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Evidence continues to grow supporting the use of a widening array of biologics for the chronic inflammatory gut disease ulcerative colitis, providing new options for patients with refractory disease that does not respond to conventional therapies such as aminosalicylates, corticosteroids, and thiopurines or with tumor necrosis factor (TNF) inhibitors.

In the induction phase of a phase III trial known as UNIFI, patients who received a single infusion of either 130 mg or 6 mg/kg of ustekinumab (Stelara) had significantly greater rates of clinical remission at week 8 than those given an infusion of placebo (15.6% and 15.5% vs 5.3%, P<0.001 for both), according to Bruce Sands, MD, of the Icahn School of Medicine at Mount Sinai in New York City, and colleagues.

Then, at week 52, after an additional 44 weeks of maintenance therapy with subcutaneous injections of ustekinumab every 12 or 8 weeks, clinical remission was observed in 38.4% and 43.8% compared with 24% of those given subcutaneous placebo injections (P=0.002 and P<0.001, respectively).

And in a phase IIIb trial known as VARSITY, a head-to-head trial comparing vedolizumab (Entyvio) with adalimumab (Humira), clinical remission was seen in a significantly greater number of patients receiving vedolizumab (31.3% vs 22.5%), which was a difference of 8.8 percentage points (95% CI 2.5-15, P=0.006), also according to Sands and colleagues.

Both studies were published in the . UNIFI was funded by Janssen Research and Development, and VARSITY was sponsored by Takeda.

Expanding Options

"The current issue of the NEJM emphasizes the expanding therapeutic options for the treatment of refractory ulcerative colitis," said Stephen B. Hanauer, MD, Professor of Medicine at Northwestern University in Chicago, who was not involved in the studies.

"The UNIFI study evaluated similar doses of ustekinumab that have been approved for the treatment of refractory Crohn's disease whereas the VARSITY study was an important comparative effectiveness study of two approved biologics for moderate-severe ulcerative colitis with different mechanisms of action (adalimumab, a TNF inhibitor, and vedolizumab, an inhibitor of lymphocyte trafficking)," Hanauer explained to 番茄社区.

"The introduction of anti-tumor necrosis factor biologics (e.g., infliximab [Remicade], adalimumab, and golimumab [Simponi]) has revolutionized the management of ulcerative colitis in the past 2 decades," wrote Richard J. Farrell, MD, from the Royal College of Surgeons in Ireland and Connolly Hospital, Dublin, in an accompanying editorial.

"However, 50% of patients with ulcerative colitis do not have a response to anti-TNF therapies or lose response over time, such that after 1 year of treatment, clinical remission is observed in only 17-34% of patients," Farrell added. He also noted that, despite the advances in treatment, over a 10-year period did not decline, "a fact that highlights the need for new biologic therapies and strategies."

"Clearly, the gastroenterologist tool box continues to grow for this group of patients with significant unmet needs for safe and effective therapies," Hanauer said.

UNIFI: Ustekinumab vs Placebo

Ustekinumab is a monoclonal antibody that targets the p40 subunit of interleukin (IL)-12 and IL-23. This agent is approved for the treatment of psoriasis, psoriatic arthritis, and Crohn's disease.

UNIFI took place from 2015 to 2018 at 244 centers around the world. The induction phase included 961 patients with moderate-to-severe ulcerative colitis, and the 523 who responded at 8 weeks were included in the maintenance phase. Their mean age was 42, duration of disease averaged 8 years, and the majority were men. Previous treatment with another biologic had failed in half the patients. Stable doses of aminosalicylates, immunomodulators, and oral corticosteroids were permitted.

Aside from the primary endpoint of clinical remission, ustekinumab also showed significant benefits on several secondary endpoints at week 8. Endoscopic improvement was seen in 26.3% and 27% of the 130 mg and 6 mg/kg groups, respectively, compared with 13.8% of the placebo group (P<0.001); histo-endoscopic mucosal healing was observed in 20.3% and 18.4% compared with 8.9% (P<0.001). Clinical responses were reported in 51.3% and 61.8% compared with 31.3% (P<0.001).

Other findings in the maintenance phase also favored ustekinumab, the researchers reported. Endoscopic improvement was seen in 43.6% and 51.1% of the groups receiving 90 mg every 12 weeks and every 8 weeks, respectively, compared with 28.6% of those receiving placebo (P=0.002 and P<0.001), while corticosteroid-free remission was observed in 37.8% and 42% of the every-12-week and every-8-week groups compared with 23.4% of the placebo group (P=0.002 and P<0.001).

The incidence of serious adverse events in the two ustekinumab groups was similar to what was seen in the placebo group. One patient in the ustekinumab group died from acute respiratory distress syndrome and another from esophageal varices through week 52, and seven cases of cancer were observed among the 825 patients receiving the active treatment, while one cancer and no deaths were reported among the 319 patients given placebo.

"In this trial involving patients with moderate-to-severe ulcerative colitis despite current or previous treatment with conventional or biologic therapy, ustekinumab was more effective than placebo for inducing and maintaining remission," the investigators concluded.

VARSITY: Vedolizumab vs Adalimumab

Vedolizumab, a gut-selective monoclonal antibody that binds to the leukocyte integrin α₄β₇, is approved for both Crohn's disease and ulcerative colitis. Adalimumab is widely used to treat ulcerative colitis as well as rheumatologic disorders such as rheumatoid arthritis.

VARSITY was conducted from 2015 to 2019 at 245 sites from more than 30 countries. Up to 25% of patients were allowed to have not responded previously on a TNF inhibitor.

Patients randomized to vedolizumab received intravenous infusions of 300 mg every 8 weeks, while those assigned to adalimumab were given 40 mg subcutaneously every 2 weeks. Dose escalations were not permitted, but stable doses of corticosteroids, aminosalicylates, or immunomodulators were allowed.

The study population consisted of 769 patients with moderately to severely active ulcerative colitis. Discontinuations because of a lack of efficacy were reported in 41 patients receiving vedolizumab and 82 patients given adalimumab.

Among patients not previously exposed to a TNF inhibitor, clinical remission at week 52 was seen in 34.2% of the vedolizumab group and 24.3% of the adalimumab group, while the corresponding numbers among those with previous TNF inhibitor use were 20.3% and 16%, respectively.

Endoscopic improvement at week 52 was observed more often overall in the vedolizumab group (39.7% vs 27.7%), for a difference of 11.9 percentage points (95% CI 5.3-18.5, P<0.001). In the anti-TNF naive group, the rates of endoscopic improvement were 43.1% and 29.5%, for a difference of 13.6 percentage points (95% CI 6-21.2), while in those who had previous anti-TNF use, the rates were 26.6% and 21%, for a difference of 5.5 percentage points (95% CI -7.7 to 18.8), the researchers reported.

Histologic remission at week 52 was seen in 10.4% of the vedolizumab group and 3.1% of the adalimumab group.

A further secondary endpoint was corticosteroid-free remission, which was observed more often in the adalimumab group (21.8% vs 12.6%), for a difference of -9.3 percentage points (95% CI -18.9 to 0.4). "It is difficult to explain the inconsistency of the results between this secondary remission outcome and the primary remission outcome," the investigators conceded.

Improvements in patient quality of life, demonstrated by an increase of at least 16 points on the Inflammatory Bowel Disease Questionnaire, were reported by 52% of patients in the vedolizumab group and 42.2% of the adalimumab group.

Serious adverse events were reported in 11% of patients in the vedolizumab group and 13.7% of the adalimumab group, but infections and serious infections occurred less frequently with vedolizumab. For all infections, the incidence rates were 23.4 and 34.6 per 100 patient-years for vedolizumab and adalimumab, respectively, while for serious infections, the rates were 1.6 and 2.2 per 100 patient-years.

One patient in the vedolizumab group died from an exacerbation of the ulcerative colitis.

The investigators emphasized that dose intensification was not allowed because of the design of the trial, which was double-blind and double-dummy, and that the doses chosen were conservative. "Real-world studies have shown improved efficacy outcomes after dose intensification in both adalimumab and vedolizumab therapies," and ongoing studies with higher doses may provide further guidance, the team noted.

Looking Ahead

"UNIFI confirmed the efficacy of ustekinumab in inducing and maintaining clinical, endoscopic, and histologic improvements, while VARSITY demonstrated vedolizumab to be more efficacious than adalimumab at standard, approved doses for inducing and maintaining clinical and endoscopic (but not corticosteroid-free) remission," Hanauer observed.

But costs remain a concern, Farrell argued in his editorial: "Although the VARSITY trial presents a head-to-head comparison of biologics for inflammatory bowel disease and aims to determine the first-line biologic therapy for ulcerative colitis, any clinical superiority of vedolizumab should be balanced against the significant cost advantages of a subcutaneous regimen of adalimumab," he wrote.

Moreover, the introduction of multiple lower-cost biosimilars during recent years needs to be considered. "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," Farrell stated.

Hanauer concluded: "At present, options for patients at higher risks of colectomy include steroid induction with thiopurine maintenance; TNF inhibitors infliximab (including biosimilars), adalimumab (including biosimilars), and golimumab; the anti-lymphocyte trafficking agent vedolizumab (with several others under development); ustekinumab (with several anti-IL-23 agents under development); and tofacitinib (with several other JAK inhibitors under development)."