Maria Abreu, MD, on When the First Advanced Therapy Fails in UC

What do you do when a first advanced therapy fails to control ulcerative colitis? Dr Abreu reviews her presentation from the Advances in IBD conference on how choose the next option among the many therapies available now.

Maria T. Abreu, MD, is director of the Crohn's and Colitis Center, professor of medicine, and professor of microbiology and immunology at the University of Miami Miller School of Medicine, in Miami, Florida.

Hi, I am Maria Abreu. I'm at the University of Miami for another 10 minutes, and then I'm going to be at Cedara-Sinai Medical Center as director of the IBD Institute, and I'm at Advances in IBD, and it's December of 2024, and I was asked to give a talk on ulcerative colitis when advanced therapy fails.

And so I followed a really great talk describing what happens after mesalamine and all the different therapies that are available. And then once someone goes onto that thing after the mesalamine and loses response or really doesn't have a great response, what do you do then? Thankfully, we have a lot of different pieces of information that we could draw from in order to make that decision about what to do next.

I described that very clearly that vedo is better than adalimumab as first-line therapy for ulcerative colitis, but then if it happens to be that after vedo, you now need to use an anti-TNF. The data show that anti-TNF either is first line or following vedolizumab, seems to look about the same in ulcerative colitis, so that that order of medication seems to make sense, right, to do vedo and then go on to an anti-TNF.

And then from there, we're about to witness a lot of new therapies in the space of interleukin 23 inhibition. All of us are used to ustekinumab, which inhibits interleukin 12 and 23, which is version 1.0. And version 2.0 are different interleukin 23 specific inhibitors, the first of which approved was risankizumab, followed by mirikizumab, which we're familiar with from Crohn's disease. And finally, guselkumab, which is approved for ulcerative colitis. And I expect that guselkumab, even though it's approved for ulcerative colitis, the data are also very robust for Crohn's disease. So it'll find its way.

And so what's curious is all of these drugs seem to work similarly well as second-line therapies. But in reality, if you look at the information, if patients are naive to therapies, they always look better than patients who've been previously exposed to other biologics. That is a recurring theme. We're probably going to have some patients--we have patients from the clinical trials of risankizumab and guselkumab who had been on anti-TNF, who'd been on vedolizumab, and even 20% that had been on JAK inhibitors before they went into the clinical trial—and those patients also responded. Again, the numbers, the separation from placebo was high, but the numbers overall of clinical remission were low.

Over time, though, I think that one of the things that we're going to have to learn is to be a little patient, especially with patients that have been refractory to other therapies. In a clinical trial—in the artifice that is a clinical trial—if you haven't responded within the first 12 weeks, you're considered a failure. But we know that about 50% of those people ultimately go on to respond to the therapy that they were on. So in real life where we don't have the pressure of being in a clinical trial, I think we probably wait a little bit longer. The nice part about these IL-23 inhibitors is that they're very safe, and so that's not an issue, and they're safe in pregnancy and all that jazz.

And then finally, JAK inhibitors are very potently effective for ulcerative colitis.  Tofacitinib was the first of its kind to be approved for ulcerative colitis. If you compare across studies, which I know we're not supposed to do, upadacitinib looks a little bit more effective than tofacitinib. And so I think for many of us, if we're starting a de novo JAK inhibitor, we probably start with UPA and UPA, even in patients that have been treated with previous medications, and there was, again, a high percentage of patients that had been on anti-TNFs and vedo, and to some extent, even ustekinumab, it seems to work. They always work better as first-line therapy. But nevertheless, since we're more or less forced because of the FDA restrictions to use after an anti-TNF, importantly, it seems to work well after an anti-TNF as well.

So I think we've certainly filled in a lot more options. I also mentioned during my talk that there's a study that's going to be ongoing that combines guselkumab with golimumab, an anti-TNF. So an IL 23 with an anti-TNF, at least in the study, which is already published. It was a very effective combination. The combo did better than either one alone that was in patients that were naive to therapy. Those studies going forward will be in patients that have been on previous medical therapies because it's hard to justify needing a combo approach from the very beginning.

Having said that, though, we know that if we get people into deeper mission early on, you can coast a bit better than if you just sort of spit at the fire and let them kind of be inflamed, be inflamed, be inflamed, and let that go on for an indefinite period of time. So starting strong with effective therapy is really a message that I think we're trying to get out to the wider world instead of incrementally very slowly going up on our therapies. So anyway, I think it's a very bright future for all the different therapies that we have, some to be used eventually in combination therapy as the next level of care that we provide to our patients.