Good afternoon and welcome to the Equillium virtual KOL event. At this time, all attendees are in a listen-only mode. A question-and-answer session will follow the formal presentations. As a reminder, this call is being recorded and a replay will be made available on the Equillium website following the conclusion of the event. I'd now like to turn the call over to your host, Bruce Steel, Chief Executive Officer at Equillium. Please go ahead, Bruce. Thank you very much. Good morning and/or good afternoon to everybody for joining today. We greatly appreciate you taking your time to learn more about the Aryl Hydrocarbon Receptor and our EQ504 program. We will, during the course of the day at the company side, be making potentially some forward-looking statements, so we refer you to our disclaimer here. We are very pleased today to have doctors Francisco Quintana and Dr. Brian Feagan, who are experts in their fields covering immune-mediated disorders and gastroenterology, respectively. We will be discussing an overview of the Aryl Hydrocarbon Receptor and why this is such a compelling drug target across a range of potential immune-mediated diseases. Obviously, our focus as a company with EQ504 will be directing this program initially into the treatment of ulcerative colitis, where, despite an enormous amount of investment in many approved drugs across different modalities, there remains a very high medical need, with remission rates remaining still below 30% despite available therapies, so very pleased to have this opportunity and for you joining the team. Importantly, my colleague, Dr. Steve Connelly, who will be leading our overall event today, and so we appreciate your time. I will turn this over to Steve, and as discussed, we will have time following the presentations for Q&A to address questions you may have towards the end of the session. Thank you very much. Thanks, Bruce, and it's my pleasure to introduce our first speaker, Dr. Francisco Quintana, who holds the Kuchroo Wiener Distinguished Chair in Neuroimmunology at Harvard Medical School and is an associate member of the Broad Institute of MIT and Harvard. His research investigates signaling pathways that control the immune response, and he's most well known for his research into the Aryl Hydrocarbon Receptor. Key contributions in this area include the role of AHR in modulating effector and regulatory T cell functions through both IL-10 and IL-22, which both play a really important role in mucosal immunology. As an advisor, Dr. Quintana was also involved in the development of Tapinarof, as we know, VTAMA, the first FDA-approved AHR modulator for the treatment of both psoriasis and atopic dermatitis. Overall, Dr. Quintana's research in immunology has resulted in over 230 peer-reviewed articles and book chapters. I'll hand it over to you, Dr. Quintana. Thank you so much, Steve, for the intro. So, what I'm going to do today is actually to give a brief overview on the role of the Aryl Hydrocarbon Receptor, or AHR, and its relevance and importance as a candidate target for immune regulation. So, the way we found AHR was actually starting with the very basic question, right? We know that the immune system has, you know, accelerators and brakes, right? It has mechanisms that regulate its activity. So, our idea was to come up with a novel method to identify unique regulators of the immune response, and in particular, regulators that could be targeted therapeutically. So, in order to do so, we decided to take an unorthodox approach at the time. We decided to develop the zebrafish as a model where to study the genetics of autoimmune disease and also as a model where to identify regulators of the immune system. At the time, we were probably the first ones doing that, and that led us to identify the Aryl Hydrocarbon Receptor, AHR, as a unique regulator of the balance between effector and regulatory T cells. And that initial study was published in 2008. And over the years, we have actually kept studying the role of AHR in the regulation of the immune response and actually extended our initial investigations to define the effects of AHR directly mediated via its signaling within T cells, but also via its signaling in other disease-relevant cells, not only in the context of autoimmunity, but also in the context of infection and tumor responses. So, first of all, what is AHR? How does it work? When you want to think, when you think about AHR, the easiest example I can give you is actually to think about the signaling that we know is mediated by steroid receptors. And what I mean by that, AHR is a protein, right, that when inactive, it sits as part of a complex within the cell cytoplasm, complex with other proteins. Now, one important thing about AHR is that it's a ligand-activated transcription factor, meaning that under most circumstances, if there's no ligand, if there's no chemical that binds to AHR, nothing happens. However, when AHR binds its agonists, and we're going to discuss them briefly, what happens is that AHR undergoes a conformational transformation. It actually is released from this protein complex that keeps it in the cytoplasm, and then it migrates into the nucleus where it binds to specific regions of DNA in order to control the expression of specific genes. So, here, what we are talking about is a gene or is a protein that is activated by small molecules and can control the expression of genes relevant for the regulation of inflammation and the immune response. So, the moment we found that, we thought this was a very exciting target because we immediately thought potentially you could design small molecules, chemicals that regulate the activity of AHR and hence regulate the expression of inflammation autoimmunity-relevant genes. Obviously, when AHR is activated, there are multiple mechanisms that act as negative feedback loops, right, like to suppress its overactivation. The simplest one is that actually AHR is degraded. Also, AHR-activating chemicals, right, agonists or ligands that activate AHR also degrade. What I just showed you is the canonical, is the classic way by which we understand AHR controls the immune response. However, there are additional mechanisms that have been described, yet it's not very clear how important they are for the regulation of the immune response. The simplest one to consider is that, as I mentioned, AHR is part of a complex, a protein complex in the cytoplasm, and one of those proteins is actually a kinase. So, when AHR is activated and then is released from this complex and goes into the nucleus, this kinase is actually released, and then it triggers a cascade kinase that can also mediate some of the effects of AHR associated with inflammation. In addition, AHR can trigger the degradation of some proteins, and that could help, for example, in the balance between pro and anti-inflammatory T cells. And finally, what we have shown is that also AHR establishes complexes with other transcription factors that are central for the regulation of the immune response. For example, it regulates the activity of NF-kappa B, which is your classic transcription factor driving pro-inflammatory responses. By binding to and interfering with NF-kappa B-driven transcriptional responses, AHR directly suppresses pro-inflammatory gene expression. As I mentioned, AHR is a ligand-activated transcription factor. So, what about those ligands that activate AHR in the context of physiology? Well, those ligands are provided by multiple sources. Some of them are provided just by the diet without any further processing, as it has been shown to some ligands or small molecules provided by the diet. In addition, our own metabolism, right, the host metabolism can produce multiple AHR agonists. Many of them are actually associated structurally and in their synthesis with tryptophan because one characteristic we know is that AHR ligands, they have to have a certain planar structure to really fit into the pocket that it's needed for AHR activation. One of those ligands produced by the host is called ITE, which we and others have investigated extensively, particularly in the context of the ability of the gut in order to limit inflammation, and with regards to the gut, another important source of AHR agonists is actually the gut microbiome. It has been shown that the gut microbiome can actually process and metabolize dietary components. For example, it can process tryptophan in order to generate additional tryptophan metabolites, which act as AHR activators, as AHR agonists, and by doing so, limit inflammation. Now, when we think about the effects of AHR in the gut, right, as we are talking about today in the context of inflammatory bowel disease, which are the cells that are known to be responsive to AHR signaling? I'm not doing that. Just one sec. Somehow I'm not in control. If you could direct me to my presentation. Yeah, bear with us a second, and I'll try to get back to that. So, when we think about the gut, right, and the potential use of the gut of AHR to regulate gut pathology, to treat gut pathology. So, I think that one of the advantages and a unique characteristic of AHR is that it can control both immune cells, right, cells that are known to promote inflammation, but also non-immune cells, cells that are actually targeted by the inflammatory response. When we talk about the immune cells, right, in the gut, we talk about your classic T cells. Both effector and regulatory cells are responsive to AHR, and we're going to discuss that. As you know, T cells, in order to be activated, they require what we call antigen-presenting cells, for example, dendritic cells and, up to a certain extent, macrophages. Both of these cell types, dendritic cells and macrophages, are also regulated by AHR, and we're going to discuss it, and in addition, AHR also controls innate lymphoid cells, which are a type of immune cell, innate immune cell, which is very important for the regulation of gut pathology, for example, via the production of the cytokine IL-22. In addition, AHR also controls central, extremely important components of the gut that are relevant for gut physiology and pathology: epithelial cells, goblet cells, which are important for the production of mucus, Paneth cells, which are important for the production of antimicrobial products, and also the stem cells that give rise to many of these cells. Why is that important? Because now, if we have the appropriate AHR ligand, the appropriate AHR activator, we can modulate both inflammation in the gut and also the ability of the gut to heal, to regenerate after inflammatory pathology in the context of inflammatory pathology. So, when we look into the effects of AHR in these innate immune and non-immune components of the gut, I think that there are two cytokines that we and others have shown are central for its ability to control gut pathology. On the one hand, IL-10. IL-10 is a classic cytokine thought to be anti-inflammatory, known to act on immune cells. In other words, IL-10 is produced by cells of the immune system and usually acts on other cells of the immune system in order to suppress inflammation. In the specific context of AHR in the gut, IL-10 or AHR-driven IL-10 production has been shown to limit pro-inflammatory responses in macrophages and dendritic cells, also to limit the pro-inflammatory activity of Th1 and Th17 cells. Indeed, something that is very notable is that we described that AHR drives the differentiation of a specific subset of T cells, which are called TR1 or type 1 regulatory cells, which actually produce IL-10 as a way of dampening gut inflammation. In addition, IL-10 is important to limit not only what we would call autoimmune or self-inflammatory responses, but also to modulate our responses to the commensal flora. We do not promote or react with excessive pro-inflammatory responses to our own microbiome. In addition to IL-10, AHR drives the expression of IL-22, which is extremely important in its ability to control the activity of non-immune cells. To put it short, IL-22 is a cytokine that acts on non-immune cells to promote barrier integrity and barrier repair through multiple mechanisms, and those are associated, for example, with the establishment of tight junctions between epithelial cells. Actually, it's important to promote the proliferation, survival, and repair of those epithelial cells and actually promote wound healing after inflammatory damage, and finally, IL-22 is also important in driving the production of antimicrobial peptides that are going to keep pathogens at bay in the gut. Now, how can we get a little bit more into the effects of AHR in the regulation of autoimmunity or, in particular, of gut inflammation? Well, what AHR does is it acts both in parallel. Its activation regulates both the activity of innate immune cells and adaptive immune cells, in particular, T cells and the innate immune cells that activate them. The classic activator of T cells or autoimmune T cells, pro-inflammatory T cells, is the antigen-presenting cell, in this case shown here, dendritic cells. Dendritic cells control the differentiation and activation of T cells via the production of cytokines. What we and others have shown is that AHR signaling in dendritic cells, first of all, promotes or drives the expression of cytokines such as IL-27, which are known anti-inflammatory cytokines. These are cytokines that are going to drive the differentiation of anti-inflammatory cells and actively suppress the differentiation of pro-inflammatory cells. Similarly, AHR can drive the production of metabolites that will do the same. They will promote the differentiation of anti-inflammatory cells while suppressing the activation of pathogenic T cells. In addition, AHR also acts directly on regulatory T cells, both those expressing FOXP3 and those producing IL-10. When it does so, AHR stabilizes these anti-inflammatory T cells, these regulatory T cells. It makes them resistant to pro-inflammatory environments so they can still bear anti-inflammatory activities. Indeed, AHR also drives the expression of molecules that mediate anti-inflammatory mechanisms. AHR drives the expression, for example, of a molecule called CD39, which is very important for our ability to regulate pro-inflammatory responses in inflamed tissues, for example, in the inflamed gut. In addition, AHR activation can directly drive the differentiation of pro-inflammatory cells into anti-inflammatory cells. Indeed, it has been shown by us and others that AHR activation in a classic pro-inflammatory cell in the gut, Th17 cells, can actually drive the differentiation into anti-inflammatory cells that produce IL-10. And one of those works, or one of the works describing that, it's a beautiful paper published in Nature by Rick Flavell. So, now, in addition to its effects on T cells, right, if we step back, what does AHR do in the gut and when does it do it? First of all, AHR activation in the gut is part of homeostasis. In all of us healthy humans, AHR is constantly tonically activated in the gut by, as I mentioned, endogenous metabolites, metabolites produced by the gut flora, metabolites produced by the diet, and that results in the production of IL-10, IL-22, which basically keep pro-inflammatory responses under control. This also actually promotes the repair and promotes the health of our epithelial barrier. On top of that, AHR also will act on additional non-immune cells of the gut in order to promote stem cell health, goblet cell health, so on and so forth. Now, one important point I want to highlight is that when you target AHR, right, not only do you deactivate pro-inflammatory responses, not only do you promote anti-inflammatory responses, you can also induce beneficial activities in non-immune gut cells, in particular, stem cells. In particular, it has been shown that AHR activation by multiple ligands can promote stem cell development, can promote their differentiation into goblet cells, can promote the production of mucin, and what is important also can induce all those activities while keeping at bay potential detrimental effects of stem cells such as their malignant transformation. AHR in stem cells really operates as a regulator promoting tissue repair while at the same time limiting the occurrence of malignancy or malignant transformation. All of these, all of these functions, right, have prompted or suggest that we can actually exploit these homeostatic mechanisms in order to treat autoimmunity. As I mentioned, we and others have shown that the gut flora and other sources activate constantly AHR in the gut. What is important to mention is that that regulates inflammatory responses, that regulates also responses mediated by non-immune cells. The last point I want to make is that these responses occur not only in the gut, but can also permeate or benefit other tissues. For example, we have shown that some of these AHR agonists, right, can also make it to several tissues, including the brain, just to give you an example of how far away they can go in order to limit inflammation. Why is that important? Because although obviously the initial focus is to develop AHR agonists that treat gut inflammation, you might foresee in the future targeting this pathway also to limit inflammation outside the gut, for example, in the CNS. So, just to summarize what I told you today, basically, AHR is a central regulator of inflammation and pathology, and it does so by acting both on immune and non-immune cells. AHR limits pro-inflammatory responses, promotes the reestablishment of the epithelial barrier, and actually regulates intestinal stem cell function. The combined effects on these three important components of gut physiology and pathology identify AHR as an attractive target for therapeutic intervention, and as we are going to hear later on, this is a target for which we already have clinical validation. The last point I want to make, although initially you might want to focus on the gut, you might foresee developing a pipeline with applications for inflammation and autoimmune diseases in other tissues. Thank you. Thank you very much, Dr. Quintana. A really helpful overview there of the AHR pathway. Now, I want to remind listeners that we will have a Q&A session at the end, but for now, we'll move on to our next speaker, Dr. Brian Feagan, who's Professor of Medicine at the Schulich School of Medicine and Dentistry, a gastroenterologist at the London Health Sciences Centre, and Senior Scientific Director at Alimentiv, formerly Robarts Clinical Trials Inc. As a gastroenterologist with training in clinical epidemiology and biostatistics, his research has focused on the design, conduct, and execution of large-scale randomized controlled trials in both Crohn's disease and ulcerative colitis. And over the past 30 years, he has been the principal investigator for over 140 randomized controlled trials. His research has been devoted to the development and validation and optimization of outcome measures to assess the efficacy of novel therapeutics in both ulcerative colitis and Crohn's disease. As such, Brian's deep experience in the development of therapies for inflammatory bowel disease, and despite the war scars that that carries, he remains passionate and optimistic about the early stage development of novel therapeutics that could improve outcomes in inflammatory bowel disease. Brian, over to you. Well, thank you, Stephen. I've been charged with giving a brief tour of therapeutics in 2025 in 10 minutes, so this will be somewhat superficial, but I'll try to do justice to the following topics, and that is just to give you a state-of-the-art, state-of-the-union address of IBD therapy in general, try to speculate where we're headed, and then summarize the opportunities that are available for new compounds. So, if you're a cynic, this is kind of a litmus test. Is the glass half full in 2025 or half empty? I am a bit of a cynic, and I start out with that case by saying that here we are, 30 years beyond the introduction of TNF antagonists, and in the best of cases, in a naive patient, we're lucky if we get 50% of patients in remission, and if a patient has failed advanced therapy, the numbers are very low, so if you're concerned that the needs are all met in IBD therapeutics, that's definitely not the case, and another problem is that personalized medicine, which has been so transformational in oncology, has failed rather spectacularly in IBD therapeutics. Unfortunately, in 2025, we still don't know the basic causes of IBD, ulcerative colitis and Crohn's disease, so we're kind of fighting with one hand tied behind our back given that situation. Now, on the positive side, we've developed multiple MOAs. We have multiple drugs now, and we have two MOAs that many other clinicians who treat autoimmune disease would give their right arm for, and that is anti-integrin therapy and vedolizumab and 12/23, and these are completely safe molecules, so the message being, we don't have to have systemic immunosuppression to treat IBD, and we must be doing something right because surgical rates have fallen in both UC and Crohn's disease, and there are many more MOAs on the horizon, so where are we headed given that background, and I'll talk about horizon agents, and it's hard to ignore the TL1As, and important distinction, this is not TNF. This is a regulatory cytokine, which broadly serves to amplify the immune response, and it affects many T cell pathways and may have an antifibrotic effect, and we've seen now multiple trials. This was the initial experience with a synthetic control group, which is actually the Roche drug currently. Generally, in patients who have severe UC, and these are the type of patients who go into new chemical entities, we see clinical remission rates between 5%-20% at the outside and a good, well, that's in a naive population at the very extreme. With an effect size of 30 plus, it is about as good as we get with our conventional agents. This signal was replicated in a study we just published in the New England Journal back a few months ago in a controlled study with the drug that was acquired by Merck, tulisokibart. Here we see very consistent data. Again, we now have data from Crohn's disease with the Teva compound confirming activity in Crohn's disease. So, there are, last count, I stopped counting at about seven TL1As and very high chance of success given the background. Now, alternatively, oral alpha-4 beta-7 would be a great addition to our therapeutic armamentarium because vedolizumab has been a very successful drug, completely safe, effective in ulcerative colitis and in many other conditions as well. So, unfortunately, our initial experience with this. This is Morphic data showing that you can get receptor occupancy with the alpha-4 beta-7 positive T cells in peripheral blood with this compound. But the initial experience, which was just reported at ECCO, a phase 2A study failed with a dose that saturated the receptor. The trial had a very high placebo rate, and maybe we can come back to that in the discussion. It's something that we thought we had completely under control in UC trials, but we're finding there's still exceptions to the rule. Now, I wanted to talk about the 23s because this has been a very important new intervention in Crohn's disease, particularly, and you're all familiar with the psoriasis story where 23 has been transformational, surpassing the experience with ustekinumab, which is a very good drug and superior to TNF antagonists, so we hope that this would play out with Crohn's disease, and in fact, it has with regard to the agents. There are now three agents approved, I'm just showing some data for induction in risankizumab, where we're seeing better induction results for endoscopic endpoints than we've seen with our traditional agents, and this is just the initial, I showed you the phase two data. These are the phase three data, and this drug is now being broadly used in Crohn's disease, where arguably it's a preferred agent. That raises the issue. Well, could you get oral therapy with this? J&J has developed an oral peptide for psoriasis targeting IL-23, and they've released a press release. Again, at the ECCO meeting, sorry, at the UEGW meeting a few weeks ago, they showed positive results in IBD therapeutics. This is very attractive to think about partnering for other agents. The newest MOA is RNA silencing, and this is obefazimod. We previously have seen positive phase 2 data, and there has been a press release from the phase three program where two independent induction studies were positive with an effect size similar to what was observed in the phase 2b study, with no safety signal at this stage in the game. Now, it's still early days, but on the basis of those data, the three positive induction studies, I would say the chance of failure in maintenance is very low, less than 5% for sure. So, this will be potentially a new agent oral therapy. But having said that, none of our existing monotherapies really have turned the corner, and we've had ways of really dealing with that in other conditions in GI, and hepatitis C therapy would be a good example, where combination therapy over a period of many years actually evolved to cure the condition. So, this is a potential example of how we improve the current situation, and we have a very good example where the combination of azathioprine and infliximab in both Crohn's disease, the SONIC results shown here, and in ulcerative colitis, SUCCESS has shown additivity. That's led us to explore additivity with biologics, and J&J probably pioneered this area, guselkumab, golimumab, and you see the VEGA study. Here we see the results for response and remission at week 12, where we get clear additivity. This has been followed on by a phase 2b study in both UC and CD, exploring this concept with exposure to both agents out to a year. This readout will occur in the first half of next year, and this should really either put a damper on the enthusiasm for combination therapy or just fuel the fire. I just wanted to come back with TL1A. The notion that it is antifibrotic is a very intriguing one. Fibrosing Crohn's disease, fibrous stenosing disease is a signature of Crohn's disease, and we have no current therapies that are validated for that purpose. TL1A will be explored in that indication. Recently, we've seen a signal from Agomab with an ALK-5 inhibitor where there's direct interference with TGF beta, which is the cardinal cytokine in fibrosis. This is very encouraging that we've seen an initial signal that maybe antifibrotic therapy is possible, and that's quite a breakthrough. I'll just conclude. We have multiple new agents. However, they have their limitations. I've talked about the horizon agents and apologies if I've left off your favorite agent. Combination therapy is the new black. I think there's two competing visions of this: oral polypill, however, Gilead model for many years, or extended half-life fixed dose combination monoclonals that you could envision dosing a couple of times a year. I don't know which of those visions is going to play out. I suspect they're mutually compatible, and we'll have to see. There's certainly huge opportunities for new MOAs to provide novel combinations. Overall, the future is complicated, but bright. I'll close there. Thanks, Dr. Feagan. Appreciate that overview. We can dive deeper into some of those concepts as we think about meshing new MOAs, combinations, and/or how one tackles the unmet need here in the Q&A session. Maybe with that, we'll move on to EQ504 presentation that I'll give myself. I'll try to give you an overview of really what we're trying to do with EQ504 on a background that has already been fleshed out in terms of mechanism of action by Dr. Quintana, as well as really where the need is in ulcerative colitis. Now, we've already talked about the MOA. We've already talked about the need. Let's just dive straight into it. The modulation of AHR is actually clinically validated in both skin and GI disease. On the left-hand side, you can see VTAMA or tapinarof, which is an AHR modulator, which is administered topically as a cream, and that's been able to derive biologic-like efficacy in both psoriasis and atopic dermatitis. Really moving the needle for something that is a small molecule applied topically and having biologic-like efficacy. It's really that perhaps dual mechanism of the modulation of the inflammatory component as well as the barrier function that leads to such profound results there. Now, similarly, in the field of inflammatory bowel disease and ulcerative colitis, there have been multiple phase two trials conducted with a botanical called Indigo naturalis, which is actually enriched for AHR agonists such as indirubin. This has been tested in multicenter placebo-controlled trials. In one of those trials, they saw clinical remission rates up to 50%. More recently, in a study conducted at Stanford University in patients who had failed multiple lines of biologic therapy, combinations of biologic therapy and/or JAK inhibitors, what we call perhaps refractory patients, there was a 27% remission rate at week eight. Now, those studies are highlighted here in these three panels. The first study by the Naganuma Group, that was in Japan, a multicenter trial, placebo-controlled dose-ranging study, and they saw over 80% clinical response rate and a 50% clinical remission rate. Now, in the more recent study where that botanical was then added to an enterically coated capsule to deliver that drug directly to the colon, they saw a 90% clinical response rate and a 42% placebo-adjusted clinical remission rate. So, again, very strong clinical remission rates indicative of endoscopic healing, mucosal healing driving the scoring there. And as I pointed out, there was a small open label study conducted at Stanford University by Saki et al. And what they showed there in patients who were failing multiple lines of therapy and/or combinations, that they too were responsive to Indigo naturalis or AHR modulatory therapy, and that 27% of those patients who were considered treatment refractory achieved clinical remission by week eight. And in many of these studies, not only did they show clinical remission, but they correlated that with induction of AHR pathways by induction of CYP1A1, as well as showing that there were increased levels of IL-22 in those patients. Now, let's talk about EQ504. So, we talked about the wide variety of ligand sources here. Some of those are exogenous unnatural chemicals, and some of them are endogenous natural chemicals. And really what we have in EQ504 is an analog of ITE, a molecule that's a synthesis of tryptophan and cysteine. It's made in the guts and lungs of humans, and it's a very strong inducer of T regulatory function through IL-10, as well as reducing Th17 cells and cytokines. And the really important element here, as we've discussed, is it's a very strong inducer of IL-22 in tissues. Now, EQ504 is very potent in its activity. And on the right-hand side, you can see in a reporter assay here comparing the potency against Indigo naturalis, shown in blue. And Indigo naturalis is at the 16-to-1 indigo-indirubin ratio that was described in the Stanford University study. So, this is a synthetic surrogate. And that EC50 there is about 138 nanomolar, whereas the EC50 of EQ504 is subnanomolar at about 0.67, which makes it, alongside Eli Lilly's AHR agonists, some of the most potent AHR agonists developed de novo to date. So, let's quickly highlight some of the key elements of the mechanism that are related to the mucosal homeostasis. So, I've not listed all of the cells and pathways that are important here, but a few that I want us to function on that I think are really important when we consider ulcerative colitis. And that is that on the immune cell side, EQ504 can modulate both macrophages, and it reduces pro-inflammatory cytokines and activity of inflammatory M1 macrophages and polarizes them to an anti-inflammatory subset of macrophages listed as M2. And here we see high levels of IL-22 secreted from these macrophages in situ amongst these epithelial cells. Now, on the T cell side of things, we can boost T regulatory cells. And I'll show you some data here in just a moment, where we can induce T regulatory cell number, frequency, and function, more specifically in its ability to induce this expression of IL-10 and IL-22. Now, not shown here, but published by Equillium at various conferences, is our suppression of TH1 cells and cytokines, as well as the induction of IL-22 from TH22 cells. Now, on the barrier function tissue repair side, we know that modulation of AHR via activating ligands can maintain barrier protection by inducing tight junction maintenance, mucus production, as well as regenerating those cells that have become damaged to accelerate wound healing and repair. And really, there's a very intricate crosstalk between IL-10 and IL-22, the immune component and the tissue component that maintains immune homeostasis in tissues. Now, one of the experiments we conducted is an epithelial wound healing assay. So, we take intestinal cells, we score them, and then we add either a PBS vehicle or EQ504 or indirubin, the active component of Indigo naturalis. And what we see shown here is that those AHR modulators are able to induce CYP1A1, so that's a positive activation marker. And then from a wound area, so sort of think about this as the sort of clinical endpoint of this assay, which is how quickly and how deeply can you repair tissues, the AHR activators are able to induce much stronger, much quicker wound healing of those intestinal cells versus vehicle alone. And commensurate with that, what we see when we look at those cells is that they're expressing high levels of IL-22 receptor alpha to absorb and take on that IL-22 cytokine expressed in that milieu. Now, on the cell side of things, we won't go into all of the cell subsets, as I pointed out, but perhaps we'll talk about T regulatory cells, given that this is the recipient of the Nobel Prize this year, and we're very lucky at Equillium to have Dr. Fred Ramsdell, who is one of our founding advisors, who won the Nobel Prize this year for T regulatory cells as an important contributor to this work. That is, when you take naive T cells and you add AHR agonists to these, you can induce T regulatory cells. And here we're looking at the CD39 high, TIGIT high T regs, and we can see that compared to vehicle alone, we're strongly inducing the frequency of those T regulatory cells. We've shown in assays, not shown here, but published, that these T regulatory cells have greater suppressive effects against Th1 and Th17 cells, reducing their frequency and pro-inflammatory cytokines. Now, when we take those T regulatory cells and we look at the cytokine output, again, we're seeing very strong induction rates of both IL-10 and IL-22, the green for EQ504 and the blue for indirubin, again, the active component in Indigo naturalis. The take-home message from here is that from the regulatory perspective in GI cells, we can induce regulatory function and suppress effector function. A classical model that's often conducted for ulcerative colitis or IBD in general is the DSS colitis model, where mice will ingest a chemical that causes colitis in their GI tract, and then you intervene to see if you can rescue this phenotype. Now, we've compared here against Cyclosporine, which is, you know, generally considered the molecule of last resort clinically at high clinically relevant levels. We compared against indirubin at 10 mg per kg, which is the published data dose out there from folks who've studied this. And we did a dose-ranging study where we identified one mg per kg as the effective dose of EQ504 in this model. And that's about equivalent to a five mg total in humans. And what you can see on the right-hand side, namely body weight change, which is one of the classic outputs here from in-life and terminal at the termination of the mice, is body weight. And those who just get vehicle lose a lot of weight, up to 20% before those animals are sacrificed. But if you intervene there with Cyclosporine, indirubin or EQ504, you can see that you can protect those mice from weight loss. And if we look at the tissues, and this is very similar to what we aim to do in our clinical studies, if we look at those colon tissues in those mice, those treated with vehicle have no CYP1A1 induction, indicative of no AHR activation. The same can be said for Cyclosporine, no AHR activation. But when you look at indirubin or EQ504, you see strong levels of target engagement of AHR. And similarly, if we look at IL-22 expression or IL-10 expression, the AHR activators, you see large amounts of IL-10 and IL-22 expression, certainly more so for EQ504 in this particular experiment. Now, that's important because these are the key drivers, we believe, of efficacy and activity in this model. When we look at the histology, one of the perhaps more intuitive ways to think about this is what's actually happening to those tissues. This is vehicle. We see a lot of lymphocyte infiltrates. We see a lot of crypt structure, hypertrophy, edema in these colon tissues, mucosal erosion, and just an enormous amount of lymphoid aggregate and infiltration. But in the cyclosporine treated positive control, you can see that there's reduced lymphoid aggregation, the morphology is preserved, and those animals are losing less weight. Similarly, when we think about EQ504 administered at one mg per kg in these animals, we see, again, preserved morphology of the crypt and villi. We see reduced lymphoid aggregate and a preservation of weight in those animals. Now, moving on, one of the things that we aim to do with EQ504 is deliver this molecule directly to the colon. I'll talk in just a moment about how we intend to do that. This is an experiment where if we give the molecule orally as a suspension via the oral gavage, or we take rats and we cannulate them and we deliver it directly to the colon, is that by delivering it directly to the colon, we can create higher peak exposures in colonic tissue versus the peripheral blood versus oral. That's intuitive. When you give a drug orally and it goes systemically, then you're going to be out into the peripheral blood and eventually into the colon, whereas if you give it directly to the colon, you can create higher peak tissue exposures before that then subsequently moves into the systemic at typically much lower levels. Now, how we intend to do this in humans is nothing new. People have been using enteric coating and targeting mechanisms for many decades. In fact, many of our conventional therapeutics in the field of IBD are already enterically coated and directed to the colon, so by using tried-and-tested, clinically and commercially validated technologies, we will formulate EQ504 to deliver directly to the colon to start dissolving at the ascending colon through the transverse and through the distal colon regions, and by doing this, we hope that we can optimize dosing in the target tissues to create higher tissue levels and lower systemic exposures, and that's what's shown on the right-hand side, is that when you give a drug conventionally and systemically, that drug will naturally diffuse out ubiquitously, whereas if you can give a drug enterically coated targeted to the colon, you can create these higher local tissue concentrations with much lower levels of systemic exposure. And so this hopefully will manifest in our ability to deliver a drug that has a greater potential of engaging the target more fully in those colon tissues with a much lower level of safety and tolerability challenges that may occur, as does with any drug. Now, how we think about this molecule to Dr. Feagan's sort of overview here is where is the state of play and where is the opportunity for drugs? We don't have a panacea drug where we have a functional cure like we do in things like psoriasis. And so there's still a lot of opportunity in a field that is typically treat to target. And so the classical place that an oral molecule will be deployed is an oral prebiologic. A molecule like EQ504 that is oral, GI targeted, and non-immunosuppressive makes a lot of sense to deliver this after failure of conventional therapy or potentially in combination with conventional therapy to those patients who have more severe disease. Now, what we've seen additionally in the studies like the Stanford University study, where you're looking at patients who failed multiple lines of advanced therapy and/or combinations or JAK inhibitors in that advanced therapy category, you can still drive fairly compelling rates of clinical remission, suggesting that this molecule does have enough in its mechanistic armamentarium to be able to attenuate very severe treatment refractory disease. You could anticipate that this molecule could be deployed in those patients who've been failing multiple lines of advanced therapy. Now, perhaps the more intuitive and compelling way to think about a molecule that is, again, GI targeted, non-immunosuppressive, and has a differentiated mechanism of action is in combination, and so you could anticipate this being used in oral prebiologic setting and then the ability to layer on additional levels of immunosuppression from our wide variety of approved agents, be it from the Entyvio-like molecules, the alpha-4 beta-7s, all the way through to TL1As, and perhaps at the worst case scenario, perhaps alongside JAK inhibitors, so there's a very compelling case to think about a mechanism such as EQ504 and AHR modulation as a very good candidate for a polypill, as Brian would say, but certainly in the idea of combination therapy to really try to lift the ceiling of efficacy that we see. Now, lastly, what are we planning to do in the clinic? In the clinical development, we plan to create data and value early. There's multiple clinical studies of Indigo naturalis that we believe establish strong proof of concept in the efficacy of AHR modulation and target engagement through CYP1A1 and elevation in the levels of IL-22. Our initial study will be a SAD-MAD study in normal healthy volunteers, where we'll look at safety, tolerability, blood and tissue pharmacokinetics and pharmacodynamics, as well as taking biopsies from those patients and looking at target engagement and activity in the colon, where we aim to demonstrate that we can engage AHR, but also elevate the levels of IL-10 and 22 in those normal healthy volunteers. That's a phase one that's planned to initiate in mid-2026. But we have the opportunity, with the funding on hand, to potentially achieve proof of concept with the addition of UC patient cohorts following the SAD-MAD study, in which case then we can move on from proof of mechanism to perhaps a more stronger proof of concept demonstrating that the selected dose from the SAD-MAD studies is efficacious in patients. So, in summary, AHR agonism and modulation, we believe, is a very compelling target for tissue-based immunology, one that is also clinically validated in both the skin and the gut. And through EQ504, we have a specific and selective multimodal mechanism of action that modulates AHR and promotes mucosal healing while dampening inflammatory responses, and that this will be formulated as an oral medication targeted to the colon with the ability to maximize tissue exposure and minimize systemic exposures. And that this, as a target product profile, would be very interesting in the treatment of ulcerative colitis in many different ways. But the broad positioning at both an oral prebiologic with biologic failures, as well as potentially in combination with various other agents, really sets this up as a potential medication that could really start to move the needle in ulcerative colitis patients and therapeutic paradigms. So, that's the end of the presentation section. I think from here, we can move on to the Q&A session with Dr. Quintana and Dr. Feagan. And perhaps with that, maybe I'll take my opportunity to ask the first two questions individually. And so perhaps starting with you, Dr. Quintana, you were an advisor to Dermavant and were familiar with the development of tapinarof, the first FDA-approved AHR modulator, a small molecule that we know when applied topically generates biologic-like efficacy. What were some of the key findings and takeaways from that that sort of differentiated AHR modulation as a mechanism against some of the more targeted immunosuppressives that might be cytokine targeted or JAK inhibitors, for instance? I think that one of the advantages offered by AHR targeting is the fact that it's acting not only on immune mechanisms, but also on mechanisms of tissue repair. That differentiates AHR targeting compounds, right, or approaches from those that are solely targeting the immune system. Excellent. And maybe switching from skin to the GI, Dr. Feagan, the skin is not the only area AHR modulation has been tested in. And we talked a little bit about those Indigo naturalis studies. We were specifically focusing on perhaps the more robust phase two placebo-controlled studies. But what's your sort of takeaway from those studies in terms of AHR modulation as a potential approach to ulcerative colitis, as well as the data that was generated and how that may stack up to other earlier stage trials? The two bona fide randomized placebo-controlled trials of the Japanese study, which was reported, I guess, about seven years ago, and then more recently, the Israeli study. I think when you look at the totality of the data, there's no question that there's an effect there. The magnitude of the remission data, and I always like to look at clinical remission, which is the regulatory endpoint as the benchmark. We're seeing, you know, roughly a 30% effect size, which is good as anything we have, including some of the newer agents I mentioned. I think overall, it was pretty compelling. And if you look at the data from the Japanese study originally, which was approximately 80 patients, 30 per group, roughly, it looks like they showed the dose-response curve as well. And the lowest dose was not very effective, but the two highest doses had clear-cut efficacy. And that study was terminated early because of a case of pulmonary hypertension with the Indigo naturalis product. So, I think your approach is sensible to try to limit systemic exposure, and that should be feasible. And we have other examples of that approach being successful. And maybe just to build on that, one of the things that I thought was quite compelling from that data was mucosal healing. As we think about the armamentarium that is approved and/or in development, how important do you think it is to have a molecule with bringing not only the anti-inflammatory effects, but effects that can drive mucosal healing to what is essentially classically dominated by just pure anti-inflammatory or immunosuppressive? There's a number of aspects to your question. I think that, you know, the notion of mucosal healing is somewhat of an ethereal concept in that, you know, we for years used mucosal healing to indicate that patients had achieved a Mayo score of zero or one, endoscopic subscore of zero or one, having started with two or three. Well, obviously, if you still have a one, you're not healed, even though that was the. It still remains a component of the clinical remission definition. We're thinking beyond that now. The histopathology has been reinvigorated. It was a component of the first randomized controlled trial in IBD therapeutics in 1955 by Sidney Truelove, and we've reinvented it. That now histopathology, we think, is a more meaningful endpoint than perhaps endoscopy, and for a gastroenterologist, that's antithetical, but it looks like that is the way things are going, and there's a very large controlled trial just testing that hypothesis, which is what is the treatment target, and you see. My prediction is that things are going to move towards histopathology, and of course, what that will do is accelerate interest in mechanisms that actually have adjunctive effects on healing in distinction to just blocking cytokines. I think Francesco's outline really showed the potential of that and, you know, raised the whole issue. Can we get there with a single agent, or can we get combinations? There's a number of really good potential oral combinations that you could think of with this agent. Excellent. Perhaps at this time, I can hand it over to our moderators at LifeSci to pull questions through from our forums. Great. Thanks, Steve. So, please hold for a brief moment while we pull for questions from our analysts. So, our first question comes from Tom Smith at Leerink. Please go ahead, Tom. Hey, guys. Good afternoon. Thanks so much for taking the questions and for putting together this really comprehensive event. Maybe if I could just start with a question for Dr. Feagan. I was wondering if you could elaborate a little bit on your thoughts with respect to the Obefazimod phase three induction data and how you see that agent fitting into the treatment paradigm. Then how do you think about the potential similarities and differences between that compound and EQ504 and perhaps the proposed mechanisms between those two compounds? Yes. You've touched on a number of issues. I guess there's no denying that Obefazimod has an effect. As I said, the effect size is in the middle of the pack. It's not sort of our best agent you see is apheresis. And the point estimates from the three studies of induction aren't in that magnitude. They're more like 15% than 30%. The mechanism has been a sticking point, I think, for many people. It's claimed that it's anti-cytokine, and there are some limited data to support that. There's an effect on IL-6, which I think might raise some concerns. Having said that, you know, with the Monoclonals, we ran into a problem with GI diseases with perforation, with IL-6 being protective. Francisco could maybe comment on that. But I think there's enough there, and we haven't seen a safety signal so far. And, you know, I'll put the caveat we need to see 1,000 patients followed for a year to really exclude a rare event. But it looks pretty clean. So, that opens up the possibility that it's anti-cytokine. So, any other mechanism that isn't anti-cytokine could be in play. And that's why I think it's really exciting that we have a number of oral agents coming down the pike that are different mechanisms, MOAs, in distinction to just blocking alpha-4 beta-7. You know, alpha-4 beta-7, it's chocolate and peanut butter for anti-cytokine therapy. I mean, that's an ideal combination potentially, but the Morphic results were sobering. Got it. Yeah, that's helpful. Appreciate that color. And then just maybe one for the Equillium team here. I was just hoping you could talk about the work that needs to be completed here prior to starting the phase one study and maybe elaborate a little bit on the gating factors there. And then how quickly do you think you could advance this compound into the proof of concept cohorts? Thanks so much. Yeah, sure. So, we are currently developing the formulation. As Dr. Feagan has alluded to, these are not new by any means. These enterically coated colon targeted formulations are already deployed, not only in ulcerative colitis or Crohn's disease, but in other areas, IgAN, for instance, you know, you're starting to see these creep up into other areas. And so, we're at a stage where we've completed all of the key IND enabling work. We are now just taking our API, moving that in through the development and the manufacturing phase. So, we generally view this as sort of a low-risk but somewhat time-consuming set of processes as we move through to get ourselves clinical trial material to start a trial mid-next year. So, that's where we are. I think in due course, we can provide a bit more clarity on exactly what that formulation is and what the trial design will be as we approach that trial next year. Hey, Tom, Bruce Steel here. I think part of your initial question was somewhat focused on the thesis that we know is, you know, in sort of play on Obefazimod as a potential AHR modulator based on independent research that has been conducted. Steve, do you want to comment further on some of the things that we're working on? Yeah, sure. I mean, there are a number of molecules out there either in development or approved drugs that have AHR modulatory properties. That's just a byproduct of the fact that AHR combined a wide variety of ligands, and more recently, I guess there was some discussion and data out there in the scientific community that obefazimod does indeed activate AHR. We recently tested this in-house alongside, and we do this with dozens of different molecules and AHR modulators, and we have also recapitulated and reconfirmed that obefazimod does have AHR modulatory properties. It can induce CYP1A1, slightly less than Indigo naturalis and certainly less than EQ504, but very much more and very much clearer AHR activation effect, so we'll continue to do additional work there as we think about comparing this. But our thesis with EQ504 has been to develop a very potent, very selective molecule and to deliver this directly to the colon tissues where we can optimize target engagement. Really helpful. Thank you, guys. Thanks, Tom. Yes, thanks for the questions, Tom. Our next question comes from Cha Cha Yang at Jefferies. Please go ahead, Chacha. Hi, thanks so much for hosting this. And this is Chacha on for Roger Song. I was wondering if you could give some more insight into baseline characteristics for your UC patients as you go into your POC trial. And then I also have a question about how long you expect your enrollment for your phase one healthy volunteer study to take and whether you think the requirement for biopsies is a gating factor for that. Yeah, sure. Let's work backwards because that's certainly where we spent most of our time as the phase one, as you can imagine. We believe that the phase one, like most phase 1s, could be fairly rapidly enrolled. We plan to initiate this study in Australia. That'll be a classic SAD/MAD study. We will do sigmoidoscopies in those patients. Our understanding is that is not a gating item. That is fairly routinely done. That is an outpatient procedure. It's very different than when we think about colonoscopies that require a lot of prep, a lot of additional workup. We believe we'll be able to get normal healthy volunteers, dose them in a multiple ascending style, and then also colon biopsy them on a somewhat frequent basis, then we can actually look at optimizing target engagement in the tissue. We think it's really important to understand what's going on in the tissues because that's really where we're treating the disease. We can understand what's going on in the blood, but that may give us a sort of false sense of what's happening in those colon tissues. I think that's a truism of any drug, biological, oral. If you're just looking at the blood, you really don't have a good sense of maybe target engagement in the colon. As we are a priori going to be delivering this drug directly to the colon, we want to basically ensure that we're selecting a dose on optimizing colon tissue exposures versus what we can just read from the blood. Now, in terms of patient characteristics for an ulcerative colitis study, we have not defined any of that moving forward. That's something that we'll be looking into in the new year as we think about what might be the right approach here to get some sort of phase 2A or phase 1B-like proof of concept out of the capital we have on hand. So, I can provide further updates when that's resolved. Stephen, maybe I could just add that the ability to do FLEX-SIG in the normal healthies, given the work that's out there about PKPD, if there is not drug in the rectum, that's a problem for the formulation. So, this would be a really critical thing to do at an early stage to validate that your release properties are ensuring adequate exposure in the distal bowel because patients won't be happy with active ulcerative colitis if the rectal inflammation is not controlled. Yeah, absolutely. Awesome. Thanks so much for the color. Thanks for the question, Chacha. Our next question comes from Ram Selvaraju at H.C. Wainwright. Please go ahead, Ram. Thanks so much for taking my questions, and thanks for providing such a comprehensive overview of so many different topics. I think, you know, for Dr. Feagan, I wanted to revisit what you had said earlier about the challenges associated with achieving complete healing of the intestinal mucosa. And I was wondering if you could opine on to what extent you think this goal might be achievable through the use of combination therapies. And based on the totality of the data that you've seen so far clinically, which combinations are most likely to get closest to that goal? And then the second question is for the Equillium team. When you look, and this is perhaps somewhat provocative and premature given where you are in development with 504, but when you look at the obefazimod clinical development program, what do you think are the most relevant takeaways from that, from a clinical trial design parameter standpoint, like, for example, but not limited to efficacy endpoint selection, that would be most applicable as you think ahead beyond the phase one to potential efficacy studies with EQ504? Thank you. Okay, well, I'll start with the notion of what is healing. I've alluded to the fact that we're increasingly thinking about histopathologic healing. There is a very large multi-center study sponsored by Takeda, which is actually randomizing patients with active UC to one of three treatment targets. That's cessation of bleeding, symptom-based. The second arm is cessation of bleeding plus endoscopic response, which is the clinical remission endoscopic definition plus symptom resolution. And the third is the trifecta of adding on histopathologic remission. And we've reported results from the study of 760 patients that we followed for up to almost three years. And what we've discovered actually is that histopathologic remission is much more prevalent than we thought traditionally. The old adage was symptoms resolve first, then endoscopy, and then histopathology. And what we've demonstrated already in this very large study, which was quite methodologically rigorous, is that histopathologic healing occurs more frequently than we thought. And so, you know, it's not a bridge too far to think about this as, you know, a therapeutic target. And with regard to which combinations are going to get there, unfortunately, we don't have really mucosal healing or mucosal immunologic data that predicts in animals which combinations are synergistic. I mean, J&J chose guselkumab plus golimumab on the basis of a number of gene pathways intersected with the combination. And potentially that's a way forward. But mostly it's been empiricism based on orthogonal mechanisms. And that's where I think this mechanism is so attractive because you could imagine it being combined with, as was suggested earlier by Stephen, that say an oral IL-23 potentially augmenting the anti-cytokine effect. But, you know, there's going to have to be a lot of healthy empiricism here. Thanks, Dr. Feagan. Ram, appreciate the questions. To your second part, I'd say, you know, first and foremost, we're focused on getting through the SAD/MAD, and as Steve identified, our plan to get to some rapid early proof of concept work with patient-level data that would then form further development. Obviously, there have been, you know, dozens and dozens of UC studies over the last several years. So, pretty well-developed clinical/regulatory pathway already. I don't know that we'll be reinventing that wheel, but I'd say we'll want to get through our early stage of development, see what we observe there, and then spend, you know, an appropriate amount of time with our key clinical advisors, including Dr. Feagan and others, to, you know, fully flesh out our more advanced development, you know, program and planning. And just to elaborate on that, I was wondering if you could just briefly comment on, A, the way in which one would define achievement of clinical remission if you expect to utilize sort of the classical paradigm there, and B, if you have any views on induction versus maintenance therapy paradigms for defining what the therapeutic impact of 504 would be. So, Ram, I think we'll be looking at sort of all of the above. And certainly the obefazimod data, I think, is in part compelling because of the longer-term results that have been observed there. So, again, we'll certainly be looking at clinical remission with a focus on, you know, clearance of disease in the GI tract and, you know, the other parameters that go into standard, you know, assessments. I think, Ram, early on, we'll have an opportunity to, you know, in these smaller targeted trials, is to really, you know, consult the KOL community and think about, well, where is the puck going here? What should we be collecting? And validate that early. I think so often the challenge with later-stage trials is that once you've selected something and you've built a thesis on it, it's sort of hard to change that later on, right? And, you know, try to convince somebody that, you know, all your assumptions on prior data will hold on a new way of thinking about things. So, you know, we are blessed in having a very good KOL network. We've been a company that's focused on mucosal immunology for quite some time with Brian, with Bruce Sands, and a number of other advisors who've been very close to. We'll consult them about how we think about that going forward. I think we'll be very open-minded about how we approach that, given the premise of what we're trying to achieve, which is to really change the mucosal barrier function to change the mucosal immunology environment there. I think, you know, a lot of biomarkers, a lot of histopathology, and really taking a look at those tissues. One thing I'd like to do is to bring Dr. Quintana to this conversation about maintenance. Now, one thing that came up when we were looking at and doing diligence here with modulating the AHR pathways is the ability to think about this in a maintenance paradigm where you can sort of prime or change, fundamentally change the inflammatory milieu there, the T cell subsets, their tolerogenic capacity, where this is also a mechanism where a dose de-escalation or some sort of lowering of therapeutic paradigm might lend itself to the fact that this does fundamentally change the T regulatory cells, the antigen presentation, et cetera. In some of the early animal models, you could actually provide protective effects prior to the ulcerative colitis or the colitis insult in animals without having to dose. So, Fran, perhaps you can walk us through some of that data that you think is germane here to how we might think about a maintenance paradigm in ulcerative colitis patients. Yeah, I think it's interesting. I mean, there are several pieces of data that are actually exciting, I would say. There's data, for example, on humanized mice, where it was clearly shown that you have mice harboring human T cells, right? And those Tregs actually induced via AHR activation were shown to not only suppress active inflammation in mouse models of IBD, but actually to retain their phenotype. And that's a very important point. Many of the technologies or approaches we have might even be able to induce Tregs, but usually they are not stable enough in order to withstand the challenge of being an inflammatory environment. So, that's point number one. Based on that, you could, on the one hand, think of combination therapies where you can actually block, right, ongoing inflammation with very acute, strong interventions and then provide maintenance of that anti-inflammatory response and actually maintenance of epithelial integrity via AHR activation, particularly when you consider the lack of side effects, right, or of adverse events. I think this is something very important to consider. You're not inducing wide immunosuppression, and so, because of that, I think that at the end of the day, what you're doing with EQ504 is actually mimic what I was saying earlier. AHR activation is actually part of gut homeostasis. It's actually a mechanism that most of us have functioning as a way of preserving epithelial integrity, the function of stem cells, and regulating inflammation in the gut. This is what we're mimicking. This is what we're actually exploiting when dosing EQ504. So, in terms of that, it seems like a very physiological approach to induce and maintain anti-inflammatory responses within the gut. Thank you. Thank you. Thanks for the questions, Ram. Our next question comes from Catherine Novack at JonesTrading. Please go ahead, Catherine. Hi. Good afternoon. Thanks for taking my questions. Just a question on, you know, some of the risks of enteric-coated delivery for ulcerative colitis drugs. Do these patients have alterations in pH that could potentially disrupt drug ability to deliver to the correct site? Yes. That is a known challenge, so to speak, between normal healthy volunteers and those with ulcerative colitis. There are three main ways people think about delivering a molecule to the colon. The classic, probably the oldest way to think about this, I think, is pH. As you point out, in a proportion of patients, that pH can change, but it also might change individually within a patient over time. It's not like this subset of patients is always sort of a dysregulated pH. Another way people have tried to tackle that was to add a time component, but also GI transit times change quite considerably. More recently, and this is sort of published data out there in the literature, that they actually use a combination of approaches. For instance, pH and microbiome. We've got a number of prodrugs that are out there leveraging the microbiome as the drug comes into the colon that the microbiome will be able to digest this and release the active metabolite. There's similar mechanisms there available for enteric coating where you can use a, like, for instance, a dual pH and microbiome. In patients who have a normal physiologic pH where you get to a more neutral sustained pH in the colon, the pill will dissolve. For patients who have an acidic environment, then you have a second fail-safe trigger that allows you to release that drug. Those drugs are on the market. They're approved. The clinical data to date in those does suggest that they have a more robust, more accurate way of delivering drugs to start dissolving at the ileocolonic junction at the start of that colon. I think that those levels of variability in patients, there are mechanisms out there that are clinically and commercially validated to overcome those. It's probably no secret here, the way I'm sort of elaborating on those, those are ones that Equillium is currently considering. Okay. But is it not fixed yet, the strategy that you plan to use for enteric coating? It's fixed, but we just haven't provided public guidance or data on that at this time, and that's something certainly we would do ahead of the phase one, is to provide more details on the formulation, more details on the phase one design. Okay. And then just one more question on the DSS mouse model. Obviously, you know, understanding why it doesn't make sense to deliver systemically in humans given the broad expression of AHR. But, you know, as this was systemically delivered in the mouse model, is there any indication that there's immune modulation outside the gut that contributes to the resolution of colitis? You know, any thoughts on that? Yeah, it's really challenging to give the molecule directly colonically to the DSS colitis mouse in a formulation. Formulation beads are usually too big. So, we give this just sort of either orally or through IP, and then we resolve the disease that way. So, certainly there'll be some systemic exposure there. We can show that we can enrich colonic exposure, but those don't sort of mesh exactly over with the DSS colitis model. So, we do not believe that we are driving efficacy in DSS colitis because of systemic immune modulation. We believe it is all happening locally. This is driven by the fact that when we look at the cells that are producing large amounts of IL-22 or the cells that are being modulated, they're almost all, if not exclusively, gut resident. Now, it's a question perhaps Brian can weigh in on is, how does the community think about ulcerative colitis? Is it a local disease or is it a systemic disease? I think, you know, ulcerative colitis generally precedes the extra GI manifestations. Once you can get full mucosal healing and remission, then those extra GI manifestations go away. Whether those extra GI manifestations are really causative to the underlying ulcerative colitis and that you would need to modulate them, or in our DSS colitis model where the disease tends to be more localized and that we have systemic exposure in the mice, but we won't have systemic exposure in the humans, is that I truly believe that this is a local disease and that the expression, the exposures of our drug in DSS colitis in the peripheral are not contributing to the efficacy. When we look at the mouse disease model, we look at how much drug is in the mouse disease tissues. That also correlates with dose response. Steve, I'd say that it shows how boring our lives are in IBDology, that this is one of the hot topics, chicken and egg type analogy. My view is that some of these are probably overlaps in different diseases, but the most common extra-intestinal manifestation is arthralgias, joint aches. If you look at the direct comparison of TNF antagonist Adalimumab in ulcerative colitis to vedolizumab, one drug works systemically, the other doesn't work systemically. The control of extra-intestinal arthralgias in that trial, they were very highly similar. So, I'm with your view. Fran, I know that for as many mouse models I've done here, you've done arguably far more and across all the different, call it the adoptive transfer, the TNBS, the DSS. Do you have any sort of thoughts here regarding these molecules? Where do you think that these molecules are really providing their therapeutic benefit given systemically or locally in these animals? Do you think that there's benefit systemically that we should be targeting, or do you think local modulation of AHR should be sufficient? So, on the one hand, I think that local modulation, right, theoretically might be extremely helpful because you would be enforcing or you would be regulating this deregulated activity of innate immune cells. You would be promoting epithelial barrier recovery and healing. Having said that, right, if you go for a systemic mode of delivery, that should also be extremely beneficial. Indeed, we have shown that those, for example, TR1 cells I was talking about, right, they are very important in their ability to arrest gut inflammation. The second point I would like to make is that if you have epithelial disruption, some of that compound might potentially make it into circulation, and that can only be beneficial from my point of view, again, because you're going to be inducing cell types and cell responses that are known to deactivate inflammation and actually promote tissue healing. Thank you. Thanks. Thanks very much, everyone, so our next question comes from Minh Le at Guggenheim. Please go ahead, Minh. Hi, everyone. Thank you for taking my question. Just a quick one for me. I want to ask about the mechanistic differences between your AHR targeting versus Immunix CERT-6 modulator. I understand that there are two different pathways, but they do have a similar convergence in the sense that they both lead to epithelial cell survival, repair, and anti-inflammatory gene expressions such as IL-22 and IL-10. I mean, I know that they are currently advancing their CERT-6 into celiac, but given the overlapping mechanism, there could be a path forward into UC. Could you maybe please help reconcile the differences between these two MOAs, whether there is robust evidence in one or the other? And next one, is there any good comps that we can look at that is also going specifically into gut epithelial tissue healing as opposed to a traditional inflammatory targeting like TNFs and IL-23s? Thank you. Maybe I'll start with a mechanism question, and I'll ask Fran to sort of weigh in here. You know, I'm not an expert in CERT-6, so I'll provide that caveat up front. The way I think about AHR is that we know that those patients with Crohn's, colitis, celiac disease appear to have less AHR activation or less AHR activating ligands. That, as Fran pointed out, the AHR physiologic response is important for maintaining mucosal biology. The way we think about AHR is sort of a system evolutionarily conserved to maintain barrier function, whereas CERT-6 might just be a way to help in a sort of more directed, narrow way to modulate barrier function. Now, one of the important things about modulating AHR, and specifically IL-10 and IL-22, there are other pathways, but if we just focus on those two cytokines, is that there's a very strong interplay between IL-10 and IL-22, call it an immune epithelial crosstalk. When we modulate AHR, we're modulating really a system aimed at maintaining barrier function, maintaining the immunology around that barrier function. It's improving mucosal. It's producing antibacterial peptides that help with pathogen responses. It's tightening up those junctions. It's helping cells repair. It's not just sort of helping strengthen tight junctions. And I think if you were to take just a molecule that would modulate just barrier function, one might argue that it's hard to modulate barrier function with a persistent onslaught of immunological insult. And so, something that we've always been very attracted to with AHR modulation is that we're bringing the anti-inflammatory side that has been sort of tried and tested there with, you know, the numerous molecules that have been tested, approved in ulcerative colitis. But what we are bringing to it is the ability that once we've arrested the inflammatory insult, is the ability then to help restore barrier function. So, Fran, perhaps you've got some opinions here too. Yeah. So, as you know, CERT-6, so it has been described to lead or to favor barrier reestablishment. You know, if you look at the biology of it, it has very important roles in gene expression, right? Very basic roles in gene expression, and I think that's something that differentiates it a bit from AHR is actually its potential or its less clear association, for example, with malignancies, so, in that sense, again, I go back to what I mentioned earlier. AHR is actually a mechanism that operates in all of us. It's constantly activated at tonic levels by the gut flora, by dietary components, right, in order to bring homeostasis, and it does so by acting in multiple aspects or multiple components of gut physiology and pathology, inflammatory components, epithelial components, stem cells. You can target TL1A and try to replicate that. But in that sense, it's not something that is so physiologically regulated. So, in other words, my impression is that on the one hand, AHR activating compounds are closer at replicating what undergoes, what happens, or what is part of healthy physiology of the gut, and then also are less likely to be associated with adverse events, at least theoretically. And maybe you can repeat your second part of your question because perhaps that's something Brian can... Yeah, my second question was, is there any good comps that we can look at in this area that also targets the epithelial barrier integrity and the tissue generation as opposed to those traditional inflammatory targeting? There have been several programs targeting various agonists designed to improve barrier function, which failed. I'm not familiar with anything that's directly comparable. Great. That'll be the end of our Q&A session. I'll pass it to Bruce for some closing remarks. I would like, again, like to thank everybody for joining the call today. Sincere thanks to Doctors Quintana and Feagan for joining us and providing such interesting color on the program and the unmet need here in ulcerative colitis. We're very much looking forward to advancing EQ504 towards patients, and if we were not able to get your question today, please feel free to reach out to us directly, and we'll do so in that form, and again, thank you very much for your time.