Challenges in UC Treatment

Miguel Regueiro, MD: What are we missing, or what are the challenges you face with traditional ulcerative colitis treatment?

Ellen J. Scherl, MD: We are missing 95% of patients with moderate to severe ulcerative colitis getting either biologics, small molecules, or any of these novel therapies. I’m basing that on Corey Siegel, MD, MS,’s data from the Truven Health MarketScan database, where only 5% of patients with moderate to severe ulcerative colitis are using biologics. What are the other 95% getting? They’re getting 5-ASAs [5-aminosalicylic acids] for all too long. The steroid monotherapy is the second most common therapy for moderate to severe ulcerative colitis. To Dave’s point, part of this is when does the mild/moderate patient change to moderate/severe? We must do better at figuring that out. Those are the challenges. We have all these great medications that you’ve heard Marla mention. In the first line, many of these drugs work better when we’re talking about anti-TNF [tumor necrosis factor]–naïve patients. We must do this earlier and more effectively with the new therapies that we have.

Miguel Regueiro, MD: That’s an important point because we linger too long on therapies that are not healing the bowel. This is when we ultimately see the complications. Even fibrosis and ulcerative colitis, we’re now understanding, cancers leading to colectomy. Another unmet need right now, and we’ll come back to this at a different time, is that we still don’t have the 80% to 90% true remission rates. We’re getting better. Marla mentioned the new JAK1 inhibitor, upadacitinib. We’re probably seeing a tick up in our efficacy rates, but we’re still not at that threshold that we want to be. Ellen, go ahead, and then Marla, last words.

Ellen J. Scherl, MD: With the upadacitinib data, we’re over 60%, in the high 60% range, in terms of steroid-free remission. I want to go back to something that we learned from the rheumatologists in their BeSt study, 7 weeks of 4 steroids. When we look at Crohn disease with the SEAVUE trial, we’re seeing over 60% with SEAVUE, Crohn disease, and commit over 55% when we do a forced taper in steroids. Even though steroids were introduced more than 70 years ago, we don’t use it with this forced limited type of approach, which may be the way we should learn from our rheumatology colleagues and from the studies we just mentioned.

Dr. Miguel Regueiro, MD: Marla, do you want to add anything?

Marla Dubinsky, MD:Yes, there are a couple of reasons for this ceiling, or the plateau that you’re mentioning. The fact that 74% of patients were responders after 8 weeks on UPA [upadacitinib], that means 74% were randomized to the maintenance, which is a major celebration. We are getting higher response rates. But the problem with all the numbers is at the end of the year, because X amount stay in remission, so you always have to multiply it by the number who get into maintenance. So at the end of the year, it’s not 50% of everyone who started unless it’s a treat-straight-through design. That’s on clinical trial design. However, I think there are a couple of things. We’re starting drugs too late. In the meantime, to get a patient on an effective therapy could be 8 to 9 years. You already have bowel wall damage, even chronic rectal inflammation, compliance issues, and other reasons for urgency.

Secondly, the future is combination therapy. For us to assume that 1 therapy class, Dave mentioned we have close to 300 genes, so who knows how many biologic pathways we’re actually dealing with? We must understand that up front we need a combination approach in order to get to a more durable maintenance strategy. At ECCO [the European Crohn’s and Colitis Organization meeting], we first saw the combination of guselkumab, which is an IL-23 inhibitor, plus golimumab. When you look at induction at 12 weeks, guess what worked the best when you went beyond symptoms, when you went to the mucosa, or looked for other deeper remission criteria? It was the combination. You know there will be a combination of a JAK inhibitor plus maybe vedolizumab, ustekinumab, or an IL-23. I think that is the key. But we need to understand the behavioral health impact on symptoms. We cannot dismiss that every symptom is due to underlying inflammation. Also, we can’t assume that 1 pathway is going to get us to the end of the road, and we must understand how we best sequence our therapies. That’s my take on why you’re mentioning the plateau.

Miguel Regueiro, MD: Two things I want to mention, coming back to precision medicine. If we did have biomarkers that gave us a signature of the best therapy, that’s important. The other part is an analogy with oncology that you brought up and we can talk more about. Not oncology in terms of cancer, I realize that’s a bad statement to make, but oncology in terms of using multiple treatments to treat a disease, that’s where we’re headed in the future. I completely agree.

Transcript Edited for Clarity