here is pretty sentimental and nostalgic for me. The ASG, which is hosting us today, played a major role in my personal and professional development. I spent 10 to 15 years heavily involved in the organization and I feel a really tremendous debt of gratitude to the ASG for what it's given me the opportunity and the doors it's opened for me. Secondly, I wanna say it's great to see all of you here because you all have an important role because what you hear from Nimi and I are not the normal in EOE because how we practice, we are eosinophilic esophagitis. This is kind of, we're passionate about it and some of the questions that came up, how this is handled in the community and by the non-eosinophilic esophagitis expert is very different than how we handle it. It's not a question of good or bad, it's a question of awareness. Two other quick points before we start. Number one, the question that came up, this is not a serious disease. In fact, perforation is a serious, the only time this becomes a life-threatening problem is if you have a spontaneous perforation called Borjavi syndrome or when you have an instrument-induced perforation when these things happen in the middle of the night. And we try to avoid that. The other aspect about this not being a big deal is that it does affect quality of life, anxiety and things like that and we'll get into that in a moment. Lastly, all of you are gonna have a real big role in educating people. This is not just a matter of we have this unbelievable drug that's the first FDA-approved drug. There is a major gap in physician awareness and understanding of this disease for reasons that have come up already. And enough with the editorials. Let's start with a case. 20-year-old Penn varsity swimmer with EOE dating back to first grade. An endoscopy in 2017 with strictures, furrows, rings, exudate and adult scope, which is nine millimeters in diameter. Oh, you did? Yeah. Could not pass. I'm waiting for the echo again. And the only therapy at the initial visit was a BID-PPI. Here's the endoscopy and you can see some of those features that Nimi has already discussed. So you really, you see some vessels here, you see those furrows here and it's hard to appreciate, but it narrows considerably. At pathology, 35 eosinophils per high power field, rare eosinophilic microabscesses and other features as well. And then two years later after noncompliance, he comes to the emergency room with a food impact shown there. And what you can't really tell is that the fidelity of the picture is not as quite as good as you get with adult scope, because this was done with a pediatric scope, which couldn't pass, which is six millimeters in diameter. A normal esophagus should be 16 millimeters in diameter. On budesonide, one milligram BID for two years, after two years of noncompliance, you've gotten rid of the inflammatory features. You can see it's a very narrow esophagus still on the left, right here. After dilation, you can see the rent that's caused here, which is what we want to see. But our goal was to get to 16 millimeters, which we got, but that's not all in one session when you're starting off with someone with a five or six millimeter diameter esophagus. And on budesonide, a milligram BID after two years of noncompliance, he's still not in deep remission. He's not in histologic remission, and he's not an endoscopic remission. So what I'd like to go over in the time allocated to me is to go over our current understanding of pathophysiology, elaborate a little bit more on what Dr. Gonzalez has said, to really go over what the goals of therapy are, and I want to emphasize that the treatment options in 2022, how do I assess response to therapy? This has been touched on already, but I want to really drill down on that a little bit more. The data on chronic therapy, and what is the current status of your compound, novel steroid delivery systems and other biologics, and a moment on refractory EOE. So I want to spend just a few minutes in the pathophysiology of EOE, because you are going to be working with a compound that directly impacts that inflammatory cascade. So I think it's important to make sure everyone understands how your compound works, and what it does and doesn't get. So the simple best article looking at this comes from a review, that's most understandable from a review in 2018, looking at the pathophysiology of EOE, and just to kind of review what Dr. Gonzalez said. You know, exposure in a predisposed individual to aeroallergens or food allergens, then leads to the esophageal epithelium producing interleukin 33, something called TSLP, which then stimulates the immune system to begin a Th2 response. That Th2 response then leads to secretion of a variety of different cytokines, TGF-beta as well. And then at the end of the day, what you're left with is you're going to have esophageal inflammation, loss of a barrier function, and remodeling, and then it's just a feedback loop that keeps going on and on and on. And we're gonna talk more about what dupilumab does as well as other compounds in a moment. But let's review just briefly what these various cytokines do. So TSLP is way upstream shown here. So you have the food, you have the esophageal epithelium, and TSLP is one of the first things that's secreted, thymic stromal lymphopoietin. It's released by activated epithelial cells in response to an environmental trigger. It promotes that Th2 response, and it is associated with many, many different atopic conditions. And there are drugs under development now working upstream of your compound that are gonna try to inhibit this. IL-4, important for you as well. This induces that Th2 differentiation. It increases the secretion of eotaxin-3, which is downstream right here. Eotaxin-3 is gonna draw eosinophils out. It also impacts mast cell proliferation and activation. So this is a disease that's not just the eosinophils and the esophagus. There are all these other inflammatory cytokines that contribute to eosinophils coming in, but they have other effects as well. And the mast cell, we've learned, is part of this too. And then IL-13, again, important for you as well as some of the competition that's coming up. This is associated also with other atopic illnesses. It leads to eosinophil chemotaxis. That is, eosinophils driving into the esophagus. Importantly, it leads to collagen deposition. That is the dreaded endpoint of this disease, fibrosis. It affects smooth muscle contractility, because early on, before you get a narrow-caliber esophagus, you can have an impact on the muscle of the esophagus. And it disrupts that epithelial barrier, again, part of that disease loop. The barriers disrupt it, allows allergens to get in more easily, and on and on we go as well here. And lastly, eotaxin-3, which I showed you, which is downstream, right here. And that is just something that is made, that is a compound that's made that's gonna lead to eosinophil inflammation. And finally, the mast cell. So these are present in the mucosa and the submucosa. They can increase the smooth muscle mass, again, part of that remodeling process, and it increases the profibrotic TGF-beta-1 that's involved in remodeling. What's the most important thing to remember from this? It's that, at the end of the day, it's more than just the eosinophils that are contributing to what's going on. We're gonna skip this. This is supposed to have been hidden, so this is in your slide deck, but for some reason it's not hidden. And Mimi has covered this, so I'm gonna skip through this as well. And let's get to the goals of therapy that we have. Again, very, very important. The goals of therapy are, in fact, really simple. You wanna eliminate symptoms. You wanna reduce mucosal inflammation. You wanna correct disease consequences. You wanna prevent complications. So we have this concept, just like an inflammatory bowel disease, and Dr. Gonzalez has talked about this, our goal is treat to target. And if you're talking to a patient, the only target of these three that you can comprehend are symptoms. In fact, our goal is deep remission when we have resolution of symptoms, inflammation, as well as endoscopic findings. Now, again, importantly here, it's nice when these are all lined up together with the smiley face at the top, that you have symptom resolution, histopathologic remission, and endoscopic improvement. But you can have ongoing symptoms without eosinophils because of scarring. You can have ongoing symptoms with eosinophils because the disease is not controlled. Or you can have ongoing symptoms without any scarring related to anxiety and hypervigilance. So all three components of this are important to assess, which is why we bring people back for endoscopy, which is why there's a disconnect between eosinophil and esophagitis centers of excellence, and other practices, because the sense that people have is you treat a patient's symptoms, not their endoscopy, not their x-ray, not their biopsy. You just treat their symptoms. And we think that if you do that, you're under-treating this disease. So the goal here is deep remission. So let's turn to the treatment options that we have now in 2022. And before we get into the treatment options, what are the issues? And this is gonna see if my slide set was fixed because I have a feeling it's not. Oh, it was. So this was always my first bullet, but this has now changed. This changed on our way to DDW, on our flights on that Friday of DDW. On our flights on the Friday of DDW, all of a sudden, everyone's phone was exploding. My phone was off, so I saw this when I landed. But until that Friday, there were no FDA-approved therapies. There now is an FDA-approved therapy. But that being said, again, really important to understand that the only way to assess response to therapy, those three components, is endoscopy. And endoscopy does involve costs and inconvenience. But there is currently no alternative that we have that provide us clinically meaningful information. An unmet need here is to find non-invasive or blood-borne ways of sorting out the other components of remission. And this is, again, what the eosinophilic esophagitis centers do, but does not take place, for the most part, in community-based practices. Patient-reported outcomes for clinical trials, but just simply, when we talk to patients as Dr. Gonzalez has alluded to, are not accurate because patients say routinely, not only don't they have any symptoms without digging deeper, but one thing that was not discussed is that patients say when you ask someone why they've been living with this for all these years, they say, well, that's kind of how I've always been. They just assume that that's them and that it's normal for them to have trouble swallowing. So you have to basically ask patients, you have to do that dive into what their symptoms are. Now, again, as much as you'd like everyone's first and only choice of therapy to do pilumab, it's not quite that simple. There are a number of variables to consider when you are going over therapy, and this next section of the talk will really be based on how I will go over all of these options with a patient, and that really is a discussion that really cannot take place over the phone. And the variables to consider is efficacy of the compound, what is the patient preference, how severe is the disease, is it covered by insurance, what are the dietary resources available, and importantly, shared decision-making informs all of our approach to this. It's not just you have EOE, I'm gonna put you on compound X. This is your disease, this is how you get it, this is the natural history that we think of untreated disease, although we're not sure that everybody goes on a fibrostatic pathway. We think that's the case, and as a colleague at Medical College of Wisconsin used to say, esophagus is a terrible thing to waste. So shared decision-making is really important, and every time we talk to someone with EOE, we don't know exactly how they're gonna react other than unless they go to Northwestern, most college students, high school students, the people in their late teens, early 20s, when you discuss diet with them, they look at you like you are from a different planet. Does that happen to you at all, or you are the diet queen? But people that, you know, I'm not giving up my cheeseburger, I'm not giving up my ice cream, and Lord knows I'm not giving up pizza. So shared decision-making guides therapy. Here's an example why, this is from a survey that was done by Joy Chang at the University of Michigan, looking at the importance of shared decision-making in treatment decisions for EOE. So if you are looking at shared decision-making, and if you see high shared decision-making, the satisfaction is 57%, compared to only 30% where shared decision-making was not part of what happened. And the specialists that did the best here were the gastroenterologists, but satisfaction was seen only in 52%. So the options are the Ds, diet, drugs, PPI, topical steroids, dilation, and the new agents, and again, I apologize because I modified these slides last week and they didn't get changed, but the next D, obviously, is dupilumab. Fifth, excuse me. So let's go over this. This is how I go over things with a patient. Is diet gonna be an option for you? Well, before we even get into the details of diet is that if we were to find one of these approaches that would work for you, do you think, in all honesty, that you would be able to comply with that? Usually when you go over this with patients, typically the response is gonna be, I'm not sure, I don't think so, but for the motivated patient, the discussion continues. So an elemental diet where you eliminate everything, it's really canned amino acids and things like that, the response rate is exquisite. It's 94%, but it's pretty inconvenient and it's pretty expensive. The six-foot elimination diet, which eliminates the six most common foods groups, which are dairy, wheat, eggs is the big three, soy, peanuts, tree nuts, and then fish and seafood, that has a pooled response rate of 68%, and the allergy-directed elimination where you're doing allergy testing has a response rate of 52%. If you look at response purely by histologic response, and this is from the AGA Joint Task Force guidelines. Now, this is from Nimi's group looking at, you discuss the six-foot elimination. If you are put on a six-foot elimination, this is what happens afterwards. The first thing you do is you don't just tell them about it, the next step is to meet with a dietician, and then you undergo an endoscopy in six weeks, and if the endoscopy is normal, endoscopy number one, you introduced two foods, which are gonna be, first, you're gonna add seafood and nuts, and then if you're still doing well, you'll get another endoscopy done, and the next two to introduce are soy and eggs, and then if you're still doing well, another endoscopy, and you reintroduce wheat, and then you look at milk. So in the best situation where it's a single food, and it's dairy or wheat at the very end, you're looking at four endoscopies, but you have to start all over again in a way if you do not respond each step of the way. So lots of endoscopies, these are done every six weeks, significant time and expense commitment here. So in the event that you find that you go on this and it works, the six-food elimination diet, this is an online survey study that was done of 42 patients who responded to the six-food elimination diet. Only about a half remained on this at three years. So it's hard to stay on this, and why do people stop? Exactly what you'd think, suboptimal symptom control, social situations, and diet-related anxiety. And furthermore, there are, it's typically not one food, it may be six foods, but often it's more than one food, as you can see here, and the number of foods you can see on the right-hand side, but the biggies are usually dairy, wheat, and eggs. Now, this has led to trying to do, instead of a top-down approach of six foods working your way down, a bottom-up approach, starting with the one, two, or three, or four most common foods, and dairy is one example. This is work that took place here in Chicago at Josh Wexler's group, looking at elimination of cow's milk protein in children with EOE as monotherapy, given that for eight to 12 weeks, histologic remission at 51%. So, in individuals who are motivated and you wanna try to look at lightning in a bottle, then you can go from a bottom-up approach of starting with one food, and typically it's dairy or wheat are what I will start with. And what to eliminate, here are the ingredients. If you're on a six-food elimination, we've talked about it, four food, dairy, wheat, eggs, and soy, and the two food are gonna be wheat and dairy, and the one food is gonna be dairy, usually, as how that goes. So, that's the S-fed, the F-fed, the two-fed, and the one-fed. So, that's one option, is a diet. Requires the motivated patient and someone to be honest with themselves and upfront understanding. A second option, and I'm giving this to you not in order of preference, but in order of how I started with, is PPIs. And what's the pooled response rate of PPIs? It's 42%, it's basically a coin flip, and you could say, why would anyone wanna do this? There are a lot of reasons why people would wanna do this, and not the least of which is people feel better a lot more when they're on a diet. Which is people feel better a lot more than they are in histologic response. Now, there are a variety of potential mechanisms that PPIs can work, and it's not related to anti-secretory effects. These are anti-inflammatory effects, there are antioxidant effects, there can be immune cell inhibition, decreased endothelial cell adhesion, reduced cytokine expression, and the transcriptome is downregulated with PPI therapy. Furthermore, it can improve the mucosal barrier and decrease exposure to allergens. So, PPIs on the other hand, if you look up PPI adverse events on Google, the first thing that's gonna come up is a variety of law offices to contact because of all the bad things that PPIs can do. And patients, and you may have heard this in your own discussions with family, friends, et cetera, is that people are really worried about all these purported adverse events, and this slide basically summarizes it's anything that you can think of as the best way to state it. But, when you look at adverse events with PPIs, it's important for people to be aware that these are association studies, not causation studies. It's not the same as cause and effect, so associated with is not the same as caused by. The level of the association is very low magnitude, and it falls within a so-called zone of potential bias with the odds ratio shown here between .33 and three, and the inference taken when such a low odds ratio was seen is that it should really be guarded in this, and with one exception that I'll show you in a moment, almost every association of PPI adverse events fall within this zone of potential bias. In the only randomized controlled trial that looked at PPI adverse events over time, the only thing that, in a prospective study, the only thing that there was a signal for was an increase in enteric infections, so bacterial infections, not C. difficile. So, as you discuss, or as you're making your physicians aware of various options, PPIs remain an excellent option. The adverse event issue has been completely overrepresented. These drugs have been around for decades. They're safe, they work, they're very good, and they're very inexpensive. Now, let's turn to topical corticosteroids. Topical corticosteroids, when you look at their efficacy in this pooled analysis, it's 65%. Roughly 2 3rds of people are gonna go into histologic remission with topical steroids. So, you have your diet option, you have your PPI option, now you have your topical steroid option. And in the best study done with this that was done by Evan Dell and looking at budesonide, which is one option that people have, versus fluticasone, another, these are medications that have been made for asthma. They have to be repurposed for the use in EOE, and before this study was done, the hypothesis was that since budesonide is swallowed in a liquid suspension that people make, versus fluticasone, you spray it into your mouth and then you try to swallow it, and Evan had done previous studies that showed part of what you swallow actually goes into your lung. The hypothesis before this study was done was that budesonide would be superior to fluticasone. In fact, they're both comparable when used at comparable doses, and the effect is the same for both, for budesonide, 71%, for fluticasone, 64%. Interchangeable, and again, in shared decision-making, if a patient wishes to go down the road of topical steroids off-label, which is perfectly fine, then we have to see what do you prefer. Do you prefer to spray or do you prefer to mix? So there are issues with topical steroids. As I mentioned, these are repurposed medications. The delivery of the drug has not been optimized for the esophagus, it's optimized for the lungs, and the instructions are complex. We have to have an instruction sheet printed out, you have to go over with patients verbally, and then you have to see, it's the budesonide, what I call the budesonide cocktail mixer. What can you mix it in? You can mix it in Splenda, which I don't recommend anymore, it's yuck. You can mix it in honey, you can mix it in maple syrup, or as one of my patients brought to my attention, something called Thicket, but it's a little bit of this and a little bit of that, and you don't know if you're optimizing. Typically, try to bring it to about a teaspoon or two teaspoons of the mix. It's not FDA approved, and there can be insurance issues with this as well. And anytime you say steroid, patients are worried about long-term effects because aren't steroids bad for you if you use them a lot? The Joint Task Force said the following, there is no increased risk when compared to placebo in short-term studies. There have been scattered and very rare reports of adrenal suppression or local fungal or viral infections that are really very easy to treat. Dilation is something that I typically reserve until after I get the effects of an anti-inflammatory therapy. And this is an example of a SAVRI dilator wire, and this is a narrow caliber esophagus shown in image A, and then you can see the rent in image B and C, and D, it's not for the faint of heart. The image D is with a balloon dilator, the different types, and I think as part of the coursework here, you'll be exposed or have been exposed already to the different types of dilators that we have, and here's an example of them. On the left are the SAVRI dilators. The advantage of SAVRI dilators and the approach to this is that this is a pan-esophageal disease, and this dilates the entire esophagus. The balloon is a little bit more focal, although you can drag them up through the esophagus. The balloons are not reusable. The SAVRIs are reusable, so there's cost issues involved with that as well. It's really, they're both comparable, and it really is dealer's choice. And when you look at efficacy in terms of clinical improvement, and this is not histologic improvement, the improvement is seen in 95% of patients, so patients feel better with dilation, and you can say, well, why doesn't everyone just got dilated? Well, a few things with it is that that can result in discomfort. Chest pain can be seen at about 9%. People can be hospitalized at less than 1% because of chest pain, bleeding rarely, and perforation rarely as well. So, I typically like to take the approach that was in Evan Dellin's guideline in the past, and I think, I'm not sure if this is how the Northwestern group does it as well, but I typically like to wait until after the effect of medical or dietary therapy has been assessed. Again, I quote Iko Hirono from Northwestern. You know, narrowing didn't occur overnight, and we're not gonna get it better overnight either. This is a gradual process. There's not a rush to get it done. There's not a rush, but you wanna move in an ordered fashion. The typical effect of dilation is for at least a year, and the conservative approach that I follow is to start low and go slow. The goal is an esophageal diameter of 16 millimeters, and if you're starting with a narrow caliber in the six, seven, eight millimeter range, that's gonna be multiple sessions, typically three millimeters or time, or one can take the approach of waiting to see if there is a rent scene, and if there's a significant rent, you stop that session at that time, and instead of bringing someone back in six, eight, or 12 weeks, you generally bring them back in between two and four weeks. So you have to tell people up front there can be multiple sessions that are needed. We've talked about this, and importantly, this does not address what's going on beneath the surface. So you can, this breaks up fibrosis, but everything else, the eosinophilic inflammatory pathway continues, aeroallergens, cytokine activation, TH2 activation, and that entire pro-inflammatory response continues around and around. So really, you're putting a Band-Aid on the problem. It's not ideal first-line therapy, although some physicians, including my mentor, believe that that's the case. What about combination therapy? This was alluded to in one of the questions. Oftentimes, we'll see patients in our office who are placed on what I call triple therapy. They're placed on a topical steroid, a PPI, and an elimination diet. So just think about that. You have trouble swallowing, and your doctor tells you, I want you to take twice a daily PPI. I want you to mix up one of the steroids, and by the way, like you see a dietician commence a six-food elimination diet, your head is spinning. And not only that, not only are compliance problems, but if it works, then the job of the gastroenterologist is then to untangle what exactly of those three have worked. So the goal of therapy is not only what I call deep remission, but you're looking for the lowest dose or the lowest amount of an intervention that's gonna keep someone in deep remission. If you're starting on triple therapy, you have no idea where you stand. As I said, it's common. It's very understudied, very limited data, and the issues of cost, compliance, and this untangling that we have to do is part of the conundrum. So how do you assess response to therapy? So as I've alluded to multiple times, and Dr. Gonzalez has alluded to, symptoms are not a good way, and probably one of the best studies that was done was this, but was done by Katja Saverina in Switzerland, who developed a very well-validated symptom reporting measure that is used in clinical trials as well. And that showed that if you look at remission using symptoms by whatever metric, endoscopy, histology, and no matter how you define histologic remission or endoscopic remission, there's a very poor correlation between symptoms and what's going on biologically in a given patient. So as such, again, if you remember nothing else from this talk and this session today, symptoms alone are not enough to guide therapy. We've talked about this, and I'm gonna skip this because Dr. Gonzalez has gone over this very well, but again, if you simply, or if your doctors or people you're talking to or your friends, if the question is do you have trouble swallowing, the answer is often no. But the follow-ups are do you eat slowly? Do you avoid certain consistencies? Do you need a chaser on a regular basis? The answer to that is often yes. So asking about trouble swallowing alone is not enough. So to assess response to therapy, you're looking for the following. Histopathology, the goal is less than 15 eosinophils per high-powered field. The aspirational goal is to get as close to zero as possible. Resolution of symptoms in the absence of dietary modification, so you don't need the chaser. You can eat freely whatever you want. And endoscopy is the resolution of the features of inflammation. What Dr. Gonzalez showed you is that the features of inflammation that go away are exudate goes away, edema goes away, and linea furos go away as well. Fibrosis features can improve with medical therapy, but things like rings will typically not resolve in the absence of dilation. And the guidelines, in fact, concur with this. And again, this is an important unmet need that all of you have the potential to impact, is that people look at us funny at national meetings or when we speak about this, is that what do you mean you need an endoscopy? I can just tell. And in fact, our professional guidelines do agree that the use of endoscopy with biopsy to assess disease activity after a change of therapy is reasonable for all the reasons that we've talked about already. And what about chronic therapy? What's the rationale for chronic therapy? This was alluded to. The disease does persist without treatment. And this has been shown in the natural history studies that Dr. Gonzalez has shown, as well as the placebo arms of clinical trials. As Dr. Gonzalez has shown, prolonged disease duration without treatment leads to fibrocytic complications. And what was not shown, but we'll get into in a moment, is that when you stop therapy, disease activity recurs rapidly. And this is from Evan Dellin's study, that randomized controlled trial looking at budesonide versus fluticasone, off-label use of both. And in that study, patients followed over time. 57% had a symptom recurrence prior to one year. The median time to recurrence is about nine months. And for the 33 with recurrent symptoms, the median time was 130 days. And you'll see variations of this. And I typically quote patients that within six to nine months, there's about an 85% chance that you're gonna relapse off of therapy. And we cannot predict who's gonna recur. Furthermore, in that trial, Evan went to the trouble of getting people in remission. But what happened after therapy stopped? The EREFs, the endoscopic reference score increased. The esophageal caliber decreased to what was seen prior to treatment. And the previously dilated strictures narrowed again to the pretreatment diameter. So again, if you go to the trouble of dilating somebody out on multiple sessions, it's nice to be able to tell someone, you are in a good place. We don't need to keep doing this as much. And if you stop therapy, the chance of us having to restart all over again is quite high. Now, the data in support of long-term therapy, this is what we think, but the data is somewhat soft. It's observational and it's suggestive, and it is a narrative that goes along with how we view this disease. Topical steroids in a Swiss cohort, if you look on the histograms, you can see these basically are quartiles of corticosteroid use over time. And quartile four are individuals who use steroids the most often, quartile one the least often. And the chance of food bolus impactions recurring decreased with longer compliance and longer duration of topical steroid use. Similarly, if you control inflammation, can you decrease how often you need a dilation? In fact, in a small study, it suggests that's the case. Everybody starts on the top line with the same diameter after dilation, but the number of dilations needed after control of inflammation are much lower than those who did not have inflammation controlled. And in long-term data, looking at the orally dispersible budesonide compound that's available in Canada and approved in Europe, the median time to relapse in a placebo arm was 87 days, and it was over a year in individuals who were maintained on chronic topical steroids and the budesonide orally dispersible. So who were candidates for maintenance therapy? This is where it's a no-brainer. If you start with a narrow caliber salvage it's gonna be a significant lift to get to a diameter of 60 millimeters. Once you get there, you certainly wanna stay there. Recurrent food bolus impactions, it's not anybody's idea of fun. Strictures, you'd like to dilate, get to your end point and not have to repeat. A rapid return of symptoms off of therapy. A prior spontaneous or dilation-induced perforation, that's a big deal. And then comorbidities, and if there are comorbidities, endoscopy is a big deal. There are risks and benefits. Anytime you do endoscopy, they're lower in the healthy, they increase as you get older. And this is from Alex Stroman. He's very practical. He said, what if you end up traveling to areas where food impaction can cause increased risk? So one of the things that I've been doing is I've been looking at the risk factors and I've been looking at the risk factors and I've been looking at the risk factors where food impaction can cause increased risk. So one of my good friends right now and colleagues is traveling to Machu Picchu, and that's not a place where I think you want to get a food embolism impaction. I hopefully will go to Patagonia at the end of the year while we're hiking through the Andes. I hope, I wouldn't want to get a food impaction there. So what about maintenance therapy? This was endorsed by the AHA guideline. It was a conditional recommendation with very low quality evidence. In patients with EOE and remission, following a short-term course of topical steroids, the task force suggests continuation of topical steroids over discontinuation of treatment. There's some caveats with this. It's not automatic. Some patients are very concerned about adverse effects with corticosteroids and they may wish to proceed in a different manner. All right, we're finally gonna get to your stuff. So as Dr. Gonsalves mentioned, this is a very, very exciting disease space to be involved with over the last 10 to 20 years. We've come a long way, and from where we first started, we're not even knowing what this was to where we are now is really quite traumatic. And here are the novel topical corticosteroid options for EOE, and we'll take the first one out of the equation because everyone knows what's happened there. Still in the running is a DARE's compound, which is a fluticasone, a Lodi's compound, fluticasone orally disintegrating tablet. That's in a phase three study. The Falk-Farmer compound, the budesonide, I've already mentioned, I'll show you more data for in a moment, and in fact, that moment is right now. So this is the induction phase. I showed you the long-term results of an orally dissolvable budesonide tablet. What does that mean? You put it on your tongue and you let it dissolve and it drips down in the esophagus. And the response for this, and really striking, the clinical histologic remission, namely people in clinical and histologic remission combined, 57.6%. That goes up to over 80% after 12 weeks. This is after six weeks of study. Clinical remission, again, is very nice. And histologic remission, which is unheard of in most studies, histologic remission here, less than 60 eosinophils, you're seeing that in upwards of 90, 95% of individuals. Endoscopic remission also in a high number. So importantly here, and as Dr. Gonzalez mentioned, I typically, based on this study, will use topical corticosteroids for a 12-week trial because you can see some increased benefit if you go beyond eight weeks to up to 12 weeks. But these results are really the best results with any of the topical steroids. Now, fluticasone-appropriate orally disintegrating tablet versus placebo, the eREFS, at weeks 12 to 52. This is some preliminary information that came out. This looks like this works over the course of one-year maintenance therapy with fluticasone orally disintegrating tablets. And dysphagia is improved as well. So let's get to the biologics. I'm sorry it's taken so long. But as in this diagram from a JAMA article that I was fortunate enough to participate in last year, there are a variety of different pathways that we can have for looking at biologics in EOE. The one of most interest to you, obviously, is where dupilumab fits in, which is IL-4 and IL-13. Sendakumab is IL-13. Liruntilumab is the eosinophil. Benrolizumab is the eosinophil. Proxampamp inhibitors at eotaxin-3. And there are others under development. So really, targeted therapy. You know, pan-inflammation, that's the topical steroid, where isolated areas is gonna be things like the PPIs. And the initial part of the disease is the food exposure at the very top. That is really at the point of stimulation of the entire disease. So as you're well aware, it's not just Sanofate and Regeneron that have skin in the game here. There are a variety of drugs under development. So Celgene BMS's compound, Sendakumab, is an IL-13 monoclonal antibody that binds to the IL-13 receptor. Your compound you're well aware of, IL-4 alpha receptor monoclonal antibody that blocks IL-4 and IL-13. Allicose is laryntilumab, which is an IV compound. It's a Cyclic-8 monoclonal antibody that leads to eosinophil apoptosis, and also leads to mast cell stabilization. Arena has Atrazumab, which is a selective inhibitor that really reduces lymphocyte levels at sites of inflammation. And Revolo has a compound that resets the immune system by preventing chronic pro-inflammatory immune response. I think I'm preaching to the converted here. I think everybody in this room knows how dupilumab works, but just to make sure we're all on the same page, it's an IL-4 receptor alpha monoclonal antibody. Inhibits signaling of IL-4 and IL-13. I showed you where that acts on the inflammatory cascade. It's approved for multiple other atopic conditions. And when you look at peer-reviewed literature, not FDA approval, here's what's out in peer-review. The 12-week randomized controlled trial that both Dr. Gonsalves and I participated in, that was the phase two study, if you look at less than 15 eosinophils per high-power field, the response was 83%. If you look at less than one, it's 13%. So very high response for that less than 15, and 65% for less than six. And again, depends where you set your threshold for eosinophil response. And in that trial, multiple other endpoints were improved. And it improved symptoms, it improved the eosinophils, it improved the HSS, which is another scoring system. But one of the most exciting parts of this is that this is the first study that clearly showed a compound that can improve distensibility. So this is by using endoflipid technology that measures compliance of the esophagus. There's some data here that suggests, and it was statistically significant, although it was a secondary endpoint, that dupilumab can improve distensibility of the esophagus, and that's what our goal for. We want that organ that none of us thinks about that gets food from here into here without us thinking about it, lets things down smooth and easy. Now, how that's gonna hold up long-term, we'll see. Sendakabab, the IL-13 compound, that's in a phase three study right now. It's a monoclonal antibody. It binds to IL-13 to the receptor. And there has been already a phase two trial that's looked at this as well, looking at two different dosing regimens, weekly 180 and 360 milligrams, looking at eosinophil counts. So do either dose improve eosinophil counts? The answer is yes. You look at the proportion with less than six, about 50%. You look at absolute counts, they drop nicely. And an exciting signal with this compound was that this worked in steroid refractory patients just as well as individuals who were steroid naive. So you have dupilumab, which shows an exciting signal in addition to eosinophil in terms of compliance. This compound has an exciting signal for refractory patients. This is one of the real important sweet spots, perhaps, for biologics in the future, is individuals who are refractory to other therapies that are not yet FDA approved. And this drug, at a 52 weeks open label, continued to work over the course of a 52 week open label study. And not only did parameters stay good, but they improved over time as well when you look at symptoms, eosinophils, EREFs. And lastly, a moment on refractory EOE. What is refractory EOE? Patients who have persistent symptoms, inflammation, or histology, or a combination of both. I wish I knew about this at the beginning. This is what happens when your flight gets delayed. So what are variables to, so when patients are refractory, it's not just 1-800-SANIFI-REGENERON or dupilumab prescription. There are a number of factors that one has to consider. So as I showed in the beginning, you wanna line up symptoms, histology, and endoscopy. There may be disconnects along the way. So is there histologic remission with ongoing clinical symptoms versus both histologic and a clinical non-response? This could be related to compliance. It can be related to inadequate dosing. It can be related to inappropriate administration of steroids. They should be administered away from meals. It can be related to everything is histologically gone, but there's ongoing fibrosinosis. And this new entity that we know of called esophageal hypervigilance. And this is my last slide, or my next to the last slide. So this is some novel work that took place in Northwestern. And the group at Northwestern looked at 103 patients with EOE and dysphagia and difficulty eating certain foods. And they looked at individuals who had, looked at these individuals and found that ongoing symptoms could not be predicted by endoflip characteristics, namely compliance, endoscopic features, or histology. In fact, what they found was individuals who had ongoing symptoms had more esophageal hypervigilance as measured by a variety of symptom scoring tools and more symptom-specific anxiety. And there was no correlation between the physiology and symptoms. And the question is, why is that? So again, that question that came from the back, this is a no big deal disease. Who cares? It's not gonna kill you. You know, quality of life is a big deal for what we do. So improving people's quality of life is where the compound that you are gonna be working with is gonna have a major role and there's something to be said for that. So to summarize, the goals of EOE therapy are symptom improvement, control of inflammation, and prevention of complications of remodeling. Shared decision-making is crucial in terms of how management decisions are made. Both dietary and medical therapies are effective in most, but not all patients. And right now, we can't predict what therapy is gonna work in what patients. That's a major unmet need as the portfolio of options continues to increase. And the confusion factor for patients and physicians and caregivers is gonna continue to increase. You can't rely on symptoms alone to guide therapy and we need to be more aware of this entity of hypervigilance and anxiety. Relapse is the norm after cessation of therapy and the lack of FDA approval remains a major unmet need. Again, I had submitted updated slides that didn't make it into the slide deck and there are multiple compounds to treat EOE that are in the pipeline, but no FDA approvals to date other than Dupilumab. So before I stop, I want to acknowledge Seeger. This is, Dr. Gonsalves has mentioned this. This is a consortium that both of us are lucky to be part of. I think the thing that another editorial comment didn't make is that you'll find that the eosinophilic esophagitis and eosinophilic disease research group, this is a really nice group of people and the present company accepted, really collegial group. It's pediatricians, adult folks, gastroenterologists, allergists, basic scientists, translational scientists and importantly, part of the Seeger consortium is the patient advocacy groups who have had a major impact in the direction of research in this field. It's a highly collaborative group and hopefully you'll find this group as enjoyable to work with as I have. And thank you very much for your attention. Thank you.

eosinophilic esophagitis

inflammation

treatment options

biologics

refractory EOE

endoscopy

symptom resolution

research