IBD Drive Time: The Best of DDW, Part 2

In part 2 of this podcast, cohost Dr Millie Long discusses her picks for the "Best of DDW" on inflammatory bowel disease with her cohost, Dr Ray Cross. 

Raymond Cross, MD, is director of the IBD Center at Mercy Medical Center in Baltimore, Maryland, and professor of medicine at the University of Maryland.  Millie Long, MD, is a professor of medicine, vice chief of education, and director of the fellowship program in the Division of Gastroenterology and Hepatology at the University of North Carolina at Chapel Hill.

TRANSCRIPT:

Hi, this is Millie Long from University of North Carolina as one of your cohosts for IBD Drive Time. I am thrilled to do a collaborative interview with my cohost Ray Cross from Mercy in Maryland. And Ray and I thought what we would do is just give a highlight of some interesting abstracts that were presented recently at Digestive Disease Week in May of 2024. So let me jump into some of my three. So while Ray was focusing on some of the real-world data, I took a look and visited some of the clinical trials presentations.

And so I selected 3 that I thought were interesting and important. The first is presentation number 763. This was presented by Marla Dubinsky. And it looked at, it was basically a subanalysis from the SEQUENCE trial. So we all have seen the original SEQUENCE data, which was a head-to-head open-label trial of risankizumab versus ustekinumab, with an outcome of clinical remission in kind of a treat-straight-through-design over 48 weeks, where essentially risankizumab was found to be about 20% superior to ustekinumab.

Now, obviously, the trial wasn't perfect. It was open-label, people knew what they were on and you know there's some data that there was a little bit more dropout in the ustekinumab arm so you know it's not perfect but it did give us the idea that, just as has been shown in the psoriasis literature, that perhaps the IL-23 mechanism may have added efficacy benefit when compared to the IL-12/23 mechanism.

So what this study did is—because the original data presented for SEQUENCE were really the clinical data, the clinical remission data— was it actually looked at the biologic endpoints. And what I mean by that is looking at changes in baseline of C-reactive protein, fecal calprotectin, a composite endpoint of what they called biologic remission, which is kind of what we do in practice, which is that the patient was in clinical remission and they had fecal cal or CRP normalization. So this is helpful in that it kind of provides another flavor kind of mechanisms that we may be doing in clinical practice to see if a drug is working and how these 2 drugs compared.

I probably should have mentioned that in the initial SEQUENCE data they looked at endoscopic remission as well and saw those same those same deltas, but we don't always rescope people that quickly, and kind of often will use some of these proxy, you know, biologic markers. And so essentially, whether they looked at week 8, 24, or week 48, they did see a greater reduction in fecal cal, high sensitivity CRP, kind of by the individuals who are on risankizumab as compared to ustekinumab. So kind of across the timeframe, you're starting to see this greater reduction in biomarkers that started earlier, right? Even by week 8, where we have some of these data.

And then essentially when you look at the biologic remission, and remember that this included clinical remission plus these fecal cal or high sensitivity CRP normalization, at week 8, it was risankizumab 26.3% versus 21.9% for ustekinumab. At week 24, it was 42.8% for risankizumab versus 24.9% for ustekinumab. And then at week 48, this is where we really see that approximately 20% delta again with 46.3% versus 27.5%. So, you know, these data are consistent with what we saw in the initial SEQUENCE data, again, where they looked at clinical remission and endoscopy. But it's kind of nice to see the biomarker reduction and to see that this difference is present as early as week 8. Granted, it was only about 5% at that point, but it really, by week 24, you're starting to see almost that 20% delta and that it's consistent at week 48.

I thought it was helpful just in terms of how we practice because I do check biomarkers in practice, and as someone is kind of starting a drug to ensure that things are improving, certainly we see the same difference for these 2 drugs with that mechanism.

Dr Cross: So, Millie, I don't think…that's not surprising, right? And you made this point a couple of times that the delta was pretty consistent with what they saw with endoscopy and so forth. And these were all TNF-exposed patients. So these weren't naive patients.

Dr Long: Correct.

Dr Cross: I think you and I practice identically in this regard that if available, and it's almost always available, we use risankizumab in anti-TNF exposed patients over ustekinumab. So I guess what's the role for ustekinumab? I still think it has a role in bio-naive patients. I still think it works pretty well there. Are you using any ustekinumab at all, or is it pretty much straight riza? I don't mean to put you on the spot.

Dr Long: Yeah, no, absolutely. So I am, but interestingly where I live in this world, we actually are going to fail, must fail 12/23 prior to getting IL-23 unless I appeal. So I'm using a lot of it. But I am very comfortable using an IL-12/23 in a biologic-naive patient. Remember, we haven't necessarily seen this difference in naive populations—and thank you for emphasizing this was the TNF-exposed—but in a TNF-exposed population, I'm probably going to fight harder to have the IL-23 because we do have this differential kind of benefit, But really, when you look back even at SEQUENCE data, I'm sorry, at SEAVUE data, which was ustekinumab versus adalimumab, ustekinumab has a really high rate of clinical remission and endoscopic response within the first year. So I think it's a very good drug in naive populations, like the SEAVUE population. So I think that's probably where I would use it. If I had a patient who couldn't do the 3 upfront infusions with risankizumab and wanted to get to sub-q sooner, or sometimes that happens with people traveling for work and other reasons, or if I had, you know, it was in a situation where from a cost perspective, the ustekinumab was better for the patient or from an insurance approval standpoint.

So I'm very comfortable with the IL-23 and the naive population. I think it's probably comparable. But in the exposed, we're seeing more and more of this data that perhaps there's this differential effect.

Dr Cross: And I don't think that this is artificial based on trial design— the perception that ustekinumab doesn't work as well, so the patients are going to drop out quicker. This is what we see clinically. This is what we would have anticipated based on reviewing their pivotal trial data and comparing across trials, which we're not supposed to do. And Peter Higgins has this good quote that when you analyze the clinical trial and you look at the flow diagram for the study, patients vote with their feet. And the drug that doesn't work as well, people are going to leave the study. And that's exactly what this showed. I just think that they were getting a less effective treatment, so I'm not going to take this anymore, I'm going to leave the study. And unless you feel differently, I think that that I think this is real, what we're seeing here.

Dr Long: Right. And I think it absolutely is something, and we've even seen it in psoriasis, right? So I don't think this is hard to believe that you get added efficacy with IL-23. You know, the design, yeah, there are more people, the patients knew what they were on. And so if they, it's possible that if they're feeling a little better, but not perfect, they stayed in if they were on riza, but they didn't, on ustekinumab, but it's really hard to know. And there may have been some incentives to kind of have access to riza for longer if you're on that arm. But in the big scheme of things, I agree with you. This is a delta that is believable.

Dr Cross: All right, what else do you have, Millie?

Dr Long: All right, so in the theme of head-to-head and trying to understand this difference in IL-23 versus IL-12/23, the next abstract is presentation number 985. And this was represented by Gert de Haans, and it was the efficacy of mirikizumab, a different IL-23 that's been approved now in ulcerative colitis, but not yet in Crohn's disease, that looked at miri versus ustekinumab in patients with moderate to severe Crohn's disease. So these were results from the Phase III VIVID-1 study.

So in this study, it is basically a randomized, double-blind, double-dummy, active and placebo-controlled treat-through study. So in this study, patients didn't know what they were on. So this is not open label as the one we just discussed, for what that's worth.

And basically, patients were randomized 6 to 3 to 2 to miri versus uste versus placebo. So they have kind of all of these comparators within here. And what they looked at was endoscopic response as well as clinical remission at week 52 in this kind of treat-straight-through.

And so interestingly—remember this study, unlike the SEQUENCE study that only included people who'd previously been exposed to TNF—this had a mixed population of naive or exposed patients. And what they found is that miri achieved all the key major secondary endpoints compared to placebo, which is great, and it achieved noninferiority to ustekinumab for clinical remission. And it basically didn't achieve superiority to endoscopic response in the overall population and biologic failed patients. So again, just pulling out the ones that had previously been on biologics, there was a numerical trend towards greater response rates for endoscopic response and clinical remission, but not significantly so. And the safety profile looked good for all agents.

And so, essentially, the take-home point here is, is that mirikizumab achieved noninferiority to ustekinumab for clinical remission, and that in biologic-failed patients, miri had this numerical trend towards greater response, and it had an acceptable safety profile.

So here we're seeing something a little bit different, right? Where you now have an IL-23 versus an IL-12/23 that didn't meet the end point. It basically, it met noninferiority, but it did not demonstrate superiority. And this may have had something to do with the study design in that it included both biologic-naive and biologic-exposed. And so perhaps, as we were talking about before, the fact that the naive patients have less of a delta between these 2 mechanisms may at least partially explain some of these differential study results. Is that what you're thinking as well?

Dr Cross: Yeah. Clearly mirikizumab works, right, for both Crohn's and UC and it's just, the positioning is hard for me, right? Particularly we have a biosimilar of ustekinumab coming, right? So if you're a payer and you're looking at these results, are you going to authorize the biosimilar of ustekinumab over miri? Are you going to convince a patient as a provider to do 2 injections a month compared to 1 injection every 8 weeks? I think it's really hard for me figure out where I'm going to position this drug and it has nothing to do with efficacy or safety.

If I remember right this study had a novel primary outcome which was a short-term week 12, I think, PRO combined with endoscopic outcome at week 48 which is a little weird but if you think about it that's how we practice right? That's like treat to target, right? You do an early symptomatic assessment and then you do an endoscopic assessment later. And I've heard other people criticize this because the ustekinumab responses were higher than what were anticipated. But I think that's because this group of patients, I think only like 10% of them had ileal disease. So it was really an enhanced responder population, right? Probably less fibrosis that was because you have less ileal patients and maybe that's you know maybe that's why ustekinumab numbers were a little better.

Dr Long: Yeah, in reality it's a good point. Disease location–it was about 10% evenly across the groups—placebo, miri, usta—colon was about 40% and then those with ileum and colon involvement was about 50%. So you do see a lower small bowel only, and you and I both know that's a really hard group to treat, certainly.

And that, you know, about half of this population was no prior failed biologics, and then the others were varying degrees of 1, 2, or more than 2 in here.

The other kind of characteristics, you know, their mean CRP was in the 7 to 8 range, you know, their duration of Crohn's disease was about 7 years in each group, so it's not that it was a super early group, unlike, you know, for example, when you look at SEAVUE, which was the uste versus adalimab study, that was a much shorter disease duration.

So you know, I think it's hard to put it together, but I agree with you that that there does in this study appear to be less of a difference between miri and uste, but it's kind of a different design, a different population, but certainly we're not seeing, even if you look at what the overall delta is. So let's look at the clinical remission at week 52, even in the biologic-failed population, it was about a 10% delta. Now it wasn't insignificant, but that's not a 20% delta like we saw kind of in the other study, right? So it just makes it a little bit harder on where to utilize and position, you know, these drugs.

But I think it also speaks to the fact that, you know, ustekinumab in this study at, you know, a year all participants had almost a 50% endoscopic response rate and, you know, a clinical remission rate of, you know, that as well. So it's a pretty good drug. So if we are using biosimilar ustekinumab, it's a pretty good drug.

Dr Cross: Yeah, and in SEQUENCE, if you saw those kind of response rates with ustekinumab, there wouldn't have been a 20% delta

Dr Long: Right, exactly, exactly. So it just goes to show you that we really shouldn't be comparing across studies, right? Because every study population is very different in terms of who's included. In order to compare across studies and you know you'd have to actually have a comparable group of patients and so I think we just have to study more of this and understand in the real world how these drugs are working, but at least in our practices it sounds like are pretty similar like for the naive patient I'd be comfortable with any IL-23 or IL-12/23; in the biologic exposed patient, you know, from the data we have so far, it seems like risankizumab would be the best choice, right?

Dr Cross: Yep, for the moderate patient and probably UPA for the severe patient.

Dr Long: So one last abstract before we wrap up, and this is presentation number 1177, presented by Adar Zinger. This is from the University of Chicago group. So this is a real -world study, kind of like some of the ones you initially presented that looked at risankizumab effectiveness in ustekinumab-naive and ustekinumab-experienced patients. And so this was out of the University of Chicago IBD registry.

And so essentially they included all patients treated with risankizumab in their center and they actually standardly measure kind of fecal calprotectin as well as a Harvey Bradshaw index and obtain colonoscopy after a new start. So those data were included. And they included 102 patients that were treated with risankizumab who had at least 12 weeks of follow-up. And of these just fortuitously, it was about half and half where they were ustekinumab-naive and ustekinumab-exposed.

And you can probably imagine that the ustekinumab-exposed patients had longer disease duration, higher rates of prior bowel resection, and exposure to multiple advanced therapies, right? Those folks, all those characteristics make sense. And the baseline Harvey Bradshaw index was higher in this group as well.

But that said, both groups had kind of improvement over the follow-up period. At week 12, 74% of the ustekinumab-naive and 55% of the ustekinumab-experienced patients achieved steroid-free remission. And at week 26, those numbers were 76% and 60%. And then in the subgroup of patients these numbers get much smaller—it was only about anywhere from 7 to 15—but in those patients who had a fall of at least a year, 71% and 40%, meaning the ustekinumab-naive and experienced patients were in steroid-free clinical remission at week 52.

So what I think this is helpful is that in my clinical practice, for those patients who have previously been on ustekinumab, is there a role of trying risankizumab? Do you have an incremental benefit? And I think this tells us that, yes, you could have an incremental benefit. It's probably not as high as in those individuals who've never been on an IL-12/23, but it's high enough that certainly you can have incremental benefit for your patients and have attained a steroid-free clinical admission.

Is that what you've seen in your practice as well, Ray?

Dr Cross: Yeah, yeah, I've had some people that lost response or didn't respond to ustekinumab and I was able to capture them with risankizumab, so I don't have as many as University of Chicago, but definitely anecdotally, I've seen this in real life and I think this is super useful.

I guess the 2 questions for me, or the 2 questions I have, if you have a patient on ustekinumab at 8-week dosing and they're partial responders or maybe even a primary nonresponder, do you try to optimize the ustekinumab or you just switch them immediately to risankizumab?

Dr Long: So in my practice, I used to optimize ustekinumab all the time. It's a pain in the butt to do so. There are a lot of insurance denials along the way. And we do know from data actually recently published in the American Journal of Gastroenterology that insurance delays are actually a real negative for our patients and can have worsened outcomes. And so in my practice, I've fully changed this. So if I have that patient who's kind of maybe a partial responder to ustekinumab, but not all the way there, I switched them out because I feel like I'm going to get that incremental benefit and it's going to be approved 100% of the time and the patient's out of pocket has not changed. Rather than me trying to appeal for weeks and weeks and weeks, you know, those are important weeks to the patient. So that's why I've started to pivot. I don't know if what you have done in your practice.

Dr Cross: Well, it's mixed. And I actually talked to patients about this and have them as part of the decision. But I think your points are all valid. And I think that I was very blessed at Maryland and I had this amazing team around me that could get things approved fairly quickly. But I recognize in the real world it's not always like that, right? So I tend to still try to optimize. But I think your point is valid.

The other question I have is if you have someone on every 6 weeks or every 4-week dosing of ustekinumab, do you still try risankizumab? Is that patient inherently different?

Dr Long: I think it probably is something of a different patient, but in my practice, I have still tried risankizumab. Now, it probably isn't my first choice, you know, if that patient, that same patient who's on Q4 weekly ustekinumab and is not doing well, I would probably go to a JAK if they haven't—I mean, I'm assuming they've probably already been on a TNF and they're ustekinumab—and a JAK, I would probably try to change mechanism if they're truly not doing well on Q4-week dosing, ustekinumab. But I have in some of these patients switched to risankizumab and you do capture some. So I think there is something of an incremental benefit.

Dr Cross: And even though the numbers are small, I'm sure that the Chicago group will dig into those details a little bit for the full paper.

Dr Long: Right. And it'll be useful once they have that too for, you know, kind of, if there are any insurance issues, it's always just nice to have published data that shows efficacy in that setting that in previously exposed patients, this can be an efficacious route to take.

Dr Cross: All right, Millie, this has been great

Dr Long: Thanks, yeah, this was fun.