Beyond TNF Inhibitors in Ulcerative Colitis: Promising Data

Nicola M. Parry, DVM

September 27, 2019

The availability of tumor necrosis factor (TNF) inhibitors changed treatment for many patients with ulcerative colitis (UC), but not everyone responds to these drugs, and even among those who do so initially, response often diminishes over time. Now, two trials, published online September 26 in the New England Journal of Medicine, show that many of these patients do respond to other types of biologic therapy.

In the head-to-head VARSITY trial, "vedolizumab [Entyvio, Takeda] was superior to adalimumab [multiple brands] with respect to achievement of clinical remission and endoscopic improvement," write Bruce E. Sands, MD, from the Icahn School of Medicine at Mount Sinai, New York City, and colleagues in the VARSITY study group.

In the UNIFI trial, "ustekinumab [Stelara, Janssen Biotech] was more effective than placebo for inducing and maintaining remission," write Sands and colleagues in the UNIFI study group.

The findings are potentially important for long-term outcomes, writes Richard J. Farrell, MD, from Connolly Hospital and the Royal College of Surgeons in Ireland, Dublin, in an accompanying editorial.

"Despite an improving treatment landscape, long-term rates of colectomy for ulcerative colitis have not declined over a 10-year period, a fact that highlights the need for new biologic therapies and strategies," he writes.

With this in mind, Sands and colleagues conducted VARSITY and UNIFI, two company-sponsored large phase 3 trials of biologics in patients with moderate to severe UC, many of whom had experienced no response to other biologic agents.

Vedolizumab Bests Adalimumab in Trial

VARSITY was a phase 3b, double-blind, double-dummy, randomized, controlled trial that compared the efficacy and safety of intravenous (IV) infusions of vedolizumab with subcutaneous injections of adalimumab in patients with moderate to severe active UC.

The trial took place across 245 sites in 34 countries. It included 769 adults aged 18 to 85 years who were randomly assigned to receive either vedolizumab IV (300 mg; n = 383) plus subcutaneous injections of placebo, or subcutaneous injections of adalimumab (160 mg; n = 386) and placebo IV.

The study's primary endpoint was clinical remission at week 52; secondary endpoints were endoscopic improvement and corticosteroid-free remission at week 52.

The results showed that after 52 weeks of treatment, significantly more patients in the vedolizumab group than in the adalimumab group had achieved clinical remission (31.3% vs 22.5%; difference, 8.8 percentage points; 95% confidence interval [CI], 2.5 – 15.0; P = .006), which was the study's primary endpoint.

In addition, more patients in the vedolizumab group experienced mucosal healing compared with those in the adalimumab group (39.7% vs 27.7%; difference, 11.9 percentage points; 95% CI, 5.3 – 18.5; P < .001).

By contrast, corticosteroid-free clinical remission occurred in 12.6% of patients in the vedolizumab group and in 21.8% in the adalimumab group, but the difference did not reach statistical significance (difference, −9.3 percentage points; 95% CI, −18.9 to 0.4).

"Few differences were observed between the trial groups in terms of the most commonly reported adverse events [AEs]," write Sands and colleagues.

AEs were reported in 62.7% of patients in the vedolizumab group and in 69.2% of those in the adalimumab group. Serious AEs occurred in 11.0% and 13.7% of patients in each group, respectively.

Exposure-adjusted rates of infection (23.4 vs 34.6 events per 100 patient-years) and serious infection (1.6 vs 2.2 events per 100 patient-years) were lower among patients who received vedolizumab than among those who received adalimumab.

One patient in the vedolizumab group died of postsurgical complications that occurred after a UC disease flare. The complications were considered to be unrelated to treatment in the trial.

According to Arthur M. Barrie III, MD, PhD, from the University of Pittsburgh Medical Center, Pennsylvania, the conclusion that vedolizumab is superior to adalimumab for treatment of moderate to severe UC correlates with his clinical experience. "This finding also validates recent systemic reviews with network analyses comparing biologic therapies for the treatment of UC," he told Medscape Medical News.

"The study also highlights the relative superior safety profile of vedolizumab vs adalimumab regarding infections," he said, and "strengthens my confidence to position vedolizumab ahead of adalimumab for the treatment of moderate-severe extensive UC."

However, Barrie noted that he might still consider recommending adalimumab over vedolizumab for patients with limited ulcerative proctosigmoiditis who prefer injectable therapy over infusion therapy.

Usketinumab Active in Moderate to Severe Disease

By comparison, the UNIFI trial evaluated use of a single IV infusion (8-week induction therapy) of ustekinumab followed by subcutaneous maintenance injections (44-week maintenance therapy) in patients with moderate to severe active UC.

The trial enrolled 961 adults aged 18 years or older. Participants were randomly assigned to receive an IV induction dose of ustekinumab 130 mg (n = 320), or a weight-range-based dose of approximately 6 mg/kg of body weight (n = 322), or placebo (n = 319).

"Patients who had a response 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)," the authors say.

In both the induction (week 8) and maintenance (week 44) phases of the study, the primary endpoint was clinical remission.

During the induction phase, more patients in both ustekinumab groups (130 mg and 6 mg/kg) achieved clinical remission at week 8 compared with those in the placebo group (15.6% and 15.5% vs 5.3%; P < .001 for both comparisons).

In addition, significantly more patients in the ustekinumab groups achieved endoscopic improvement (26.3% and 27.0% vs 13.8%; P < .001 for both comparisons), clinical response (51.3% and 61.8% vs 31.3%; P < .001 for both comparisons), and mucosal healing (20.3% and 18.4% vs 8.9%; P < .001 for both comparisons) at week 8.

Similarly, among patients who underwent a second randomization, more patients in both ustekinumab groups (every 12 weeks vs every 8 weeks) achieved clinical remission in the maintenance phase at week 44 compared with those in the placebo group (38.4% and 43.8% vs 24.0%; P = .002 and P < .001, respectively).

In the maintenance phase, more patients in the ustekinumab groups also achieved maintenance of clinical response through week 44 (68.0% and 71.0% vs 44.6%; P < .001 for both comparisons), endoscopic improvement (43.6% and 51.1% vs 28.6%; P = .002 and P < .001, respectively), and corticosteroid-free remission (37.8% and 42.0% vs 23.4%; P = .002 and P < .001, respectively).

According to the authors, the treatment regimen was well tolerated and safe.

In the induction phase, reports of at least one AE occurred in 41.4%, 50.6%, and 48.0% of patients in the groups receiving 130 mg ustekinumab, 6 mg/kg ustekinumab, and placebo, respectively. Serious AEs were reported in 3.7%, 3.4%, and 6.9% of these groups, respectively.

At week 44 in the maintenance phase, among patients who underwent a second randomization, reports of at least one AE occurred in 69.2%, 77.3%, and 78.9% of patients in the groups receiving ustekinumab every 12 weeks, ustekinumab every 8 weeks, and placebo, respectively. Reports of at least one serious AE occurred in 7.6%, 8.5%, and 9.7% of these groups, with reports of serious infection in 3.5%, 1.7%, and 2.3%, respectively.

Through 52 weeks of exposure in the study, three patients who received ustekinumab died of different causes (acute respiratory distress syndrome; hemorrhage from esophageal varices; and cardiac arrest). No deaths were reported in patients who received placebo.

Cancers developed in 7 of 825 patients who received ustekinumab (one case each of prostate, colon, renal papillary, and rectal cancer, and three cases of nonmelanoma skin cancers), and in 1 of 319 who received placebo (testicular cancer).

Discussing the results of the UNIFI trial with Medscape Medical News, Barrie described the finding that ustekinumab is effective for the treatment moderate to severe UC as an exciting and welcome development for the care of UC patients.

"I look forward to ustekinumab being approved and becoming available for patients who have failed anti-TNF therapies and vedolizumab," he said.

Barrie postulated that, given ustekinumab's positive safety record to date, it will become the preferred second-line UC therapy over tofacitinib, "considering the US Food and Drug Administration's recent warnings about increased risk of blood clots and death in patients treated with tofacitnib."

In his editorial, Farrell raises the issue of cost of biologic medications.

Although VARSITY was a head-to-head comparison of biologics for inflammatory bowel disease, Farrell emphasizes the need to balance any clinical superiority of vedolizumab against the significant cost advantages of using subcutaneous adalimumab.

He also notes that results from UNIFI may now lead to evaluation of similar regimens of biologics involving a single induction infusion followed by maintenance subcutaneous therapy, to help reduce dependence on costly biologic regimens based solely on infusions.

"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 concludes.

Both studies received support from numerous companies, and the authors have reported multiple relevant financial relationships related to these companies, including the following: being former employees; serving as consultants; serving as a vice president of clinical development; serving on steering committees, boards of directors, data safety monitoring boards, and advisory boards; serving as speakers and expert witnesses; receiving personal fees, honoraria, grants, and nonfinancial support related to attending conferences; owning stocks; and serving as the medical editor of Healio Gastroenterology. The editorialist and Barrie have reported no relevant financial relationships.

New Engl J Med. Published online September 26, 2019. VARSITY trial, Abstract; UNIFI trial, Abstract; Editorial

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