Biologics found to be effective for ulcerative colitis in industry-funded trials

An editorial said the results highlight the importance of alternative biologic treatments and regimens for some patients but noted that further research is needed on cost-effectiveness.

One recent industry-funded study compared vedolizumab and adalimumab for moderate to severe ulcerative colitis, while another evaluated ustekinumab as induction and maintenance therapy.

In the first study, vedolizumab was found to be superior to adalimumab for clinical remission and endoscopic improvement, but not corticosteroid-free clinical remission. The phase 3b, double-blind, double-dummy trial at 245 centers in 34 countries compared vedolizumab with adalimumab in 769 patients. All had moderate to severe active ulcerative colitis, defined as a total score of 6 to 12 on the Mayo scale (range, 0 to 12, with higher scores indicating more severe disease) and a subscore of at least 2 on the endoscopic component of the Mayo scale (subscores on each of the four components of the Mayo scale range from 0 to 3); colonic involvement of at least 15 cm; and a confirmed diagnosis of ulcerative colitis at least three months before screening.

Participants were randomized to receive infusions of 300 mg of vedolizumab (n=383) 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 (n=386), with a total dose of 160 mg at week 1, 80 mg at week 2, and 40 mg every two weeks until week 50, plus infusions of placebo. Neither group allowed dose escalation. The primary outcome was clinical remission at week 52 (defined as a total score of ≤2 on the Mayo scale and no subscore >1 on any of the four components). Results were published by the New England Journal of Medicine on Sept. 26.

At week 52, clinical remission was more common 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 percentage points]; P=0.006), as was endoscopic improvement (39.7% vs. 27.7%; difference, 11.9 percentage points [95% CI, 5.3 to 18.5 percentage points]; P<0.001). Corticosteroid-free clinical remission occurred in 12.6% of the patients in the vedolizumab group and in 21.8% of those in the adalimumab group (difference, −9.3 percentage points; 95% CI, −18.9 to 0.4 percentage points).

Exposure-adjusted incidence rates of infection were 23.4 and 34.6 events per 100 patient-years with vedolizumab and adalimumab, respectively. Corresponding rates for serious infection were 1.6 and 2.2 events per 100 patient-years. There were few differences between the trial groups in terms of the most commonly reported adverse events. The exposure-adjusted incidence rate of infection was 23.4 per 100 patient-years in the vedolizumab group and 34.6 per 100 patient-years in the adalimumab group.

The second industry-funded trial, also published Sept. 26 by the New England Journal of Medicine, concluded that ustekinumab as 8-week induction therapy and 44-week maintenance therapy in patients with moderate to severe ulcerative colitis was more effective than placebo for inducing and maintaining remission.

A total of 961 patients were randomized to receive an IV induction dose of ustekinumab: 130 mg (n=320 patients), a weight-range-based dose that approximated 6 mg/kg of body weight (n=322), or placebo (n=319). Patients who responded to induction therapy 8 weeks after administration of IV ustekinumab were randomly assigned again to receive subcutaneous maintenance injections of 90 mg of ustekinumab every 12 weeks (n=172), 90 mg of ustekinumab every 8 weeks (n=176), or placebo (n=175). The primary end point in the induction trial (week 8) and the maintenance trial (week 44) was clinical remission, defined as a total score of 2 or less on the Mayo scale and no subscore greater than 1 on any of the four Mayo scale components.

At week 8, 15.6% of patients who received IV ustekinumab at a dose of 130 mg and 15.5% of those who received it at a dose of 6 mg/kg had clinical remission versus 5.3% of those who received placebo (P<0.001 for both comparisons). Of note, at the same time point (week 8), a higher percentage (61.8%) of patients on the weight-based dosing (6 mg/kg) had larger decreases in the partial Mayo score and greater reductions in fecal lactoferrin and calprotectin concentrations, when compared to that (51.3%) of patients on the fixed, low dose of 130 mg. Among patients who responded to induction therapy with ustekinumab and were randomized a second time, 38.4% of those who were assigned to 90 mg of subcutaneous ustekinumab every 12 weeks and 43.8% of those assigned to that dose every 8 weeks had clinical remission at week 44 versus 24.0% of those assigned to placebo (P=0.002 and P<0.001, respectively).

Rates of serious adverse events were similar with ustekinumab and placebo. Over 52 weeks, two patients died, one from acute respiratory distress syndrome and one from esophageal varices hemorrhaging. There were seven cases of cancer (prostate, colon, renal papillary, and rectal, and three nonmelanoma skin cancers) among 825 patients who received ustekinumab, with no deaths. There was one case of testicular cancer among 319 patients who received placebo.

An editorial accompanying both studies noted that any apparent benefits of biologics for ulcerative colitis need to be balanced against the costs of the drugs. “The cost-effectiveness of all biologics will have to come into sharper focus in future trials and longitudinal studies of biologics to help determine not only their eventual place in the treatment algorithm for moderate-to-severe ulcerative colitis but also the true effect of existing and newer biologics on disease course and rates of colectomy,” it stated.