IBD Drive Time: Jimmy Limdi, MD, on the Best of ECCO

In this episode of IBD Drive Time, Dr Raymond Cross hosts Dr Jimmy Limdi from the University of Manchester to discuss his choices for the best presentations and abstracts presented at the European Crohn's and Colitis Organization meeting held earlier this year in Stockholm, Sweden.

Raymond Cross, MD, is a professor of medicine and director of the IBD Program at the University of Maryland School of Medicine in Baltimore. Jimmy Limdi, MD, is a consultant gastroenterologist and head of the Inflammatory Bowel Disease Section at Northern Care Alliance NHS Foundation Trust (NE Sector) and professor of Clinical Gastroenterology at the Manchester Academic Health Sciences Centre, University of Manchester, Manchester, UK. 

TRANSCRIPT: 

Welcome everyone to IBD Drive Time. I'm Raymond Cross from the University of Maryland School of Medicine and I'm delighted to have my friend Jimmy Limdi from the University of Manchester as a repeat guest. And Jimmy's going to review biologics and surgery highlights from the recent ECCO meeting in Stockholm, Sweden— which by the way is a beautiful city and I'm so glad that I got to explore it a little bit with Jimmy.

So Jimmy's going to go over 4 studies that he thought were important for the listeners. Jimmy, welcome back to IBD Drive Time.

Dr Limdi: Thank you, Ray. It's wonderful to be back. It was really wonderful to meet you and do the ECCO conference with you a few weeks ago. Thank you for inviting me.

Dr Cross: I think the first pair of studies you were going to talk about were related to risankizumab in ulcerative colitis and the COMMAND and INSPIRE study. So take it away. What's this study designed for these, Jimmy?

Dr Limdi: Yeah, thank you, Ray. Yes, I'd like to start with talking about the COMMAND and the INSPIRE studies, which study the efficacy and safety of risankizumab as maintenance therapy for moderate to severely active Crohn's disease. Just to remind our viewers, risankizumab, as we all know, it has already been licensed in Crohn's disease and we're about to see it getting licensed over the next few months for ulcerative colitis. It's an IgG 4 monoclonal antibody which targets the P19 subunit of IL 23, as we know. So in the COMMAND study, they tested the efficacy and safety for risankizumab as maintenance therapy in a phase 3 withdrawal maintenance double-blind randomized control trial in people who had achieved a clinical response in the induction study, which was called the INSPIRE study, at week 12 or at week 24 for nonresponders who received an extended induction.

And the primary endpoint for this study was a clinical remission at week 14. Just to briefly tell you about the study design, the responders in the induction study were randomized 1-to-1 to receive this in case you have either 180 milligrams subcutaneous dose every 4 weeks, or 360 milligrams, or placebo. And they had a full steroid taper in the maintenance, beginning at the maintenance study.

Now, what they had in the baseline at the induction in the studies was that 40% of these patients at baseline were on corticosteroids; 30% of them were…actually 75% of them had been exposed to more than one advanced therapy, of which a third had seen one advanced therapy and 20% each had had 2 or 3 advanced therapies so we're talking about a rather refractory cohort of patients in this group. And when I look at the results when you can look at the results for clinical remission at week 52 the results are striking, very impressive about 40% of patients either getting 180 or 360 milligrams achieved clinical remission with nearly a quarter in the placebo arm that's also telling us something I'll come back to that in a moment.

But again when you compare the bio-naïve group with the bio-IR —inadequate responders to biological therapy—they're looking at very impressive results, with nearly 50 and 60% of patients in the bio-naïve group demonstrating clinical remission at the end of one year and about a third or 35% in those who are biorefractory or advanced therapy IR who have also met the endpoint of clinical remission. Furthermore, they also had a number of key secondary endpoints, all of which looked, met there, had impressive deltas over placebo and showed superiority with 50% achieving endoscopic improvement, which essentially to remind our viewers again a Mayo score of 0 or 1, so what we used to call mucosal healing, and also histoendoscopic healing, endoscopic remission, which is a Mayo score of 0, and about 35 to 40% achieving corticosteroid-free remission. And I think importantly, even maintenance of clinical remission, which in clinical practice is important. So those who respond to the induction, how do they do out to week 52? And we had nearly 50 and 70% of them maintaining that through to the end of that year. And also nearly 50 % of them demonstrating no abdominal pain or no bowel urgency, which is, as we know, an important and emerging important outcome measure for ulcerative colitis.

Safety profile-wise, I think IL-23 blockers are looking truly impressive with a safe profile. There were no signals, is a short answer here. There were no signals for any adverse events, a few minor infections, some herpes zoster-related but no signal and a minor elevation but not clinically significant, not drug-induced liver injury, for minor ALT elevations. So I think on the whole it was looking very good and as a safe drug in clinical practice.

Dr Cross: And the second abstract, Jimmy, if I remember, was looking at patient reported outcome measures for INSPIRE at the end of 12 weeks and then those same outcome measures for COMMAND at week 52, if that's right, let's why don't you tell us the high-level results of that?

Dr Limdi: Yeah, I think that was a very interesting study. And I thought that was particularly interesting because to my mind, I think it's the first time that we have actually looked at individual symptoms in ulcerative colitis, some of which we, as clinicians, have probably not even regarded as being symptoms connected to ulcerative colitis, I guess, such as abdominal pain. So they assessed abdominal pain, bowel urgency, tenesmus, fecal incontinence, nocturnal bowel movements, sleep disturbance. And then they looked at a composite of all of these clinical symptoms together. And the interesting finding was that in the induction phase, even as early as 4 weeks, you could see an impressive resolution of each of these individual symptoms and as a composite, not just clinically, but also statistically significant. And then when you looked at the symptom resolution out to week 12 and week 52, there were really impressive results in terms of symptom resolution with nearly a third showing no abdominal pain, nearly 50% of them with no bowel urgency, nearly 50% no tenesmus, up to 70% of them demonstrating no fecal incontinence or nocturnal bowel awakening and indeed up to 60% of them having no sleep interruptions after they started the study and as a composite, about 1 in 5 patients actually showed comprehensive symptom resolution as a composite of each of these symptoms, which I think was a very impressive and clinically meaningful outcome. Of course, what we see in clinical practice, we'll have to wait and see when the time comes, but very interesting finding, I thought.

Dr Cross: So I just want to try to summarize that because there was a lot of really critical information. So, risankizumab was looked at in patients with moderate to severe ulcerative colitis, heavily treatment exposed population. This is a classic candy right design where you have randomized induction and then responders after induction are rerandomized, so there's a placebo withdrawal group. And so the numbers that Jimmy presents for COMMAND at week 52—for the listeners, you do have to do a little bit of an adjustment and and look at because it's only responders that go into maintenance. So that 50 to 60% remission rate for biologic-naive patients is not really going to be 50 to 60%. It's going to be 50 to 60% of responders that entered the trial. So that's really relevant because when Jimmy talks about the next study, that is a treat-straight-through design, where truly that number at week 48 or week 52 is really the number from the beginning to the end, that met the endpoint.

That's not a criticism of the study design. In fact, that study design is the most common design in IBD, although I think we're moving more towards that treat-straight-through design and importantly there was not only our classic endpoints of remission endoscopic improvement and some of the newer endpoints, but the patient-reported outcome measures also reflected what we saw with our classic endpoints, so this is definitely a drug that works. There's no question and no new safety signal, which isn't a surprise.

 But I guess, Jimmy, what I was disappointed in was one of the things that was truly remarkable about risankizumab in Crohn's is that delta in the biologic-exposed patients really was very similar to that in bio-naive patients, suggesting that there wasn't a drop-off in treatment effect. But like mirikizumab in UC, we really didn't see that in the biologic-exposed patients. We saw a drop-off. So I felt that that was a little disappointing.

And again, it seems like many of the new therapies are fighting for the biologic naive patients. So what are your thoughts about that?

Dr Limdi: That's correct, actually, Ray. And I think there is possibly a biological explanation that we need to understand with the IL-23 agents as well. One of them, which of course we haven't discussed yet, is the fact that they do tend to have an extended pharmacological effect. And therefore, even in the rerandomized patients, so those who had had a drug and then went on to placebo, we did see high placebo response rates, which probably is reflective of the pharmacokinetic effect, the pharmacodynamic effect of the drug, which is quite persistent.

The other thing we are seeing, as you said, and quite rightly pointed out, is that it doesn't seem to make as much of a difference amongst those who have actually seen and experienced an anti -TNF and lost response to it. It appears that there may be a mechanistic escape from anti -TNF therapy and when that happens—and I think this needs to be proven in the ulcerative colitis space, but it's appearing to be true in Crohn's disease from the basic sciences—that IL-23 appears to be upregulated so it kind of makes sense then to target the I -23 receptor.

I think we need to understand this in the fullness of time and with some more robust scientific data, but this certainly appears to be true and what we are seeing from the data also would reflect that.

Dr Cross: And when this is approved—and there's no doubt this this will be approved—and this is assuming that you can use whatever you want, which isn't the way it is in the UK nor is that the way it is in the United States, but where would you position this, Jimmy, who are you going to use this in?

Dr Limdi: You just nailed it, Ray. I think that we would love to position any drug any new and effective drug as first line because most drugs, once we've used our first advanced therapy, tend to be less effective when you use the second and then there's a law of diminishing returns with most of them. With this class it doesn't appear to be as true as it does with most of the others that we've seen over the years and so I think realistically we are likely to see it being positioned after failure or intolerance to an anti -TNF therapy and that may mainly hinge on the cost factor. So the availability of biosimilar drugs has actually revolutionized and democratized, I think, access to advanced therapies and so I think we may be expected to use it after anti-TNF unless someone is unable to have it for a clinical reason. So if they are unable to I would probably use it first line when I can but typically after an anti -TNF and I would position it as early in that treatment paradigm as I possibly can, seeing the results that we have just seen.

Dr Cross: Yeah, the only little caveat I would say is I think these newer drugs and the S1P receptor modulators are probably best for people with more moderate and less severe symptoms and clearly for risankizumab, any patients that has concurrent dermatologic problems like psoriasis. This would be a preferred agent, most likely. And it's all going to be about access and the payers in the U.S.

So before Jimmy talks about the second study, I just want to remind the listeners that we are sponsored by the AIBD Network and we are available on Apple Podcasts and Spotify so you can subscribe to IBD Drive Time so that you can hear every episode.

So, Jimmy, I think next year we're going to talk about VIVID 1 and specifically talking about the comparison between mirikizumab and ustekinumab. So why don't you tell us a little bit about that study design?

Dr Limdi: Yes, so I'm changing gears to Crohn's disease, but sticking with the mechanism. Now we're talking about mirikizumab, which is also a humanized IgG 4 monoclonal antibody that targets the P19 subunit of IL-23. And we know that it's just been approved for the treatment of ulcerative colitis. So in VIVID 1, they looked at the primary efficacy and safety of mirikizumab in moderate to severely active Crohn's disease. As you pointed out a few moments ago, this was a phase 3, double blind, randomized control trial with a double dummy and treat-through design, which means there was no rerandomization of nonresponders or responders to placebo.

And this was in a 6-to-3-to-2 randomization, which was mirikizumab to ustekinumab to placebo. And that's how they were randomized in the study. The primary aim was the efficacy and safety of mirikizumab out to week 52 and they had a coprimary composite endpoint of a pro-2 clinical response at week 12 and endoscopic response at week 52, which is a 50% reduction in the SES-CD score. And they also had a pro-2 clinical response at week 12 and clinical remission as defined by a CDAI score at out to week 52. I think this is important with our evolving paradigm around control of disease and we can come to that again in a moment.

So they had about 1000 patients randomized to the study of which I think the study design is also quite interesting in the sense that the demographics are quite interesting in that it did have a refractory disease cohort with a mean disease duration of about 7 years, a moderate to severely active endoscopic disease with an SES-CD score a mean of 13. And I think this is interesting and important as well to a global audience, that about 25% of these patients were non-White, non-Caucasian Whites. There were Asian patients, which kind of makes it more applicable to the world as it were. And interestingly, only 10% of them had only ileal disease. And ileal disease, as we all know, is probably more refractory to any medical treatment that we have currently. And I'd also like to add that about 50% of these patients were bio-naive and only a very small proportion of them had actually seen 3 biologics or more.

In terms of the primary endpoint, the study had shown we have impressive deltas with placebos. So there was about 40% of patients achieving the pro-2 clinical response with endoscopic response. And also among them, again, like we've seen with P19 inhibitors, they did not seem to be a very big difference between the bio-naive and the bio-IR, or sort of inadequate responders to therapy, with nearly 40% in each group demonstrating this composite endpoint of pro-2 remission at week 12 and endoscopic response out to week 52. Likewise, even for the other composite endpoint of pro-2 response at week 52 and clinical remission, 45% of these over placebo did achieve that.

And again, when you break that down into biorefractory or bio-IR and bio-naive, again, not a very big difference. So about 43 and 47% of these patients actually achieve it. it. So in that sense, impressive, again not showing much of a difference between previous exposure or not. And so that's looking good in terms of drug efficacy.

In terms of drug safety, I think this seems to be a signal across the board with this agent that it appears to be safe. We're not really seeing any concerning signals, very mild elevation of ALT up to 3-fold, but again not meeting criteria for drug-induced liver injury or high slow, and some COVID infections. So we have to remember that these studies were conducted during the COVID pandemic, and one would have to consider recalibrating some of these adverse events, taking this into context. In terms of the infections I think some of them were herpes zoster, but again there's no signal. signal coming from this class. And I think we have to remind our viewers and ourselves that herpes zoster is not, you know, we do see it with many other classes of treatments, steroids, anti -TNF therapy, thiopurines, and some of the other biologics as well, even if we think that it's a JAK inhibitor thing, but it's actually, it relates to active disease and some other therapies.

So yes, in that sense, I think the study did meet its primary endpoint and it succeeded in demonstrating superiority over placebo. The interesting other thing that they did was actually include the comparator with ustekinumab in the study design. So if I take you back to the randomization, I'll remind our listeners that we had 6-to-3-to-2 randomization.

So 6 getting mirikizumab to 3 patients actually getting ustekinumab, and that double-dummy design was interesting and reported separately in a separate head-to-head study from by Rev Jairath and they basically randomized patients to either mirikizumab or ustekinumab as standard induction or placebo and then they were in the maintenance phase receiving mirikizumab every 4 weeks subcutaneously 300 milligrams or every 8 weeks ustekinumab as you do with standard maintenance. And in the placebo, responders continue to get placebo every 4 weeks, but nonresponders to placebo were given an induction of mirikizumab as per the standard induction for the study. And then they went on to get 4-weekly 300 milligrams dose mirikizumab.

Now, again, in terms of the study design, I've already talked about it, the highlights of the study were that they demonstrated that the study was able to demonstrate noninferiority for the clinical outcome but did not demonstrate any superiority in terms of endoscopic outcomes. So in late terms, it looks comparable to ustekinumab, but was not able to demonstrate a striking superiority to ustekinumab in terms of clinical practice in a relatively bio-naive cohort so with 50% of patients who were bio-naive, not really showing a significant delta over ustekinumab.

Dr Cross: Yes, I think you summarized that really nicely. And a couple of things that I really liked about this trial, very compassionate design where only 2 of 11 patients are going to get placebo, and so you're going to get either an active comparator or study drug. So very compassionate design, treat-straight-through is very easy to understand. And I really liked their primary endpoint, which was an early induction endpoint of response and then a longe- term endoscopic outcome, which is really parallels with STRIDE 2, where we're looking for early clinical response and then longer-term endpoints such as endoscopy or even transmural healing.

And I guess we saw that signal here that P -19s work pretty well in bio-exposed, but mirikizumab tied ustekinumab. So I don't know where that leaves this in our armamentarium. I think just tying ustekinumab, particularly with the biosimilar coming, is probably not good enough, particularly for a drug that you're going to need to inject more frequently. And actually 2 injections every month, not 1 injection every 8 weeks. So it'll be interesting to see how we use this.

I want to remind the listeners also that we have an AIBD really coming up at Chapel Hill on April 26th to April 27^th. Importantly, for these regionals, registration is free, so please spread the word. We hope to see you there.

And then Jimmy, maybe briefly we can review the last study, the RAINBOW study. So take it away.

Dr Limdi: Oh yes, RAINBOW. I found this particularly interesting because it really takes us us to the here and now of our practice. Remember that risankizumab for ulcerative colitis and mirikizumab for Crohn's disease are not yet licensed. We will see it this year, I think, but they're not here and now. Whereas the RAINBOW study, which was presented by the GETECCU group, which is the large Spanish collaborative group that maintains the ENEIDA registry, is a very practical study that gives us important messages for practice.

What they did was in a retrospective study of nearly 20,000 patients with inflammatory bowel diseases receiving biologics, they studied the frequency and the effectiveness of dose escalation of biologic therapy in IBD—something that we do every day or day in and day out and every week in our practice in IBD.

In the cohort of 20 ,000 patients who received biologics 25%, 26% to be exact, actually had dose escalation, which equates to about 5000 patients, and the majority, two-thirds of them, were because of loss of response, reminiscent of what we see in clinical practice. And the frequency of dose escalation was also striking in that it was about 25% at 1 year and by 5 years for ant-TNF, another 25%; for vedolizumab, 30% of them by 5 years; and 40% with ustekinumab. I thought that was striking because I'd always thought that ustekinumab probably does not require as much dose escalation but in a large study with a big denominator, I think it tells us a very different story from what we would see even in typically large tertiary centers or practices such as yours, mine, and many of our listeners.

So that was interesting. They also found or reported that after dose escalation, remission was achieved in an impressive proportion of patients. So nearly 50% of those treated with infliximab, 40% treated with adalimumab, nearly 50% treated with golimumab. And then remission was achieved in a third of patients who were treated with vedolizumab and 50% who were treated with ustekinumab.

Equally, clinical response, which is an important immediacy effect that we need to see in our patients, was achieved by nearly 90% across the board with all of these drugs, which is really telling us that the strategy for dose escalation works in appropriately selected patients.

And it is something that we should consider to optimize our treatment and make the best use of what we have when we have it, remembering that every subsequent therapy is likely to be less effective to begin.

And then we looked at how well is it maintained, the durability of dose escalation? And nearly 75% of these actually out to 5 years were able to maintain this dose escalation and durability of treatment or treatment persistence. Strikingly again, I thought that for ustekinumab, nearly 90+%of people maintained that dose escalation—something that did surprise me, although we have used ustekinumab escalation quite a lot in clinical practice. I think with such a large denominator, it gives you a better message or a clearer message, so to speak. So that was interesting.

They also looked at factors predictive of therapy discontinuation after dose escalation and what they found that for infliximab, it was previous biologic exposure; for adalimumab, it was the use of monotherapy; and for ustekinumab, a diagnosis of ulcerative colitis as potentially predictive of treatment discontinuation. So I think this real-world study with all its potentially inherent flaws does still give us very important and clinically relevant messages for practice for here and now.

Dr Cross:  Yeah, I agree. And I think it was really remarkable when you really look at their graphs that they presented. The dose escalation was remarkably similar across all the biologics, which I think was a little bit surprising and the take-home message of that strategy of squeezing every little bit of toothpaste out of the tube before you abandon therapy is a good one. And that really applies to novel biologics as well. And if anyone, any of the authors who are listening to this, I'd love to see this submitted to the American Journal of Gastroenterology because we need this published because, Jimmy, you probably know this in the United States, providers and their staff are really under siege with dose escalation and maintaining those doses and we need more real-world evidence to show that that is an effective strategy. And I think this definitively shows that even though it is retrospective. Although it should be pointed out, they prospectively maintain their data.

So Jimmy, this has been wonderful. Thanks for doing it. It's always great talking to you. I hope that we can do ECCO again next year in Berlin. I'll be looking forward to that and hopefully we'll have you back next year to talk about the best of biologic and surgery. So thanks again, Jimmy.

Dr Limdi: Thank you, Ray. Thank you very much for having me, and to the listeners for their time.