Future Treatment Paradigms in Ulcerative Colitis

Miguel Regueiro, MD: Dave, what other novel therapies, as we look to the future, hearing about all these great therapies we have today, what comes next? Where do you think the next 5 years are?

David P. Hudesman, MD: Some of the therapies I’m excited about are the IL-23 [interleukin-23] inhibitors, which are coming for both ulcerative colitis and Crohn disease, where some of the early phase 1 and 2 data look good efficacy-wise in both disease states. The safety profile also looks good. It’s an injection every 8 weeks or so, which is convenient for the patient. Then I think a little further down the road, we have these oral small molecules, but possibly an oral anti-integrin therapy or oral IL-23. That’s further away than the next 5 years, but that’s something promising. Even in earlier phase data, there are some oral agents that are looking at the gut barrier in mild to moderate patients. Marla discussed earlier combination therapy. Hopefully we’re treating with whatever therapy earlier, and using combination therapy early. That’s how we’re going to push our remission rates as some of these new therapies come to market.

Miguel Regueiro, MD: Getting more selective therapies, the interleukin-23, maybe more JAKs, even TYK2 inhibitors. Then looking at the combination approach. Ellen, what do you see in the next 5 years as far as treatments you’re excited about?

Ellen J. Scherl, MD: From a practical standpoint, I’m hoping we will all see the medical benefits make it easier to obtain some of these oral agents such as ozanimod, the JAK inhibitors, for our patients as a steroid-sparing and steroid-avoiding strategy. That’s important because only 5% of patients in that Truven [Health MarketScan] database are getting the therapy they need if they have moderate to severe disease. That is a real issue and should guide us on how we select therapies. We talked a little about the [Britta] Siegmund, MD, data with ozanimod and the rapidity of onset of action, 2 weeks vs 5 weeks for remission. But if it takes 1 to 2 months to get approved and then denials that we must battle with in tertiary and quaternary centers, in the real world, these are not going to be efficacious. But that’s an exciting thing. I’m fascinated by new targets like TL1A, anti–IL-36 as an antifibrotic agent, and the combination therapy. Hopefully, we’ll have more molecular cellular diagnostics so that we can classify these diseases appropriately and get the extraintestinal manifestations that might be more responsive to IL-17 vs the gut, more responsive to IL-23. If we can parse that out, that will be exciting.

Miguel Regueiro, MD: Ellen, there is a lot of hope on the horizon, and these new therapies as well. You mentioned the antifibrotics, this is a realm of investigation. There’s somebody I work with here at the Cleveland Clinic, but others are looking at therapies that might reduce fibrosis. We don’t think about that as much in ulcerative colitis, but we’re now realizing this can be an issue, so these therapies of the future that work on fibrosis. Marla, anything you want to add or treatments you’re looking forward to?

Marla Dubinsky, MD: Yes, what I’m looking forward to goes back to other discussions we’ve had, to understand the order or the sequence of things. Meaning, when you are early in the inflammatory process, there are particular pathways that are predominant. Understanding that all roads lead to anti-TNF [tumor necrosis factor] doesn’t mean we can’t put the roadblocks above it. Maybe there’s a certain point where TNF becomes the only and predominant pathway. But if you catch it early, going back to this IL-23 concept and understanding the different pathways, what’s upstream, and the timing of that in the era of the inflammatory process, will change everything. We know that JAK1, for example, and JAK3 don’t hit IL-12/23. Maybe we combine a JAK with a specific targeted, TYK2 for example, may be targeting IL-12,23, or combining it with an interleukin base.

I am excited about the future and to see what all these new therapies bring. But I think we must be clever and understand the era of the inflammatory pathway to know when we need to target different pathways, and when a more broad-based oral small molecule, which goes after multiple pathways, may be warranted. I think that’s what we need to getbetter at, being able to play with all these toys in our toy chest. Because otherwise we’re going to end up at the same place we are, and it would be an embarrassment of riches, and we can’t figure out how to use them. That’s what I’m excited about in the future.

Miguel Regueiro, MD: We must be smart as far as how we use these therapies. Marla, it’s interesting, when I heard you and Ellen and Dave talk, I was thinking back almost 20 years, so 2002, we had infliximab, and that was it. It was interesting to think at that time, we were hopeful we had this new treatment, but we were a little nervous. Now we have these great therapies, more on the horizon, such great hope. The bar has gotten even higher. We must, to your point, figure out what that ceiling is. I don’t think we’re close to that yet.

Ellen J. Scherl, MD: I want to say, we still don’t know, 70 years out, how to use steroids in ulcerative colitis. That’s the first thing., let’s get this right. Short term, with or without a combination of some of these newer therapies. The second is the persistence, we know loss of response. We can do therapeutic drug monitoring, fecal calprotectin, but when you look at that retrospective Australian study PANIC, patients did better in ulcerative colitis with vedolizumab compared to adalimumab and the anti-TNFs. We need to look at these new therapies. As you’ve all said, get it right and get it right early, but also check the persistence, maintenance, and progression.

Miguel Regueiro, MD: Clearly an unmet need is to get it right in induction therapy. How do we use steroids? Obviously, we’d like never to use steroids, but maybe 1 course of steroids in a short period of time from an immunologic standpoint, may interestingly have some benefit in patients with certain disease states. More to come on that.

Transcript Edited for Clarity