Best of 2025 in IBD: Expert Roundtable from Advances in IBD
Drs Marla Dubinsky, Bruce Sands, and Parambir Dulai inaugurated the Open Air Studio at the Advances in IBD 2025 annual meeting with a review of the best research and most promising advances in the treatment of inflammatory bowel disease during this year.
Marla Dubinsky, MD, is Professor of Pediatrics and Medicine (Gastroenterology) at the Icahn School of Medicine and Chief of the Division of Pediatric Gastroenterology at Mount Sinai Kravis Children's Hospital in New York, New York. Bruce Sands, MD, is the Dr. Burrill B. Crohn Professor of Medicine and Chief, Dr. Henry D. Janowitz Division of Gastroenterology at the Icahn School of Medicine at Mount Sinai in New York, New York. Parambir Dulai, MD, is Associate Professor of Medicine at Northwestern University where he also serves as Director of Precision Medicine for the Division of Gastroenterology and Hepatology.
TRANSCRIPT:
Hello, I'm Dr. Marla Dr Dubinsky from the Icahn School of Medicine at Mount Sinai and I'm delighted to be here with my colleagues Dr. Bruce Sands and Dr. Parambir Dulai from Northwestern University Chicago and Bruce Sands, Mount Sinai, New York as well, Icahn School of Medicine. We're here today to talk about the best of 2025 in inflammatory bowel disease. The cool thing is that we are at AIBD, so we really have seen a lot of work that's been presented here today and the three of us are going to share it with you. So let's get started.
First we're going to talk a little bit about I think therapies and what's next and what have we seen in 2025. So Bruce, I'm going to start with you. You're going to tell me what you choose as first and foremost, what you want everyone out there to know.
Dr Sands:
I think in 2025, the most impactful thing that they need to know is about the still relatively new class of agents, the anti-IL 23s. So these antibodies, and there are 3 of them of course—risankizumab, mirikizumab, and guselkumab—are now all approved for Crohn's disease and ulcerative colitis. And they have very broad indications, could be used as first line therapy, as second line therapy. And the wonderful thing about this class of medications is they're extraordinarily safe. So whereas with anti-TNFs, we'd be talking with our patients about risk of infections, potentially serious infections, lymphoma, autoimmune phenomenon, all the things that we are used to talking about for the last nearly 30 years, those are not a part of the conversation when you're starting these medications.
And also some of them are delivered intravenously during induction and then transition to sub-q. Guselkumab is the one that can be given sub-q induction and maintenance. But regardless, the maintenance burden in terms of time is far less. They don't have to get intravenous infusion. It's done at their convenience and it's for each of these medications it's 4 or 8 weeks depending on which agent we're talking about. So I think it brings a lot to the table for our patients, things that they have wanted, safe, convenient, and really quite effective agents.
Dr Dubinsky:
You're right. So the revolution, we had the TNF revolution and then we moved towards really S1Ps, we moved to JAK inhibitors, and if you look at that arrow and everyone shows the slides from 1998 until 2025, very heavy loaded.
Dr Sands:
Yeah, it's very clustered on the right hand side of the calendar.
Dr Dubinsky:
Imagine what's going to happen next and we'll talk about that. What is that graph going to look like in 5 years from now? It's amazing. But in the IL23 space, since all 3 that you mentioned are approved for both Crohn's disease and ulcerative colitis, yesterday was really all about how do you position these therapies and is it different in ulcerative colitis versus Crohn's disease? Meaning does the data suggest that one is a preferred first line, for example, in either Crohn's or UC versus positioning it second line, does it work as well? So how would you sort of share how you think about these IL23s?
Dr Dulai:
Yeah, I mean this question comes up a lot, especially comes up when you have new classes. But I think the way I've sort of thought about it is when do you not position IL23s in a certain spot because they look to have really good efficacy first line. They also look to have pretty good efficacy second line. I think the main questions that come up, are there any differences between the IV or sub-q formulations which we're not seeing in the clinical trials? Are there obvious differences across the IL23s in terms of efficacy, which we haven't shown or seen quite yet? And then when you look at the relative positioning, they do work a bit better first line. And so I tend to position them a bit more first line and I think that's where they're maximized for their value. In the second line position, I think they have good efficacy and they're demonstrating good efficacy and they're in very good position. And in that situation, you're going to factor speed of onset, which looks to be reasonable, maybe not quite as fast as some of our other small molecules, but looks to be pretty good. And then I think in the more complicated patients—fistulizing Crohn’s, stricturing Crohn’s—we want to see a little bit more data to feel like it would work as well as the anti-TNF class.
Dr Dubinsky:
Yeah, yesterday there was a symposium all on sort of where to position or how to think about IL23s. And one of the things that I felt to try and convey to everyone that was there is that IL23s have a real superpower, particularly in UC, in naives. I mean we were seeing endo improvement rates that we had not seen in prior therapies. Granted, maybe there were some outcomes like the HEMI, which is the histo-endo mucosal improvement that may have not been around when prior biologics were studied. But the idea that we're seeing Mayo 0 at rates we had not seen before, so that particularly in the naive population. And there looks to be maybe for Crohn's, some of the data suggests that you could have once been exposed to IL 12/23, ustekinumab, and it looks that that could be an option in Crohn's disease. It wasn't tested in UC, so we don't know the answer flat out based on the trial, and that even patients who had failed in Crohn's, prior biologic 1, 2, 3 classes, you were seeing not as much of a delta between placebo in those exposed versus not exposed.
Dr Sands:
Still very useful efficacy and especially including after primarily anti-TNFs which accounted for the majority of prior advanced therapy use. So I think particularly in that scenario, I think a lot of things work well after one failure. Fewer things work well after two or three failures, but still you see some efficacy there.
Dr Dubinsky:
I think you showed that with the S1Ps, right? We originally at Ozanimod,
Dr Sands:
Right, with the S1Ps, it's very clear after you failed more than one advanced therapy, these agents are much slower onset of effect and maybe you're not going to get there with them.
Dr Dubinsky:
Speaking of oral small molecules, it was a big year for newer oral molecules and the one that we're most close to excitement would be those that are in phase 3. So we're going to talk a little bit about obefazimod. So maybe Parambir you can start and tell us a little bit about how does this drug actually work. It's unfamiliar to us. It's not an S1P, it's not a JAK inhibitor. What is it? Is there anything we can take away to learn more about this drug as we see it come through and await the final phase 3 data?
Dr Dulai:
So obefazimod is a micro RNA sort of up regulator. And I think microRNA are really new to us in the field, but it's actually well known and well established as a master regulator of the immune system. The Nobel Prize was awarded recently to the person who discovered microRNAs and we're now for the first time seeing a therapeutic targeting it. So by targeting microRNA, which is the sort of master regulator of whether a gene translates into a protein which is the end functional unit of the gene, it orchestrates like a symphony whether the immune cell is going to transition towards a healing or a proinflammatory cell. And to have that master regulator be targeted, you allow for some degree of immune stabilization. You're not suppressing the immune cell, you're stabilizing it and transitioning it towards a homeostatic state where it's going to be more healing in theory and you can sort of create that quiescence and that healing process.
So I think with obefazimod and the ability to demonstrate we can actually target these sort of symphony conductors and be able to regulate the immune cell without suppressing their overall function is going to be a huge win for our field. And to see it first in IBD is also a huge win for our field. And so I think that plus a lot of the efficacy that we're seeing in some of the refractory patients, which we can talk about, is quite impressive to start to link the mechanism, the overall sort of drug class that's emerging from it and then the positioning of it as it comes to market.
Dr Dubinsky:
So given what we're starting to learn about this new mechanism, Bruce, you are very close to and presented so far some of the induction data. So maybe share with us what the induction week 8 data actually look like and then maybe we can talk about the safety and whether that MOA ties in a way to safety.
Dr Sands:
So you're referring to the ABTECT 1 and 2 studies, which were phase 3 pivotal trials, 2 induction studies, exactly the same design. They explored a 25 milligram once daily dose and a 50 milligram once daily dose of obefazimod and compared that to placebo. And I should also comment on the patient population that came in. There was essentially no cap on the number of failures that the patients had had. So multiple drug failures, they came in, patients were allowed to be on steroids up to 15 milligrams of prednisone coming into the study. So many patients, about half the patients, had had prior failures and many of them had had multiple, multiple drug failures. So in every respect, a highly refractory population, of course moderate to severe ulcerative colitis.
And when you look at the results, it was very clear that the results were replicated in the 2 studies, especially for the 50 milligram once daily dose that really replicated very well. And so you saw rates or effect sizes that are approaching but not quite what you see with JAK inhibitors, with upadacitinib. So still a very, very useful kind of inductive effect. Now of course, those patients have been rerandomized into the maintenance phase of the study and we don't have those results yet, but we do have phase 2a and phase 2b studies in ulcerative colitis where there was open label, long-term extension— very long-term, there are some patients who've been treated for years. Again, a highly refractory patient population. And if anything in those phase 2 studies, the drug just seemed to get better and better over time. Really remarkable maintenance of efficacy.
And I can comment on the safety as well. So the one safety signal that you do see, and it is a dose-related signal, is headache. And you tend to see that within the first couple of days of treatment. It tends to be short-lived just a couple of days, 2 or 3 days in duration, mild to moderate. For most patients, less than 1% of patients had to stop therapy because of that particular side effect. We don't know why people get side effect, but it didn't seem to be dose-limiting for the majority of patients.
Importantly, what we don't see are infections. We don't see opportunistic infections, certainly in the short term we haven't seen cancers, but also in that long-term experience, open label experience. And after the phase 2 studies, we saw no signals of immune suppression or malignancy or major adverse cardiovascular events. So in all respects, this seems to be well tolerated, safe, once daily, and oral. So it really could add to in an important way to our armamentarium for moderate to severe UC.
Dr Dubinsky:
Moderate to severe uc, whereby it's looking like it has efficacy in very refractory including JAK..
Dr Sands:
JAK inhibitor failure.
Dr Dubinsky:
So that's like I remember the box on that part of the graph.
Dr Sands:
Looked even better.
Dr Dubinsky:
You're like, wow, this is great. Because what I try and explain is that sometimes we use JAK as like this is it. There wasn't anything after JAK typically patients who may have progressed and you see failed TNF times 3, failed integrin, maybe USTE, or more recent IL 23, been through the gamut of biologics. We’re hopeful that JAK works and it may not.
And the fact that there was, even though it was, there was not an insignificant number of patients, actually.
Dr Sands:
That's right. Yeah.
Dr Dubinsky:
It wasn't just 30 people that had failed.
Dr Sands:
Although the majority of those JAK inhibitor patients were tofacitinib-treated, just because of the timelines of the study.
Dr Dubinsky:
True enough.
Dr Sands:
So we don't know for sure after upadacitinib this would also be successful, but I would expect it probably will be, but time will tell.
Dr Dubinsky:
It was interesting. People will ask why week 8 in terms of some of our trials, and we'll talk a little bit about others that have looked at week 12 predominantly, and we'll talk about TL1AA of course, which is the next batch, of therapies that would be coming to the market if positive in their phase 3s was the idea that why week 8? How do we compare as clinicians a week 8 versus a week 12? Does it matter?
Dr Sands:
In the days of old?
Dr Dubinsky:
Okay, yes.
Dr Sands:
Many studies for induction you see actually looked at week 6.
Dr Dubinsky:
Vedo looked at 6.
Dr Sands:
Yeah, veto week, correct. And best example. So I think in this case it was just a wise decision to try to replicate what was done in phase 2a and 2b. They happened to have chosen week 8. It shows you it works pretty quickly and we won't know exactly what it would've been if you continued at week 12, but of course in maintenance you will have patients Continuing
Dr Dubinsky: So
Dr Sands:
Eventually you'll know.
Dr Dulai:
And to that point, I think it can't be understated in terms of the safety because in such a refractory population in our trials, the major safety driving event is disease worsening. And so for you to not see substantial disease worsening in an extremely refractory population and not seeing serious adverse events related to that is another testament to the efficacy of the medication. Because with JAK failures and multidrug failures, you would've expected a much higher rate of those kinds of disease flares.
Dr Dubinsky:
Yeah, because when you think about position, we talked about small molecules, so 70% of patients who went into the etrasimod, so the S1P, were naive, they had not seen an advanced therapy. It was a nice naive, dominant population showing really good efficacy, treat straight through.
Dr Sands:
That's the right positioning for that particular class.
Dr Dubinsky:
That's right. And then we have the JAK inhibitors, which are sort of originally failing TNF, maybe 1, 2. Now the label for upadacitinib, I'm not sure if our audience knows that had been changed. So the label now is a little bit maybe…
Dr Sands:
So hard to understand.
Dr Dubinsky:
It's hard to understand. It leaves it up maybe to us to decide what is failing an approved systemic therapy. A lot of folks ask me, does that mean steroids? Up to you to decide what the label says? And when a TNF would not be advisable? Again, it's hard.
Dr Sands:
It's always been for us to decide what is appropriate.
Dr Dubinsky:
It is a recommendation, you're right.
Dr Sands:
But this gives maybe a little bit more cover for broader use.
Dr Dubinsky:
And for folks that may have been concerned that where to position it, taking these very refractory patients saying this is it, but maybe moving JAK inhibitor as a second option, which is really a nice position. OBE sort of fits right now. Maybe the spectrum, it's not necessarily just in naives and refractory. So I think there's a lot of interest on where this new oral.
Dr Sands:
Wouldn't you love an agent that could be used anywhere in the positioning and hope of success?
Dr Dubinsky:
That's on the oral excitement. There was another oral excitement that I'm excited about personally just because of the IL23, we talked about the IL23 boom over the last recent past really being the big target assets in the market that were coming to the market, came to market. This one is an oral IL23 receptor. You being the basic scientist among us. Do you want to talk a little bit about very high level the difference between this molecule potentially from the sub-q IV IL23s?
Dr Dulai:
Yeah, I think when you get to the point where you're transitioning towards targeting receptors, you're able to get to the end functional effect of the cytokine much more efficiently. And I think all of our large molecule biologics, which are sub-q iv, typically target the cytokine. They try to mop up the inflammatory signal. They may not get all of it. There's discussions about whether some localize better to the site of production versus others. But when you get to the point where you're blocking the receptor, you can do a catchall and really avoid any considerations for missing some of that cytokine sync that we've always thought about with anti-TNF therapy.
And so it is extremely exciting to have an oral drug that actually gets to the receptor at the site of inflammation. And I think the fact that you're seeing efficacy not just in IBD but in other indications is really a testament to the fact that it's not gut restricted, it can get to the sites of those receptors and really shut it off and prevent any activation with good efficacy from the other trials that we're seeing.
Dr Dubinsky:
And in theory, the safety that we're familiar with with the IL23s, the psoriasis data is very exciting. So we'll see what happens with that and if it gets approved. So the phase 2b study was presented at UEGW. So can you talk a little bit about what you think about the results? The primary outcome was clinical response, not clinical remission, but they also met that, again, it wasn't the primary data point, but tell us what…
Dr Sands:
You thought. But they met their secondary
Dr Dubinsky:
They met their key secondary outcome.
Dr Sands:
Clinical remission
Dr Dubinsky:
Right.
Dr Sands:
So I think people were maybe a little surprised that something given orally, and interestingly it's a peptide, I guess it's a cyclic peptide. It's not highly, highly absorbed, but has such affinity for the receptor that even just if just a little bit of it makes into the circulation, it's enough to treat, for example, psoriasis. So it's really an intriguing concept. And the efficacy suggests very much like the parenterally delivered IL23 kind of efficacy. We'll see if that holds up in phase 3. We'll see if it holds up in maintenance. But right now it looks quite good.
And this is in contrast to other attempts to inhibit, quasi inhibit, IL 23, for example, TYK 2 inhibitors. This is a kind of TYK 2 being one of the Janus kinases members of the family, but has a profile that is sort of like IL23 dominant. The example of deucravacitinib, which works perfectly well in psoriasis, really did not work in ulcerative colitis. So this is quite a different result.
Dr Dulai:
And that peptide component is an important part because I think the technological innovation of developing a drug that can be delivered orally and still somehow make it to the site of inflammation when a lot of our other oral therapies haven't shown as much is a huge change for how we start thinking about targeting these pathways. And I think if they're able to bring that forward and work out the process for that and show good efficacy, I think it has an opportunity to really transition a lot of our pathways.
Dr Dubinsky:
Yeah, it's just exciting. I mean, think of all this and then the other small molecule before we get, I think to back to the TL1AAs, and then we'll talk about guidelines. I think there's a lot this year, we had ACG and AGA help us, maybe, and we'll get your opinion on how to position these drugs or who to use them in. So let's talk about oral alpha4-beta 7, the Moprhic data was presented, so talk about that. And Bruce, you were the one who presented, so you are the closest to it. So tell us.
Dr Sands:
Yeah, so MORF-057 is an oral alpha4-beta7 integrin antagonist, and it made it through phase 1b. And this was a 2a study intended to show the efficacy of this drug. And it was dosed orally once daily, sorry, twice daily, actually not once daily, which is one of the limitations perhaps. And it's always hard to extrapolate from study results, clinical trials, whether the study failed because the drug didn't work or because there was a technical failure of the study. And in this case, my interpretation is this was a failure, but it was a technical failure of the study most likely. And the reason I say that is the placebo rates were enormously high, higher than we've ever seen in any other ulcerative colitis study before for clinical remission—if I'm remembering correctly, as high as 27%, just never-seen rates of clinical remission that high. And I think there are probably a number of factors that contributed to that.
But the reason that I think that the drug might actually work is there was a very clear dose response. And when you see a dose response, it's fairly believable. Of course the MOA is not an unknown mechanism of action. It's very believable mechanism of action. And so for those reasons, and if you've looked at the absolute level of efficacy, it was sort of similar to what you expect with vedolizumab, which is the biologic that blocks off alpha4-beta7 integrin. So therefore I think it was a technical failure.
Why did it fail? There's a lot of speculation about that and a lot of postmortem kind of looks at what might've happened. I think one problem was there were some regions of the world that contributed excessive numbers of patients and clinical practices vary in different parts of the world. You never know if patients are using their own prednisone out of pocket. And by the way, there was a cap at 30 milligrams a day on prednisone, which is higher than we've seen for concomitant therapy. That could have played a role as well because it wasn't just the patient reported outcomes that got better, it was also the endoscopies in the placebos. So there may have been that problem where the study was conducted.
And then finally, I just think that investigators may have prior biases about which studies they'll put which patients in. So if you look at the patient population, they were just a little bit on the milder side of moderate than on the severe side of moderate. And that may have contributed as well to the placebo rates. And I think investigators will say if they're sicker patients for something that they have a prior bias is going to be more effective than an alpha 4-beta7. So those are my best guesses about what happened. But I still believe that the drug has the potential to work.
Dr Dubinsky:
And moving forward
Dr Sands:
And it is still moving forward.
Dr Dubinsky:
So I think that gives some confidence that people are always, if only we had an oral vedolizumab or the concept of that safety and efficacy.
Dr Sands:
So there's still a lot of attention to oral alpha4-beta7, not the only one there 4, 5, 7. There are at least 2 or 3 others that are kind of in various stages of study at this time.
Dr Dubinsky:
So TBD. But one thing that we're also very excited about is the three phase 3 studies focused on TL1A. So why don't you tell us about TL1A, its mechanism, what does it do, and why this may be a unique value add to our patients?
Dr Dulai:
Yeah, so TL1A is another cytokine pathway that was identified in the last probably couple decades. So we've known about TL1A for a little while, but what's novel here is that the 3 companies have developed 3 completely different compounds that target itin slightly different ways because it is a trimeric sort of receptor or dimeric receptor or how you think about the receptor. But it has a component of not master regulation, but broader regulation of inflammation and possibly inflammation and fibrosis. And so there's a lot of excitement and interest as to whether the TL1A space could target inflammation and that transition state from inflammation to fibrosis.
And I think the other part that's really exciting about the TL1A class is that they are working on genetic SNPs that may be able to look at biomarkers and some of these considerations for personalization. Because as we've discussed many times, it's really hard to know how to position these therapies. And when you're talking to patients about the 10 available drugs and the 5 new ones coming, how do you relatively position them? And so the biomarker aspect of it and the genetic component of how it might contribute to the expression of it and its interaction with some of these receptors along the macrophage-fibroblast axis is going to be really interesting to watch.
Dr Dubinsky:
Yes, I think as we think about what's the biggest gap that we need to fill in ulcerative colitis, I'd venture to say, and our surgeons have even told us that since the introduction of JAK inhibitors, particularly upadacitinib over the more recent time that their colectomy rates have dropped; one thing they don't tell me is they're not busy enough with ileocecal resection. So particularly ileal Crohn's disease being its own unique sort of phenotype where fibrosis is sort of what happens when you don't heal it or get to it in time.
So Bruce, in the TL1A space, although I think that inflammation and controlling inflammation, you probably improve or decrease risk of fibrosis. That would be my, we've seen it with our current therapies. Although there may be this idea or this concept that wow, this uniquely also directly goes to the fibroblasts and sort of decreases proliferation or decreases collagen deficit, whatever at that moment. Or muscle hypertrophy, which we all do ultrasound. So we know we see that thickened muscular layer of the bowel wall that is probably related to myofibroblasts, et cetera. So tell us a little bit about what the earlier the phase 2 study showed, obviously they were positive, we're moving into phase 3 or they're actively in phase 3. So where do you see, based on the results from the phase 2, where do you see this drug positioning? Like I said, that slide that had everything is going to be really long. So where do we position these drugs pending the phase three?
Dr Sands:
Yeah, I think first of all, we should say that specifically there are 3e agents, neck and neck and neck in development going from phase two to phase three. There's tulisokibart, there's afimkibart, and duvakitug. These are hard to pronounce, but you'll get used to it. And they all showed efficacy in UC and in Crohn's disease with different study designs.
Without going into the details of that, but the level of efficacy in UC was fairly similar to what you would expect for a JAK inhibitor. And the efficacy in Crohn's disease, including in multiple drug failure patients, also looked quite good actually with duvakitug, for which we have the most robust Crohn's disease data, it looked remarkably good. So I think the first thing is it's effective. The safety looks good, at least in the short term. We don't see signal for infection as we might expect with TNF inhibitors. And we should add that this is in the TNF super family, but it is not TNF. And it does not broadly suppress the immune system. So we expect better safety.
And so the efficacy is promising; the durability also, there was some extension out to week 50 for some of these agents, and that also seems to be quite good. We don't yet know relative to each other whether these are very different from each other. We also have a little bit of signal that there's immunogenicity, with the caveat that we're using highly sensitive assays now that pick up the least bit of antidrug antibody. And we don't know if these are impactful in the drug levels. And that will have to be an important thing we follow over time.
Dr Dubinsky:
So one of the things a lot of folks ask is this an antifibrotic? What I say is there's no human data to show that we're reversing fibrosis.
Dr Sands:
There's animal data to show that.
Dr Dubinsky:
Yes, that's why I made the point. No human data. I was at the lab at the animal where the animal did show at that point as it was happening, as it was happen. But the idea that since disease progresses in those that are fibrostenotic phenotypes or folks who do progress regardless of great early therapy, there's still a group. Could this be more, especially in Crohn's disease, small bowel, that's what I'm really excited about. And all the transmural work and other things that will really help us understand ileal Crohn's, is could it prevent further progression to fibrosis?
Dr Sands:
I think that's the key. I think if people are thinking that a drug is going to melt away a fibrotic stricture, I just don't quite believe that yet. But I do believe that it might prevent laying down a fibrosis and progression toward fibrosis. That's going to be harder to establish in clinical trials, of course
Dr Dulai:
And I think that's really important because when you look at which patients actually get started on biologics, particularly with ileal Crohn's, they're often 2, 3 years late and they're later in their diagnosis because they're often asymptomatic, it's a little bit harder to find them. That fibrotic development process has probably already begun. And to have a drug that can come in and kind of arrest that proliferation, that interaction, and allow for the regression of that interaction to start to develop is a huge potential game changer when we think about who our population is that we need therapy for. And when patients actually get to us and the therapies currently don't arrest that transition state. That's sort of already started.
Dr Dubinsky:
And I think you both alluded to it, that in order for us…IBD is not a 52-week disease.
Dr Sands:
I've heard that.
Dr Dubinsky:
Accordingly, rumor has it that it just doesn't stop after a year of a clinical trial. So we need longer, if we're going to talk about arresting progression, we're talking about disease modification. So maybe finally we will get into a place where we could start to look longer. Have we really decreased the rates of ileocecal resection, the way our surgeons are telling us about J pouches?
Dr Sands:
It also means that we as a field need to start working hard to define what we mean by disease modification. What is the exact endpoint composed of that indicates disease modification? It's not so easy as counting lives with cancer, for example, or heart attacks and so on. So we have to come up with that.
Dr Dulai:
And with the disease endpoint, I think we assume that it would be endoscopy, but the REACT 2 trial kind of helped us sort of rethink whether it's a little bit more than just mucosal inflammation. And whether transmural or systemic inflammation, some of these things become more important because in that treat to target for endoscopy, we didn't see an obvious difference when you do an all comers treat to target for endoscopy, but in patients who have elevated biomarkers of inflammation, maybe more transmural systemic inflammation, that's where that aggressive sort of process helps. And I think that's a really important point. We need to find that right endpoint for disease modification.
Dr Sands:
But even things like transmural inflammation or transmural healing are going to be considered by the FDA to be a surrogate outcome, and they do not accept surrogate outcomes unless they're extremely well validated to ultimately translate into something that is impactful to patients. So we really have to work on this as a field.
Dr Dubinsky:
Wow. I mean, this is crazy. This is just all happening in real time in 2025, and we've got an exciting ]26 hopefully ahead of us where we'll see the obefazimod maintenance data. We'll know what's happening next. We'll follow the TL1A closely, the IL23 receptor oral…
Dr Sands:
And combination therapy is something we haven't talked about.
Dr Dubinsky:
We need a whole other hour, but okay, we'll talk. So you mentioned it because that's obviously a very hot topic. Maybe before we get into the guidelines and sort of finish up in terms of what's happened, touch briefly about what we think is going to be in 2026 as it relates to combination therapy.
Dr Sands:
Right. Well, if you recall, the VEGA study really set off a firestorm of interest because this was for the first time one of the earliest studies to look at a combination of 2 biologics or could just say 2 advanced therapies, to see if they're better than either monotherapy alone. We're talking about golimumab, so an anti-TNF approved for UC, and guselkumab, an anti-IL23 now approved also for UC, either one alone or in combination. And of course it didn't meet its primary endpoint, which was clinical response if I recall. But it really doubled the rates of clinical remission and endoscopic response. So the more objective outcomes, really you had a doubling of either monotherapy or additive, you could say.
Now mind you, these were relatively naive patients who had not failed one or the other therapy. And so this is now being looked at in the DUET studies for both Crohn's and UC—the study I referred to was just UC. So 2 separate studies, DUET-CD and DUET-UC, and also includes patients who may have been refractory to one of the component MOAs of the combination. So a sicker, more advanced population, more refractory population. And I think it remains to be seen. I don't know what to expect from the results, but these are highly anticipated results.
Dr Dubinsky:
And so Parambir, just brief from an MOA perspective, do you think one, from a safety, does it make sense to, is it just because we take 2 drugs that we have on our shelves and we combine them? Or is there a sensible combination here?
Dr Dulai:
Yeah, so I think everybody thinks maybe they just grabbed 2 drugs they already had and put them together and sort of delivered it. But the reality is there was a lot of translational and basic science work that was done leading into it. And what you've seen from that basic science work is that when you target one or the other, you have some obvious molecular changes. But when you put the two together, there wasn't an additive—there was just these plus this—it was actually sort of synergistic in the molecular effect that it had almost 5-,10-fold effect more broadly. And so there was a rational reason for putting these two specific therapies together.
And then when you look at the other spaces, particularly when you look at oncology, you start to think about concepts of priming the immune system, transitioning the immune system, forcing it to be responsive to another pathway. And that's what we're starting to think about now with combination therapy. Can you push the disease in a way where then the other drug works really well and capture a broader swath? So I'm very interested with the upcoming DUET, given they have refractory patients, can they reprogram it by essentially doing the combination, changing that broader molecular effect and then recapturing the response to something they were previously not responding to when it's combined with something else?
Dr Dubinsky:
Yeah, no, it's very exciting. I mean even the immunogenicity story for TNFs got better when you combine it with IL 23.
Dr Sands:
That's right. When you add guselkumab, we know all anti-TNFs are potentially immunogenic. Actually the guselkumab functioned in the way that azathioprine, for example.
Dr Dubinsky:
Much safer function with a combination
Dr Sands:
Much safer. Seem to suppress antidrug antibodies to the golimumab.
Dr Dubinsky:
Right? So if I'm going to my clinic tomorrow, which will happen, and I've got a patient walking in that is TNF naive or advanced therapy naive, a patient who is advanced therapy exposed, inadequate responder, maybe 3 of them. I'm going to have you take the guideline approach to naives, maybe summarize.
So we had ACG and we had AGA—2 methodologies, right? The ACG uses GRADE methodology, it's based on level of evidence, the strength of the evidence and obviously, randomized controlled trial, double-blind placebo is the highest level of evidence. So all of our drugs that were studied in phase 3 that were approved basically are approved for and suggested to be appropriate.
The ACG made one position statement, which is that based on a head to head, which was VARSITY— just as a reminder in ulcerative colitis, we have one head to head, which was adalimumab versus vedolizumab—the primary endpoint for the overall population, vedolizumab was superior and met its primary endpoint over adalimumab. But 75% of patients were naive to infliximab basically because it was 75% were TNF exposed, 25%, sorry, 25% were exposed, 75% naive. And when you looked at the exposed, neither ADA or vedo were that great in a TNF exposed patient population in UC.
Dr Sands:
They performed about the same in fact.
Dr Dubinsky:
And both not so great. Which is why we'll talk about the AGA in a minute, but I'm going to as to where they positioned in a failure patient, which I'll come to you, but in the naive and then AGA uses sort of more of that network meta-analysis approach. So tell me how you're using these guidelines. If you were tomorrow seeing, you or Parambir, type of phenotype or characteristic, how are you using these guidelines to make treatment decisions?
Dr Sands:
Well, one thing that the ACG said is adalimumab is not preferred as therapy for ulcerative colitis. So I think we can take that away.
Dr Dubinsky:
Not just in refractory, but naive.
Dr Sands:
Naive, yes, to be very clear. So that's one immediate thing that you can take away from it. The other thing that I think is quite important is they made the distinction that you don't have to go through step therapy in UC to get to deserve the advanced therapy. If you have moderate to severe severity, you can go straight to one of the advanced therapies.
Dr Dubinsky:
You don't have to fail 5-ASA.
Dr Sands:
5-ASA then corticosteroids and azathioprine, whatever else you want to give you can go straight to the effective therapies that are the more modern therapies. Which I think is very important.
Dr Dubinsky:
Very. I think what you're getting at there is that we are using drugs that are approved for mild to moderate UC for patients who meet criteria of moderate to severely active UC. You see, that's why because usually, oh, why not just give them a 5-ASA? Let's see what happens if that doesn't work.
Dr Sands:
Maybe work.
Dr Dubinsky:
Maybe it'll work.
Dr Sands:
And meanwhile the patient is suffering, they're on steroids, they're having these..
Dr Dubinsky:
Suppositories because we think what's big deal when of course patients…
Dr Sands:
It is a big deal.
Dr Dubinsky:
It is a big deal. So that's on the UC side naive. Crohn's disease naive. And then I'm going to get to refractory for both ACG and AGA in a minute. But in terms of Crohn's disease, any nuggets from ACG versus AGA?
Dr Sands:
My general take is everything works okay, first line in Crohn's disease. So it's true in both diseases except for adalimumab as we said, that generally whatever you choose is going to be based on patient preference, convenience, some specific features of the patient. Do they have perianal disease, a lot of small bowel at risk. You'll choose one thing or another, systemic manifestations, but otherwise all of them can be effective. And so it's up to you to make that decision with the patient. That's my kind of integration of everything I think.
Dr Dubinsky:
So my take also. One thing that I was very excited about is that they basically make the case for Crohn's disease moderate to severe, that there is nothing but an advanced therapy approved for moderate to severe Crohn's disease. And we need to stop, literally. I said yesterday in the morning, first kickoff session, I'm like, I'm going to put an ad on in Times Square that says “Stop the 5-ASA Madness” for Crohn's disease. And the AGA took, I mean ACG said a red light, stop using, recognizing that.
Dr Sands:
Could they be more clear?
Dr Dubinsky:
No, that's why I said we need an ad in Times Square. I said New Year's Eve because that's the biggest audience. So I was trying to find where can I get the most broad “Stop the 5-ASA Madness” for newly diagnosed Crohn's disease because it's not approved, it's not acceptable.
Dr Sands:
I'm not even sure why we're still talking about this 30 years.
Dr Dubinsky:
By the way, we're talking about this, Corey Siegel— both of you have a very strong link to Corey—put out a paper last year that said less than 15% of Crohn's patients are getting an advanced therapy in the foreseeable first 3 years after diagnosis.
Dr Sands:
Remarkable.
Dr Dubinsky:
With that like 5-ASA, prednisone, come back if it doesn't work. Meanwhile, what's happening?
Dr Sands:
In the world where the PROFILE study replated these early effective therapies step-up, top-down study that Gert D’Haens did 20 years ago showing that early therapy, and we mean really early, within a couple of weeks of diagnosis of Crohn's disease, if you do combination therapy with infliximab and azathioprine, you dramatically improve the clinical remission rates and all the good outcomes downstream.
Dr Dubinsky:
So they weren't just talking about early, because some people define early as 2 years, the same as disease modification. People sat in a room and thought 2 years is early. Meanwhile, people with Crohn's have had Crohn's for a long time. So 2 years plus 2, 3 years, however long they were smoldering.
So the idea of the PROFILE study said not just in 2 years at diagnosis, within 15 days, a colonoscopy diagnosing you. It showed that it was safer. We had one surgery in the group that got infliximab plus AZA, and that was for gallstones. And we had 10 surgeries in the group that did the step up, which is, oh, let me give you some prednisone. Oh, let me give you some azathioprine. Oh, let me increase your prednisone. Let me try and decrease it again. Let me up your AZA. And then finally get infliximab. Patients are in the operating room with penetrating Crohn's disease is one of the indications for surgery in the “let me take my time step up.”
Dr Sands:
And yet the GI community is so far from adopting that as a general principle.
Dr Dubinsky:
That's where we need to move to. And I think for us to change people's lives, to change our patient's lives, to modify the disease…
Dr Sands:
With the drugs we have
Dr Dubinsky:
With the drugs we have, granted there's a lot of drug development happening, which we're very excited and there are needs, but I think if we could start with the people that are suffering today and be better at prescribing the drugs we have today, that'll help.
So speaking of that, the last word before we say goodbye to everybody, is positioning in the patient who's been exposed to at minimum an anti-TNF. How do you use ACG versus AGA and especially the difference in methodology?
Dr Dulai:
Yeah, so I think both the ACG and AGA guidelines are helpful and complimentary to each other. When we think about prescribing and use of our advanced therapies, there's the patient, the prescriber, and the payer. And so I think the ACG guidelines are going to be extremely helpful for our clinicians to push back against the payers for being able to advance therapy early, start early, avoid mesalamine, really position early, and help them feel confident in that decision.
But then the other part of it is the patient prescriber decision on what to use. And so I think both guidelines make an attempt to provide some framework for that conversation. And that's how I kind of take both. It's a framework. It's not a “you have to do this, you need to do this, you can't do this.” It's a framework and at the core of it, whatever drug the patient's willing to start that's safe and effective for them is the one you should start.
Now, if you think about the ACG and AGA guidelines, how they provide that framework is a little bit different, right? The ACG, I think the guideline heavily weights direct comparative trials, which are few and far between, clinical judgment, some of those considerations. The AGA takes a bit more of a data-driven approach with network meta-analysis, and network analyses are great for trying to summarize the efficacy. But as Bruce alluded to earlier, there are differences in placebo rates across trials as you alluded to, there's difference in time points for endpoints. Those things influence the comparability of across trials.
The one thing that the AGA has done, which is really incremental to what they did before, is they started tiering the medications the best they could. To give you a sense of what you should step first with your conversation, what do we think are going to be the most efficacious that you should really emphasize? And then saying, okay, if you'd like to start a different one, here's potentially some drop off in efficacy to help shape that patient provider conversation. So in an anti-TNF exposed patient, I think the JAK inhibitors in the IL 23 class, which both guidelines support, are probably the best positioned in there. And I don't think anybody would argue with that. And I think it reaffirmed our ability to use them and it reaffirmed that they are higher tier. They're the ones that you really should be leaning on in that position because at that point you want to maximize onset, you want to avoid them getting worse, and you want to make sure you achieve that because it might be your last option before you think about surgery.
Dr Dubinsky:
A hundred percent. Wow. I mean, I think we could do this all day, but we're going to have to call it a day. So I want to thank everybody, all the audience for sticking with us and hearing about all the exciting research and data that we've learned in 2025, and we look forward to an amazing 2026. And thank you.
