedolizumab infusions in patients who have not previously received anti-TNF therapies.”
Noting that the UNIFI trial assessed the combination of a single induction infusion followed by a maintenance subcutaneous regimen, he suggestes that future, similar regimens could reduce the usuage of costly infusion-based regimens as well as create room in infusion units. He also notes the appearance of biosimilar infliximab and adalimumab over the past decade, and that "biologics rather than hospitalization or colectomy are now the main driver of health care costs in the management of inflammatory bowel disease."
1. Sands BE, Sandborn WJ, Panaccione R, et al. Vedolizumab versus adalimumab for moderate-to-severe ulcerative colitis. N Engl J Med. 2019;381(13):1215-1226. doi: 10.1056/NEJMoa1905725
2. Sands BE, Sandborn WJ, Panaccione R, et al. Ustekinumab as induction and maintenance therapy for ulcerative colitis. N Engl J Med. 2019;381(13):1201-14. doi: 10.1056/NEJMoa1900750.
3. Farrell RJ. Biologics beyond anti-TNF agents for ulcerative colitis—efficacy, safety, and cost? N Engl J Med. 2019;381(13): doi: 10.1056/NEJMe1910742.