Chapters Transcript IL-23 Agents: How Do They Stack Up? Course: Big Gut Seminars: Focus on Complex Inflammatory Bowel Disease So, welcome everyone again. Uh, I guess one of the benefits of being one of the course co-directors is I get to pick the talk, uh, I want to give. So, maybe this past summer, I was like, oh, this is a nice topic. I've done a talk on something similar recently, and then in the past 78 months, there's been more aisle 23s, more indications for aisle 23s, and then this talk wasn't as easy to do, especially in 20 minutes. So, it's my own fault for, uh, setting myself up for failure here, but. What I'm gonna try to do is really not get into the weeds with all the data of the different agents. I'm gonna show some data and really pick out sort of some highlights on sort of how I look at the data and how I could apply this to my practice, and we're gonna have plenty of time for Q&A, and I think that will sort of, you know, get some more info out there. So, these are my disclosures. OK, so first, why should we target IL 23 and IBD? So this comes from, I think, over 20 years now, our genome-wide association studies that showed um polymorphisms in the IL-23 receptor was prominent in Crohn's disease as well as ulcerative colitis. And then over the next few years, uh, we've learned that inhibition of IL-23 uh decreases mucosal inflammation, improves the barrier integrity. Um, suppresses some CD4 T cells, and as well, IL-17 could have some protective effects as well as pathogenic effects, but it really preserves the protective functions of IL-17. So we have eustinumab, which is our selective, which is our IL-1223 inhibitor, and that blocks the P40 subunit. So and the P40 subunit is on both aisle 12 and IisL 23, and then we have our selective IL 23 inhibitors, which are P19 um inhibitors. That's only, um, only affects aisle 23, not IL 12. So just one translational basic slide I found interesting and I, you're not gonna dive too much into the safety, uh, in this talk because I think we're all pretty comfortable that these are extremely safe medications. But um this is an interesting study where they looked at rectal biopsies, they did bulk RNA sequencing, and they did the same thing. There was another part of the study where they looked at, uh, skin biopsies for psoriasis patients and really what it's showing here, whether you're looking at CD 64. IL 23 P19 subunit or the IL 23P40 subunit and in non so control patients and non-inflamed Crohn's patients and non-inflamed UC patients really didn't have any elevation in these markers right versus if these patients were inflamed your IL-23 levels, your CD64 levels were high, suggesting right that these therapies, right, once you put somebody into remission, you heal them. They're not really doing anything, right? You're sort of they're maintaining that balance and they're not having a lot of these off target effects explaining the safety. So I just have one safety slide here. Since use of Kumab has been on the market for the longest, this is some 5-year data from the Unity trials, and you could see here whether it's adverse events, serious adverse events, infections, um, serious infections, malignancies, really no difference, uh, between drug and placebo. All right, so I'm gonna break this up for ulcerative colitis and Crohn's disease, and I'm gonna try to go in order of when these therapies were FDA approved. So this is the dosing schedule, and you see, I'm not gonna go through the details, but just so that you know, for usumab IV induction and for useticinumab, it's the same induction and maintenance dose uh for UC and Crohn's, for mirikizumab and risenkizumab. There are differences either with induction or maintenance. All of these agents aren't the same. Um, there are some subtle differences between the selective P19 inhibitors, and one of the main ones with guzelkumab is it blocks something also called CD64. And with the concept there is that it's affecting certain, um, binding to certain cells that are trying to capture IL-23 release from those cells, not only in circulation, and then there's some other subtle differences between them. OK. So, used toinumab and ulcerative colitis. So, I always like to show this side when I'm trying to look at these different uh You know, studies now in the past I was pretty good at remembering, you know, remission rates, response rates, but now there's too many studies, too many therapies. So really what I'm looking at what patients are included in these studies, what's the delta or the difference between drug and placebo, and how are these patients do, whether they're bio naive or bioexposed, right? And then I try to take that into my practice and sort of say, hey, is this a good first line medication? Is this a good second line medication, or so forth. So in the unified trials they used toinumab for ulcerative colitis, this was the first study to really show a nice delta difference between drug and placebo, whether you were bio naive or bio-exposed. We hadn't seen that before with vitolizumab. Um, then came merekizumab for ulcerative colitis, and you could see here, similar to what we saw with Eustinumab, the lucent one is the induction trial. The next slide will be lucent 2, which is the maintenance, the 1-year trial. These patients were re-randomized, but you could see here whether you're bioinofa exposed or bioinofa naive, you still see some nice separation. And looking at patients at the end of the year and again re-randomized so the apps you're taking, you're sort of selecting out the responder groups but you could see nice differences in patients that have had an endoscopic response whether they were naive or exposed at about 30% difference between drug and placebo, which is pretty impressive. We've then had risenkizumab that came for ulcerative colitis. This is looking at their one year data, um, and again this study was also re-randomized, so they again took responders and then re-randomized them to drug versus placebo, and you can see overall at the end of 1 year, about half the patients were in clinical remission, which is a pretty high number when you're looking at these studies. Clinical remission just to remind everybody's both symptoms rectal bleeding, stool frequency, as well as endoscopy, so endoscopic improvement. When you look at the advanced therapy naive group, right, and we use advanced therapy instead of bio naive since we have our small molecules, we see pretty high numbers here, right? This is a subset, but 70%, so really showing these selective IL 23 inhibitors work well. When you look, however, at the patients with risenkizumab that were exposed to biologics, there that difference between drug and placebo wasn't as much as a naive group. Now was this the patients included or study design, it's unclear, but in this part of the study they didn't show such a significant difference. Moving on to guelumab, our most recent, um, selective IL-23 inhibitor approved for ulcerative colitis. You can see here clinical remission rates at week 12, a nice difference between drug and placebo, about 15%. Just at a baseline, if you're looking at some of our older studies of Vito and some S1P, 1 of the S1P inhibitors, you're seeing close to 10%, so 15% here. Common question patients ask all the time how fast these therapies work. So with every therapy, whether it's a selective IL-23 inhibitors or any other therapy, you're always gonna have studies showing that these drugs work fast, and then you're gonna have studies showing that there's delayed responders. But usually I tell my patients that are not complex, bio naive, maybe failed one biologic. I expect to see some sort of response within 2 to 4 weeks, but some people could take up to that 3 month time frame. Looking at 1 year data, you could see here really nice difference between drug and placebo and if you go to the bottom right, endoscopic remission, so a Mayo score of 0 in the bio and Jack failures, you're seeing a difference between drug and placebo of over 20%, right? So I think just looking across, you know, the data for ulcerative colitis, and we don't have head to head trials, these agents work well. They do a good job healing. They work well in both bio naive and bio-exposed patients. OK, moving to Crohn's disease. So this is a dosing in Crohn's disease. I'm not gonna go through the details. You'll have it on your slides. OK, so before we had our selective IL 23 inhibitors, very commonly with us tokinumab, I get somebody into remission or have a great response, and inevitably a handful of our patients are gonna lose response. And do we give them another IV dose? Do I move it to every 6 weeks or 4 weeks? Do we check a level? I think many of us were just doing this, you know, pretty regularly without data. So there was this power study that was presented a couple of years ago, um, which we're taking patients that had an initial response to use toinumab and then lost response and trying to re-induce them with another IV dose and comparing them to patients that just continued subQ with a short-term outcome at week 16, and bottom line, there was no difference, right? They weren't really recapturing a lot of these patients. And then just presented at echo last month. There's another study called the rescue study, a little bit smaller, just over 100 patients, randomized double-blinded, uh, study looking at 1-year outcomes. And what they did were patients again with a secondary loss of response to eustainumab got randomized to an IV dose and then every 4-week dosing of eustainumab versus an IV dose and every 8-week dosing. I think, first, bottom line, the dose optimization recaptured less than 20% of the patients, right? And there was no difference between those two aren'ts. They also showed that the drug levels did go up with giving that extra IV dose and more drug, but again, that wasn't correlated with clinical um benefit. So now in my practice, sort of with these two studies and what we're seeing. I'm more likely gonna switch from use tokinumab, right with the secondary loss of response to a selective IL 23 inhibitor rather than saying, hey, let's go to every 4 weeks or every 6 weeks and give it 3 months. The cases I'm still doing it and if I have a patient that has a great response and maybe at week 4, week 6 they lose that response, they get the therapy, they have another great response, those patients, I'm still gonna move, but the patients that just lose response, you give them a dose, they're still sort of petering along. I think it's time to move and we have some nice data showing that now. Um, another use of kidumab study I just wanted to highlight was, um, the Stardust study. You know, when Eoinumab, the initial unity trials for Crohn's, we didn't really have endoscopic healing data, uh, with that. So this was a treat to target study. I'm not gonna get into the weeds of the study, but bottom line, when you're looking at that with eustinumab, you're seeing an endoscopic response of about 40%. And when you're seeing really healing, you don't, you know, 15%, so not the highest numbers. And then just a nice little, um, substudy they did was looking at intestinal ultrasound. This is something we're incorporating more and more into our routine practice. I think all of us will be using this more to help guide treatment. We're gonna be hearing a little bit more about that today, but showing how you could use intestinal ultrasound as well to monitor response to our therapies. So how do we use, what therapy should we use for our patients with um Crohn's disease? So we have two head to head trials. Uh, the first one was the Seaview trial. These were patients with moderate to severe Crohn's disease. They were treatment naive and they randomized them to usetekinumab or adalimumab and followed them out for a year, and there was no difference between the two, whether you're looking at clinical remission at the end of the year or endoscopic remission. But I would see is say is these clinical remission numbers, and yes there's no placebo, but we're over 60% in this treat through study design. This is one of the highest remission rates we've seen in our adult population, and the reason why these were patients that had a relatively short duration of disease that haven't been on multiple therapies. So I think the take home point from this study is get your patients on therapy early, whether it's a selective IL 23 inhibitor, whether it's Vito, whether it's a TNF. But if you get patients, if you get patients on therapy early, they're gonna do well. OK. And then one other study for positioning with eustinumab. This is a retrospective study, real world evidence looking at patients that failed anti-TNF comparing eustinumab tovitolizumab and eakinumab outperformed vitalizumab. And there's some interesting science behind this as well, and I think when, you know, we could talk about this at the Q&A's about combination therapy, but it looks like certain patients that are resistant to anti-TNF have these CD4 cells that are driven by IL-23. So there's this nice sort of science behind it that patients maybe that aren't doing well with TNF used to Kumab or selective IL 23 inhibitor might be the right next choice or maybe combining them could help. OK, so what of our select, what about our selective IL 23 inhibitors for Crohn's? So looking at risenkizumab, our first one that was FDA approved, so I would say this is the first Crohn's study to show really a nice difference between drug and placebo. You're seeing here 20%, whether you're close to 20%, whether you're bio failure or bio naive. This hasn't been shown before in Crohn's, um, um, before risenkizumab. Uh, we saw really nice similar results when you're looking at endoscopic response. And then there's a second induction study called Motivate, and these pretty much were patients that were all bioexposed, and you really could see still nice differences between drug and placebo when you're looking at both clinical remission and endoscopic response. So again, similar sort of story we see that we see with UC that these drugs work well and they also do a good job healing. Our second head to head study, uh, with this with this class of therapy was the sequence study. So these are sort of more of the studies we need to see. We have more therapies on the market. How do we position them? So these were this study was comparing risenkizumab to Eusticinumab, and these patients failed a bio failed TNF. OK, so these were not bio naive, followed them out for the year, and bottom line, whether you're looking at clinical remission at week 24 or at week 58, or if you're looking at endoscopic remission. Risen kizumab outperform used to kidney map, right? So. You know, dealing with insurance is a whole another story, but this is where I really push in patients that have been bio exposed. I'm really pushing for a selective IL-23 inhibitor rather than used toinumab and bio naive early again, I think all therapies will work. OK, so, just in the past 3 months, I think 3 months, yeah, in the past 3 months, we have 2 more selective IL 23 inhibitors FDA approved for Crohn's, so. Uh, I think in January mirakizumab was approved. I just wanna comment on this study design. This was a treat-through study design, so different from sort of the data I've shown to date, um, outside of the head to head trial. So meaning patients come into the study, they get drug, and they just continue to the end. So when you're looking at those one year response rates, remission rates, endoscopic response rates, they're really indicative of how those patients are doing. So they had composite endpoints looking at, you could see on the left, looking at patients, looking at clinical uh remission at week 12 response at week 12 and remission at week 52 and then response at week 12 with endoscopic response at week 52 and you could see here again impressive deltas difference between drug and placebo pushing 30%. On the right is using looking at mirekizumab versus eustinumab versus placebo, and they didn't really see a difference of merakizumab versus eusakinumab in this study. This study though had about 40-45% of patients were exposed to biologics. The rest were bio naive, so a little bit difference in the sequence population. And then the galaxy study, so, um, Gelumab was just approved for Crohn's disease, um, in the past couple of weeks. Similar composite endpoints, whether you're looking, one was looking at week 12 clinical response, week 48 endoscopic response together, week 12 clinical response with week 48 clinical remission, and again you're seeing really these impressive deltas, things we haven't seen before with our older therapies, 30-40% of these composite endpoints. So showing that these therapies again are effective and do a great job healing. And this is looking at the data looking at glkumab versus Eusticinumab, and in this study, which also I think a little 55% or so of patients were exposed to biologics, or sorry, exposed to advanced therapies in this study, and Um, guzelkinab outperformed Eusticinumab, um, in this study. And then one comment also that was just approved was our typical IV induction for our selective IL-23 inhibitors. There is what was also approved for guelumab is a subcutaneous induction strategy which will definitely be a lot easier for our patients. This was, uh, again similar treat through study design. It's called the gravity study. Not gonna get into the weeds, but you can see across the board difference between drug and placebo. The numbers are impressive, right? This is over 30%. This almost looks better than the IV induction studies, so I think we need to decide who we should be using IV, who we should be using sub Q. Should we induce everybody with sub Q, and we don't know that yet. We're gonna have to dive into the data a little bit more. And one last thing, and I mentioned, so biosimilars is gonna play a role in sort of prescribing all of our agents. So again, I, as I said earlier, I really push our selective IL 23 inhibitors that are more complex patients and our patients that were bio exposed have our bio naive patients you're treating early, I think. All of our therapies will work well. I think with biosimilars now insurances are gonna push us this way, and I'm completely OK with that, um, and just in the past two months, past month or two, we've had patients starting to switch to the yeast ofinumab biosimilar. So if you haven't seen that, it started to happen. So you know it's now reminding us and our staff when we're talking to patients, not saying Stelara, saying yeast tokinumab, you're gonna get one of them, it's OK, it's not a big deal ahead of time rather than saying, oh you're gonna go on the brand name and then having to deal with it when the patient gets a different one. All right, so putting this all together, um, so how do I position, uh, musoinumab and selective IL-23 inhibitors in my practice? In moderate to severe Crohn's disease or moderate to severe ulcerative colitis, first-line therapy, I think this is a great place to use these therapies. I think there are other therapies as well that will also fit well into this, so I'm not saying only these therapies, but this is a great place to use these therapies. I think I showed nicely that in moderate to severe 2nd or 3rd line for Crohn's and ulcerative colitis, these are therapies you should really be thinking about as well. They do a really good job and there's some nice science again behind the TNF failures. Overlapping psoriasis and eczema, these therapies look great for um, psoriasis. We've learned from the dermatologist that selective IL 23 inhibitors do way better than eustainumab for psoriasis, so this is a great place to use them. Where I don't think about using these therapies, in our, in our more severe cases of severe inflammatory Crohn's or sort of acute severe ulcerative colitis that are in the hospital or going to the hospital. I think we're, you know, maybe there'll be some more data that we could use them in our sicker patients, but right now I'm still using infliximab and neatocinonib. Sponddyloarthropathy, I think selective B L 23 inhibitors do, do well for joint pains, peripheral joint pains, but. Not as well as our JAK inhibitors and infliximab, central spondyloarthropathy, you're still using that, but I do think there could be some emerging data in the next couple of years that might be shipped that paradigm as well. Perianal disease leaning on infliximab and 6MP, and if that doesn't work, you padocinonib, and then don't forget surgery, right? If there's irreversible bowel damage, even though we have new safe therapies, surgery is a first line for Crohn's. It's still a great option. All right, so just some practical tips. So reminder, the mechanism of action does vary among these agents, right? Usuinumabs P40. We have a selective IL-23 inhibitors that are block the P19 subunit, and there's differences between those with Gelumab with CD 64, the other ones without. And there are clinically meaningful differences among our agents. Risenkizumab and gelummi have have been shown to be superior to use toimumab and Crohn's disease. It's unknown if this is the case in UC, although that healing data, right, without head to head data does look very good for our selective IL-23 inhibitors. Cycling within class is likely effective, right? And I think this is something where we're gonna need real world data. We have some nice data showing from patients that responded to Eustainumab and then lost response going to risenkizumab. These patients did well and presented at one of our national meetings this past year. There was nice data where they recapture when patients went from euinumab to mirakizumab. They recaptured about 50% of those patients. So I think we are gonna be able to cycle from eustinumab to an aisle 23 and within aisle 23 inhibitors. I think I showed this as well. If you're a secondary loss of response to use tekinumab, right, or you're losing response, I don't optimize dose anymore except for certain situations. I'm really pushing and switching to a selective IL 23 inhibitor. No benefit of adding immune modulators, so we're not really using combination therapy in these patients. You know, we could go more into the Q&A. There's different maintenance dosing for different therapies. In general, I tend to push towards the higher maintenance dose. These are safe therapies, but I think there's some nuances there. Combination therapy we're moving towards that, and I think there's some science I discussed around combining um an anti-TNF with a selective IL 23 inhibitor, and that's been shown nicely with Bega and these therapies are safe in pregnancy. We don't have as much data in our selective IL-23 inhibitors. I've had some patients concerned about that, but across the board, and there's a global consensus that was just published by, uh, Um Mahadevan, these are safe. You could tell the patients are safe. So thank you for listening. Just the last slide summing, summarizing all the dosing strategies that you'll have. So again, welcome to the course and thanks for your time. Published March 28, 2025 Created by
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