Mirikizumab Maintains UC Disease Clearance Over 4 Years in LUCENT-3, With Jean-Frédéric Colombel, MD

Ulcerative colitis (UC) affects an estimated 1 million people in the United States, and despite meaningful advances in biologic therapy, achieving durable, deep remission remains a central challenge in long-term disease management. The concept of disease clearance, defined as simultaneous symptomatic, endoscopic, and histologic remission, has emerged as one of the most stringent treatment targets in UC, though its clinical value over the long term continues to be studied.

Mirikizumab, an anti-interleukin-23 p19 antibody approved for moderately to severely active UC, now has 4 years of data supporting its ability to sustain disease clearance in patients who achieved clinical remission at week 52. In a post hoc analysis of LUCENT-3, an open-label extension of the LUCENT clinical trial program, researchers evaluated disease clearance outcomes in 179 patients who entered the extension as week 52 maintenance remitters.

Using modified non-responder imputation, > 50% of patients achieved disease clearance at year 4, and observed-case analysis showed that figure exceeded 60%. For the more stringent definition of disease clearance, which requires endoscopic normalization rather than remission, > 40% of patients met the threshold at year 4 by observed cases.

In the following Q&A, Jean-Frédéric Colombel, MD, director of the Susan and Leonard Feinstein Inflammatory Bowel Disease Clinical Center at the Icahn School of Medicine at Mount Sinai, discusses the 4-year LUCENT data, what sustained disease clearance may mean for treat-to-target strategies, and the broader question of whether newer biologics are beginning to alter the natural history of ulcerative colitis.

Q: Can you tell me a little bit about mirikizumab and where it fits into our current ulcerative colitis treatment landscape?

Colombel: So mirikizumab is part of these new, relatively new biologics, which are targeting very important cytokine in the pathophysiology of Crohn's disease and ulcerative colitis, which is IL-23. So there are now a lot of data that have established efficacy for induction and maintenance of response and remission with mirikizumab.

Q: Can you explain the 4 year LUCENT data you'll be presenting at DDW and what they tell us about durability and disease clearance?

Colombel: I’ll take a step back, you know, by talking about what are the therapeutic targets in ulcerative colitis, and very often, I'm taking this image of an iceberg, where at the top you have what we call clinical remission. Then, if you go deeper, you have endoscopic [remission], and then if you go even deeper, you have histological remission. For each of them, we have established criteria which are used in clinical practice and for clinical trials, so for instance, based on endoscopic index, histological index. And then when you combine all these different endpoints, you arrive to this concept, which has been proposed a few a few years ago, which is the concept of disease clearance.

Basically, disease clearance includes symptomatic endoscopic and histologic. It’s the most stringent endpoint that you can think about in ulcerative colitis. As a matter of fact, we don't know yet if it's needed to treat patients to disease clearance in order to get better long term outcomes. There is a very important study which is ongoing, which is called the VERDICT trial, that will answer this question. Patients are randomized to clinical remission, endoscopic and histologic, looking at their long term outcome, and then we will see if actually it matters. This is a different point, but I think it was important to bring that back in the context of this study.

So what we did in this study, which is a post hoc study with all the weaknesses of the post hoc study, was to look at disease clearance at 4 years. So this is only considering patients who were on mirikizumab during the old trial, right? So during induction maintenance and then the LTE, so the long term extension study at 1 year, 2 years, and 4 years. And what we are presenting now are the 4 years maintenance data. Of course, it's a kind of selected group of patients, because basically we are looking at maintenance of remission in remitters, so it doesn't take into account the full spectrum of the efficacy of the drug, right? But overall, I think the very simple message that there was very good maintenance of this disease clearance endpoint at 4 years, which I think is quite remarkable, which is a testimony of the efficacy of this drug for maintaining patients in long term remission.

Q: Like you mentioned, the data suggests that patients achieving early disease clearance are more likely to sustain it through year 4. How should this influence treat to target strategies or early decision making in clinical practice?

Colombel: I think I'm not sure it influenced early decision strategy, actually, just confirming what we already knew. But this is known from studies that mirikizumab is certainly an effective drug in ulcerative colitis, both in bio naive or bio exposed patients. So this is what we already knew from the previous trial. It’s just showing that, exactly as you mentioned, if you are able to achieve remission and even further disease clearance relatively early, there is good likelihood that you will be able to maintain.

It's very interesting, because obviously there is a group of good responders, meaning patients who are doing well on this drug. What we still don't know is, who are those patients? How can we predict short term remission and then maintenance of long term remission and clearance in the long term? Because, as with many drugs, we don't have predictors. We don't know, for instance, if this is a drug of choice that we should start from the beginning in our patients.

Q: Do you think we're moving closer to thinking about disease modification or even altering the natural history of ulcerative colitis?

Colombel: Yes. So what does that mean? That means, in the context of UC, it's mostly preventing hospitalization, surgeries, complications, right? So, kind of a composite outcome, and actually, this is a composite outcome we are using in the VERDICT trial, and the answer is yes, we already have data showing that the rate of colectomy has decreased, for instance, in a population-based study. So I'm almost certain that we are changing the natural history of the disease thanks to the new drugs that we have. Still, there are patients who are refractory to one line, two lines of therapy, and unfortunately, we are still seeing patients, those patients that we are calling “multiple refractory” patients that still need surgery. So there is still an unmet need.

Q: Is there anything else you wanted to add or highlight?

Colombel: I think very important as well, that even though it's not mentioned here, is that the safety of this drug looks very good, which is very important because when we are thinking about maintaining patients for many years under therapy, it's very important to assess their safety profile. And bottom line, when we observe those patients for 4 years, we didn't see any new safety signals, which I think is very good.

Editors’ Note: Colombel reports relevant disclosures with AbbVie, Janssen Pharmaceuticals, Takeda, and others.

References

1. Voelker R. What Is Ulcerative Colitis? JAMA. 2024;331(8):716. doi:10.1001/jama.2023.23814

2. Magro F, Danese S, Siegmund B, Kobayashi T, Siegel CA, Jairath V, et al. Mirikizumab demonstrates consistent and sustained disease clearance at four years of treatment in patients with moderately to severely active ulcerative colitis. Presented at: Digestive Disease Week (DDW) 2026.

3. Sands BE, D’Haens G, Clemow DB, et al. Four-year efficacy and safety of mirikizumab in moderately to severely active ulcerative colitis: results from the LUCENT-3 open-label extension study. Inflammatory Bowel Diseases. 2026. doi:10.1093/ibd/izag007