Feature

Q&A: VARSITY, UNIFI add to the armamentarium for ulcerative colitis

Bruce Sands, MD
Bruce Sands

Physicians have an array of biologic agents available to treat patients with ulcerative colitis, but it is still unknown which therapies are superior, as well as which therapies work best in certain instances.

Two trials – the VARSITY and UNIFI trials – published in The New England Journal of Medicine on Wednesday helped to provide information about which therapies might be beneficial to patients with UC and in what circumstances.

The UNIFI trial, which was previously presented at both the United European Gastroenterology Week and Digestive Disease Week, demonstrated that two different dosing regimens of Stelara (ustekinumab, Janssen) helped patients with moderate-to-severe ulcerative colitis achieve clinical remission and maintain a clinical response through 44 weeks.

At week 44 of the trial, researchers found that greater proportions of patients in the every 8-week and every 12-week ustekinumab groups were in clinical remission (43.8% and 38.4%, respectively) compared with placebo (24%; P < .001 and P = .002). A greater proportion of patients in the ustekinumab groups were able to maintain clinical response through week 44 and achieve endoscopic healing, as well as corticosteroid-free remission.

The VARSITY trial, which was previously presented at the Congress of the European Crohn’s and Colitis Organisation and Digestive Disease Week, demonstrated that at week 52, 31.3% of patients receiving Entyvio (vedolizumab, Takeda) IV achieved the primary endpoint of clinical remission compared with 22.5% of patients treated with Humira (adalimumab, AbbVie) subcutaneous (P = .006). Further, 39.7% of patients treated with vedolizumab achieved the secondary endpoint of mucosal healing at week 52, compared with 27.7% receiving adalimumab (P < .001).

“It’s important to note that since no single therapy effectively treats all patients with ulcerative colitis, we continue to seek better agents and improved strategies of treatment,” Bruce E. Sands, MD, MS, chief of the Dr. Henry D. Janowitz Division of Gastroenterology at the Icahn School of Medicine at Mount Sinai, told Healio Gastroenterology and Liver Disease. “We need to continue both to find newer therapies with novel mechanisms as well as better ways of sequencing and combining therapies.”

Sands spoke with Healio Gastroenterology and Liver Disease about the results of both the UNIFI and VARSITY trials, as well as the importance of head-to-head trials. – by Ryan McDonald

Healio: What is the significance of the results of UNIFI and VARSITY?

Sands: UNIFI and VARSITY are two very different trials. UNIFI is a phase 3, randomized-controlled trial that was a registrational study intended to lead to the approval of ustekinumab as a treatment for ulcerative colitis. Ustekinumab is already approved for Crohn’s disease and now we’re able to demonstrate that it works quite well for ulcerative colitis. This is significant because it provides an additional treatment option with a different mechanism of action to treat patients with ulcerative colitis. That’s important because no one drug treats 100% of patients, and having more choices is a benefit to patients. At the same time, ustekinumab is also a very safe medication and is convenient as it’s dosed every 8 weeks.

VARSITY is different in that it is the first example of a head-to-head, double-blind, randomized-controlled trial of two biologic agents in IBD, specifically in ulcerative colitis. This study is very important when considering the positioning of one agent vs. another. It was a somewhat surprising result to many that vedolizumab, which is an anti-alpha 4 beta 7 integrin antibody, proved to be superior to adalimumab in the primary outcome of clinical remission at 1 year.

Healio: VARSITY is considered one of the first head-to-head trials in ulcerative colitis. Why is it important to conduct these head-to-head trials?

Sands: The highest level of evidence that we can obtain, really, is a randomized-controlled trial. So, we can speculate all we want from network meta-analyses and clinical effectiveness studies that use retrospective data about which drug might be better positioned before another, but until you actually put it to the test in a blinded, randomized study, you really can’t be sure which drug is more efficacious.

Healio: How you do anticipate the results of UNIFI and VARSITY impacting practice?

Sands: For UNIFI, it’s simply to provide another biologic option that is effective, that is effective in both anti-TNF naive and anti-TNF-failure patients. So, for both of those populations, it’s an important addition to the armamentarium as another option with the additional benefit of excellent safety. As for the results of VARSITY this indicates that, particularly for the anti-TNF-naive patient, vedolizumab may be a better choice for most patients than adalimumab, as it was found to be more effective. And while the safety was broadly comparable in the study, there were hints of more infections with adalimumab, which is consistent with what we know from the broader safety profile of anti-TNFs. Although anti-TNFs remain an important class of agents for the treatment of IBD, and their safety profile is excellent, we see many lines of evidence that show vedolizumab has a superior safety profile to anti-TNFs.

In terms of positioning, VARSITY suggests that we should use vedolizumab before anti-TNFs for patients with moderate to severe ulcerative colitis. What we can’t say, of course, is whether we should be choosing vedolizumab or ustekinumab first because we don’t have the head-to-head trial of those agents. Both are very safe, very effective and reasonable options.

Healio: Do you foresee any head-to-head trials of vedolizumab and ustekinumab moving forward?

Sands: It would be great for the field to have more head-to-head trials. However, it takes considerable resources to perform these very expensive studies, and not all sponsors are willing to perform head-to-head trials in IBD. And, we have not seen studies such as these conducted through, for example, NIH funding, but it will be increasingly important to do more such studies. I don’t know specifically if we will see a head-to-head of vedolizumab against ustekinumab, but it would be logical to consider doing that.

Healio: The results of the VARSITY trial demonstrated that vedolizumab was superior to adalimumab. Do you still see a use for adalimumab?

Sands: Adalimumab is still an effective treatment for ulcerative colitis, but on average for the TNF-naive patient, vedolizumab is superior to adalimumab. I don't know that we can broadly extrapolate these results to all anti-TNFs, for example to infliximab, but then again, since the safety profile of vedolizumab is probably superior to the safety profile of anti-TNFs, all other things being equal, it probably should be the first choice biologic. We can also note that UNIFI showed ustekinumab to be effective in anti-TNF naive patients with moderate to severely active ulcerative colitis. But that doesn’t mean there isn’t a role for anti-TNFs and specifically for adalimumab, which is also an excellent and effective drug, since no one drug is effective for every patient.

Disclosures: Sands reports serving as a consultant for AbbVie, Janssen and Takeda. Janssen provided support for the UNIFI trial and Takeda provided support for the VARSITY trial.

Bruce Sands, MD
Bruce Sands

Physicians have an array of biologic agents available to treat patients with ulcerative colitis, but it is still unknown which therapies are superior, as well as which therapies work best in certain instances.

Two trials – the VARSITY and UNIFI trials – published in The New England Journal of Medicine on Wednesday helped to provide information about which therapies might be beneficial to patients with UC and in what circumstances.

The UNIFI trial, which was previously presented at both the United European Gastroenterology Week and Digestive Disease Week, demonstrated that two different dosing regimens of Stelara (ustekinumab, Janssen) helped patients with moderate-to-severe ulcerative colitis achieve clinical remission and maintain a clinical response through 44 weeks.

At week 44 of the trial, researchers found that greater proportions of patients in the every 8-week and every 12-week ustekinumab groups were in clinical remission (43.8% and 38.4%, respectively) compared with placebo (24%; P < .001 and P = .002). A greater proportion of patients in the ustekinumab groups were able to maintain clinical response through week 44 and achieve endoscopic healing, as well as corticosteroid-free remission.

The VARSITY trial, which was previously presented at the Congress of the European Crohn’s and Colitis Organisation and Digestive Disease Week, demonstrated that at week 52, 31.3% of patients receiving Entyvio (vedolizumab, Takeda) IV achieved the primary endpoint of clinical remission compared with 22.5% of patients treated with Humira (adalimumab, AbbVie) subcutaneous (P = .006). Further, 39.7% of patients treated with vedolizumab achieved the secondary endpoint of mucosal healing at week 52, compared with 27.7% receiving adalimumab (P < .001).

“It’s important to note that since no single therapy effectively treats all patients with ulcerative colitis, we continue to seek better agents and improved strategies of treatment,” Bruce E. Sands, MD, MS, chief of the Dr. Henry D. Janowitz Division of Gastroenterology at the Icahn School of Medicine at Mount Sinai, told Healio Gastroenterology and Liver Disease. “We need to continue both to find newer therapies with novel mechanisms as well as better ways of sequencing and combining therapies.”

Sands spoke with Healio Gastroenterology and Liver Disease about the results of both the UNIFI and VARSITY trials, as well as the importance of head-to-head trials. – by Ryan McDonald

Healio: What is the significance of the results of UNIFI and VARSITY?

Sands: UNIFI and VARSITY are two very different trials. UNIFI is a phase 3, randomized-controlled trial that was a registrational study intended to lead to the approval of ustekinumab as a treatment for ulcerative colitis. Ustekinumab is already approved for Crohn’s disease and now we’re able to demonstrate that it works quite well for ulcerative colitis. This is significant because it provides an additional treatment option with a different mechanism of action to treat patients with ulcerative colitis. That’s important because no one drug treats 100% of patients, and having more choices is a benefit to patients. At the same time, ustekinumab is also a very safe medication and is convenient as it’s dosed every 8 weeks.

VARSITY is different in that it is the first example of a head-to-head, double-blind, randomized-controlled trial of two biologic agents in IBD, specifically in ulcerative colitis. This study is very important when considering the positioning of one agent vs. another. It was a somewhat surprising result to many that vedolizumab, which is an anti-alpha 4 beta 7 integrin antibody, proved to be superior to adalimumab in the primary outcome of clinical remission at 1 year.

Healio: VARSITY is considered one of the first head-to-head trials in ulcerative colitis. Why is it important to conduct these head-to-head trials?

Sands: The highest level of evidence that we can obtain, really, is a randomized-controlled trial. So, we can speculate all we want from network meta-analyses and clinical effectiveness studies that use retrospective data about which drug might be better positioned before another, but until you actually put it to the test in a blinded, randomized study, you really can’t be sure which drug is more efficacious.

Healio: How you do anticipate the results of UNIFI and VARSITY impacting practice?

Sands: For UNIFI, it’s simply to provide another biologic option that is effective, that is effective in both anti-TNF naive and anti-TNF-failure patients. So, for both of those populations, it’s an important addition to the armamentarium as another option with the additional benefit of excellent safety. As for the results of VARSITY this indicates that, particularly for the anti-TNF-naive patient, vedolizumab may be a better choice for most patients than adalimumab, as it was found to be more effective. And while the safety was broadly comparable in the study, there were hints of more infections with adalimumab, which is consistent with what we know from the broader safety profile of anti-TNFs. Although anti-TNFs remain an important class of agents for the treatment of IBD, and their safety profile is excellent, we see many lines of evidence that show vedolizumab has a superior safety profile to anti-TNFs.

In terms of positioning, VARSITY suggests that we should use vedolizumab before anti-TNFs for patients with moderate to severe ulcerative colitis. What we can’t say, of course, is whether we should be choosing vedolizumab or ustekinumab first because we don’t have the head-to-head trial of those agents. Both are very safe, very effective and reasonable options.

Healio: Do you foresee any head-to-head trials of vedolizumab and ustekinumab moving forward?

Sands: It would be great for the field to have more head-to-head trials. However, it takes considerable resources to perform these very expensive studies, and not all sponsors are willing to perform head-to-head trials in IBD. And, we have not seen studies such as these conducted through, for example, NIH funding, but it will be increasingly important to do more such studies. I don’t know specifically if we will see a head-to-head of vedolizumab against ustekinumab, but it would be logical to consider doing that.

Healio: The results of the VARSITY trial demonstrated that vedolizumab was superior to adalimumab. Do you still see a use for adalimumab?

Sands: Adalimumab is still an effective treatment for ulcerative colitis, but on average for the TNF-naive patient, vedolizumab is superior to adalimumab. I don't know that we can broadly extrapolate these results to all anti-TNFs, for example to infliximab, but then again, since the safety profile of vedolizumab is probably superior to the safety profile of anti-TNFs, all other things being equal, it probably should be the first choice biologic. We can also note that UNIFI showed ustekinumab to be effective in anti-TNF naive patients with moderate to severely active ulcerative colitis. But that doesn’t mean there isn’t a role for anti-TNFs and specifically for adalimumab, which is also an excellent and effective drug, since no one drug is effective for every patient.

Disclosures: Sands reports serving as a consultant for AbbVie, Janssen and Takeda. Janssen provided support for the UNIFI trial and Takeda provided support for the VARSITY trial.

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