‘Why not combine them?’: Early dual biologic therapy may overcome limits in severe IBD
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DENVER — Early data suggest combination therapy with biologics or advanced small-molecules may be safe and effective in patients with inflammatory bowel disease, according to a presenter at the Crohn’s and Colitis Congress.
“We have all these different mechanisms of action right now — in newer development are some of the oral and p-19 [inhibitors],” Edward V. Loftus Jr., MD, the Maxine and Jack Zarrow Family Professor of Gastroenterology at the Mayo Clinic in Rochester, Minnesota, told attendees. “We have all these different targets: Why not combine them?”
Current therapies for IBD have many limitations, Loftus said, noting that approximately 66% of patients experience primary or secondary tumor necrosis factor-inhibitor failure through development of antibodies, with a 13% to 30% incidence of primary nonresponse in clinical practice.
Data also show the need for dose intensification after 12 weeks among 23% to 46% of patients, discontinuation among 5% to 13% and relapse after discontinuation at 12 months among 28% of patients with ulcerative colitis, according to Loftus.
“We have these mechanistic failures that we don’t completely understand and, of course, there are adverse events,” he said. “So, how do we get around it? It has been proposed that dual therapy might work.”
Results from a systematic review and meta-analysis from Alayo and colleagues showed certain combinations induced clinical remission while maintaining low rates of adverse events: Vedolizumab (Entyvio, Takeda) plus ustekinumab (Stelara, Janssen) (47%), vedolizumab plus TNF (55%), ustekinumab plus TNF (80%), tofacitinib (Xeljanz, Pfizer) plus ustekinumab (40%), tofacitinib plus vedolizumab (48%) and tofacitinib plus TNF (56%). Adverse event rates were 12.3%, 9.6%, 0%, 0%, 1% and 0%, respectively.
Loftus cited additional results from the VEGA trial, which yielded high clinical response and remission rates at week 12 among patients with UC given combination guselkumab (Tremfya, Janssen) and golimumab (Simponi, Janssen), as well as results from the EXPLORER trial, which demonstrated endoscopic and clinical remission rates of 34.5% and 54.5%, respectively, at 26 weeks among patients with high-risk Crohn’s disease receiving combination vedolizumab, adalimumab (Humira, AbbVie) and methotrexate.
“It’s an interesting concept and we’re going to have more data in the future, especially now that we have pharmaceutical companies that have multiple assets,” Loftus said. “Whether or not we’re going to be able to do this routinely in clinical practice due to insurance hurdles remains to be seen, but we have early reports that this could be efficacious. We’re starting to see more clinical trials.”
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Jessica Philpott, MD, PhD
Combination therapy in one form or another has been of interest in IBD care since the SONIC trial, which compared patients with Crohn’s disease who were treated with infliximab, azathioprine or a combination of both. At the time, surprising results demonstrated that patients on dual therapy did better in terms of clinical response and endoscopic healing compared with patients on infliximab or azathioprine alone.
Since that time, we continue to have more therapies for treating CD, which is hopeful. The problem is that we have reached a plateau in terms of therapeutic effect of any one therapy. No therapy has close to a 100% response rate to begin with, and we know that over time a percentage of patients will lose response to a given medical treatment.
It is challenging to manage patients who are not experiencing full remission with a single therapy. Some of those patients may benefit from a drug switch and some may not. We also know that with each subsequent advanced therapy a patient receives, the likelihood of that second or third therapy succeeding becomes lower. We need better solutions for this group of medically refractory patients.
Given the overlapping and complex nature of aberrant immune functions resulting in the pathogenesis of Crohn’s and the fact that each advanced therapy may only affect certain pathways, it makes sense to try to achieve a better response rate by using dual or combined therapy.
This study, a systematic review of recent studies assessing multiple combinations of pharmaceuticals, is interesting. When we first consider the approach, the question is: How safe is it? It is reassuring that the studies reviewed demonstrate acceptable safety. In addition, the reported effectiveness seems quite promising.
It is important to keep in mind that all the studies in that review are not randomized controlled trials. Moving forward, more standardized studies are going to be critical. Current trials in this vein are prospective and include the VEGA trial; we also have results from the EXPLORER trial, which examined triple-combination therapies.
I am optimistic that these ongoing efforts are going to advance care for IBD patients, because there is a great need for patients who experience refractory Crohn’s and simply switching therapy is not always successful. These studies are also crucial because data can be used in our interactions with payers when we request dual therapy and will also inform our practice in terms of which combinations are safest and most effective.
The more data we have, the more we are going to be able to move forward in this area.
Colombel, et al. N Engl J Med. 2025; doi:10.1056/NEJMoa0904492.
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Loftus E. Presentation Sp101: We should use combination dual-targeted therapy early in severe IBD patients; Presented at: Crohn’s and Colitis Congress; Jan 19-21, 2023; Denver (hybrid meeting).
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