Would you, if you didn't see results then? Yeah, it's a good, we don't know how long later to do the endoscopy for. If I'm changing a medicine over, I don't necessarily need it to be in remission at two months, but I need to show they're showing progress. So if I start a patient, if I see that person on Friday night for his endoscopy for his food infection, I start him with PPI, by a week or two later, his ESM might have dropped dramatically for him. It's really not gonna take two months for them to then go down to nothing. So if in two months I don't see any progress, I may not stop the medicine, but my gosh, we should have shown some histological response or diameter change at that point as well from two. So you may not get a full response done, but there should have been something changing for them, symptoms wise or histological for them as well. I've had some physicians say that it takes a while for the PPIs to work effectively, but based on that, that's not necessarily true. That's a good question. If there's strictures, that's probably what's happening and the fibrosis will not get better with the PPIs. But inflammatory wise, so when they come and see any of us for the food infection, we always repeat this about four weeks when they come in the hospital with us. And sometimes the entire esophagus is fully normal. You would never even know they had EOE as well. Sometimes they come with me with dysphagia, they have ATP, eczema, and allergies, and they have some problem swallowing. And some have argued, don't even start the medicine because by the time you bring them two weeks later, it's all gonna be always normal for them sometimes. So it's pretty dynamic. To your point, we don't know the personalized medicine EOE yet. We're learning that who gets better that fast and as well. Is that the right mechanism for them? Those slow responders are probably not gonna respond to the drug anyways for them as well. Or if they don't take it. Most people are not taking the right time anyways. They'll be just saying, go to your pharmacy, pick it up. That's gonna be in 30 minutes prior to your meals for it to be effective at all. If you take it after meals, before bedtime, it's not gonna help you. Yeah. Do you plan on repositioning Dupiccent? Yeah, it's a good question. So on the EcoHirano study, the improvement patients who got improvement on Dupiccent were TH2 high. They had comorbid ATP with eczema, allergy, or sinus issues for them as well. So the patient I moved over for the first one on Monday, thanks to Jordan's help with the pen she gave me as well. She could not take her, she's a great patient. I scoped her, had dialyzed her two months ago. Has been on PPI, has had a full response. But she tells me almost every day, I can't take my PPI. I'm too busy working as well. So I may take it once a week at most. She has no option to take a Flutix on steroids with her as well too. And she's very excited about using a once weekly injection as well. She also has eczema all over her hands. That's not controlled right now. Has really bad sinus allergies too. So if they can comment allergies are ready for them, I think there is a TH2 high response that I can't check on their blood tests. I check sometimes eosinophil counts, which is not kind of labeled right now. But that's where I'm using it right now. Because we still are learning where it's gonna be positioned. PPIs and steroids, PPIs thankfully are still really cheap. So you gotta, I'll compete something that's over the counter, effective. A lot of patients have no insurance. So I say use that one, we're gonna still help you no matter what happens to them as well. But I think for sure the high TH2 responders with ATP, eczema for them are already in place. Those people do really well with blocking IL-4 and IL-13. The future competitors that, there were a lot of different mechanisms, but there was one specifically that was just an IL-13, whereas dupilumab was an IL-4 and 13. Can you help me understand why someone would pick, if ours blocks two, why would you ever pick one that just picks one? Is there something different from that? Yeah, because if I pick your same medicine, that's a patent and fracture. So I can't get that approved by the FDA. So I've gotta go to different mechanisms to get approved, to get any money made on those as well too. So if I block IL-4 and IL-13 as well, unless I've chained the MOD on that one, it's a patent infringement on your drug company. So they can't use that one anymore when they go through drug discovery pipelines as well too. IL-13's already been used for other conditions, just like you guys use it for EOE. You back into it the other way. You already had it for nasal polyposis and ATP as well. And you said, oh, this is helping the EOE patients as well. That drug has already been used for other conditions as well too. They're atypic as well. So it's like IBD, we have 14 different mechanisms. One's IL-12 and 13, one's IL-11 alone. We're just, they're just trying to find any way to get drug response and get it on market to get payments as well too. So that's that part. We don't know. So you'll never get a head-to-head for RPC-4046 with your drug. Because it's not, it's gonna be losing battle for everybody. You just need to get approval. Once you get approval, you let us figure out on the back end what's actually better, who's getting better with it as well too. Now the Estrosimod works differently than your patient, and so does the BDS-9 tablets. So that's a different mechanism than you guys have as well too. Stop me if I have to go, Keith. What's the conversation sound like with your patients on how long they'll be on PPIs, how long they'll be on swallowed TCSs? I've been getting that question a lot out in the field is, so how long will they be on Dupixent? So what's that conversation sound like? Yeah, that's a hard one. So we know if I stop everything, they're gonna get recurrence of strictures for them. So giving drug holidays on a PPI and steroids are a little easier for me because there's no concern for antibody formation for them as well. You know, when you go to biologics, which we don't know for any of these biologics for you as well, but we know for the anti-TNS, which are different, that's for Crohn's. But if I stop Humira or Remicade and just give you six months off, you may get antibodies and that drug may never be effective for you again. And so one thing we're working with your guys is figuring out are there antibodies we can check for your drug? But right now we don't need to. But we can't stop Dupixent right now. I would feel uncomfortable giving a drug holiday right now knowing we know about antibody formations and other biologics as well too. Whereas PPI and steroids, you can stop it and restart it, it's fine because that's not a biological mechanism how to get it as well too. But any of those biologic ones, I told my patient on Monday, if we start this show, it's from now on. Until I have evidence, we can stop this one for you. Whereas if you miss your PPI, you may feel symptoms, but it's not gonna hurt you long term losing a drug option for you as well. But that formation is not known to be with any of our EOE studies, but it's the same mechanism. So I'm a bit worried about that as well long term. So I'm gonna try to start it unless I know that someone's compliant. I'm fortunate to get insurance as well too, and we'll be compliant taking it long term. I can't have them miss multiple months for this one. Now missing a couple days doesn't matter. But yeah, they're on it for longer. Now, PPI's, I de-escalate for them, so I'll go down the dosing. Send your foot to Hickerson, I can at least change the dose for them. I can't change it with Dupixent yet. So with the PPI's, you're basically symptom driven as far as when you give the holidays and how long you have them on it? I mean, really they're on maintenance. But there's some patients who I say, if they don't wanna be on it forever, I do give them some time off and say, all right, we know you may stretcher. The risk of stretching two weeks off of it is not a big deal, honestly. And I can trust them. They haven't had symptoms for a long time as well. So that's where nationally, our guidelines would say stay on maintenance therapy. But practically, patients wanna come off medicines and take time off, or they miss it, honestly. So instead of making them miss it, I say, just take it at Ebola's time, and then maybe you won't take a week or two off. If you're in remission at that point, it's probably gonna be okay. I have a question. Where do you see Dupixent fitting in? I mean, based on guidelines, based on what you have available now, what you're seeing, where would you, patients are coming to you already on PPIs. I'm hearing from a lot of GIs that the steroids are first line to them because they're already on a PPI by the time they get to you. Where would you kind of interject it? Yeah, good question. I think similar to what you asked earlier as well, too. So just because FDA approval probably doesn't mean it's gonna be first line, I will say. So in our group, at least in Southeast, we have a large percentage of response to PPI alone. So when they see us in the community and they come see us, once I get them the right dose and compliance, they get almost all my response in that as well, too. So I have a hard time making them over to a biological therapy right now, unless they have concomitant ATP, eczema, or THC response, they're not well-managed otherwise in this world, too. If they don't have them and they're doing well on the PPI, I will not change their dose over for them because what I don't know is, can I take it every week for them? They have a refrigerator, they got access to it as well, too. Can they pay for it as well? Are there antibody formation long-term for them as well? I don't know those things. So what'll happen, the guidelines will say, PPI, yes, steroids, yes, Dupixan also, yes, can be given. But they won't triage for us which one goes first. You need a guideline to say it's approved, and that's what it is now, but we won't triage who goes first because we don't know that. That'll happen in U.S. studies now, moving forward as we get all options available for people as well, too. A couple weeks, there's been an observation that when we're describing Dupixan as not being immunosuppressive, the next logical question is, well, how do we know that? Or where's the science behind that? Knowing that a lot of your peers, and yourself included, are familiar with other biologics that are associated with immunosuppression. So what would be the type of information we could share when that question comes up? Because it's coming up quite regularly now. And that's a great question. I actually probably asked that to Jordan as well, too. I was just seeing how well she was gonna do this list. So the important thing is, she's asking, when you have a provider and you're asking about the role of any biologic, I'll just make it in general, for anything that blocks IL-413, how do we know it's safe in terms of immunosuppression for you compared to maybe other biologics for GI trucks, so like Crohn's? And those medicines like Humira and Remicade, those are blocking anti-TNF. So there are biologics overall. So whenever you see the M-A-B, that means a molecular antibody. So you know, that's the reason it means an antibody. When it's a U before, it's humanized. If it's I, it's chimeric. So small things, but when you have stuff like infliximab, which is chimeric, high risk of antibody formation and reaction as well, too. Anything that drives anti-TNF, high risk of reactivation of hepatitis B and quant gold. For your drug, there is some D-line disorders that's been seen. It's on your black box package as well, too. And also the parasites. But it doesn't block anti-TNF. And that's a critical role for immunosuppression for a lot of diseases as well, too. So you can use the data that you already have on your other conditions, because you guys already have that from approval as well, too. But when you block IL-413, those are only really useful for parasites and some weird D-line disorders as well, too. But not like the anti-TNFs. They're not the same mechanism as well. Because we know how to manage them and what to monitor them in the long term as well, too. But it's a different blockade. And things with IL-413 are not super helpful for the rest of the disease. For T-cell lymphomas, which we see for other medications that cause immunosuppression as well, too. That didn't happen, as far as we know, with this drug or IL-413 blockade. Yeah. Seen an increased risk in upper respiratory infections, right, compared to the placebo arm now. These are different than serious infections that are associated with type one inflammation and things of that nature. Is there, mechanistically, what do you think is going on there, that you see that increase, but we know it's not immunosuppressive? Yeah, it's a good question. And I think we're stealing data from the atypic patients who probably have some underlying infections. We probably didn't undertreat them as well. So I won't know as much about that, as opposed to my allergist for using it for that, because I wonder if there's some undertreated diseases at present for them, and we do let them de-mask them as well, too. We're early for EOE, so I don't know if we'll see that as well, too. But I think the atypic patients who have a lot of allergies or sinus issues, I do cancel her on Monday. I was like, you know, these can happen, but she has really minimal dose. It's more eczema for them as well. But I think that's a real signal to be mindful of for them. So it's not the same as the reactions to the Humira Remicade, but it's the same pathophysiology of blocking immune system, and that may have been helping clear some infection in their upper respiratory tract as well. I got one for you. So it sounds like you were pretty comfortable using PPIs to control the symptoms, and not changing therapy. Like, if someone's on a PPI, and their symptoms aren't controlled, are they still at risk to progress onto that fibrotic state? And if they do progress, is that state reversible with PPI use, or maybe do PIXEN use? Talk about that for a minute. Yeah, so your question is, if you have an inflammatory phenotype, and you're on therapy, your risk of going to fibrous knot disorders, as long as you're in histological and symptom response, you're not gonna progress with no symptoms and no histology of inflammation at present. So you don't go from inflammation, or no inflammation to just fibrousness on its own. The counter to that is that we're genetically driving all these patients. So some people bypass inflammatory cascade. It's rare, but it can happen. You know, some patients have never had inflammation their whole life, maybe they did. Something that's genetically different about those patients, and those were inflammatory alone as well, too. But if you have the inflammatory cascade, where you had inflammation, you treat them, and they get better, their risk of going to fibrous knot is not gonna happen. And that's that same cascade, because they're already better. There's no more drivers of inflammation going onto esophagus. Isn't it true that you said also that that doesn't always match up, though? Like symptomatic remission and histologic remission. So they could be symptomatically controlled, then their eosinophil count could be really high, and then they could be maybe progressing. Is that not accurate? But if their inflammation on their biopsies are normal, they're not gonna progress their fibrous knot disease. So yeah, patient symptom alone is not enough. But endoscopically is better, even if they have symptoms, honestly. If they're endoscopically have no inflammation, they're not gonna progress their fibrous knot disease. So you'd have to have a repeat scope to know that. Yeah, I would not let someone go years without a repeat endosc. Because they probably, they may, these therapies, we still don't know who should get what. That'll happen in our lifetime as well, too. But you maybe miss the whole target about PPI use or steroids, or even Dupixan or RPC-406. Like, you just don't know. And so we need a repeat biopsy to show what's going on for them as well. One more question. About that fibrosis, right? Is there any scoring of that to dilate it? Yeah. Is that a possibility? I mean, we use an EREF score, and EREFs to S is stricture. No, no, no, I mean to actually score it, to cut it, right? That's what we do, yeah, yeah. So me and Dr. Chan just tear it open every time we go in there. Okay. And so it's pretty brutal. You'll see it tomorrow when you go to your esophagus. You don't have strictures. But you can't use medication to help that anymore. You can't use food elimination. So all we have is brute force now, which is fun for us. But we go in there, we endoscopically either do a bougie dilation or balloon dilation. It opens up the stricture and stuff. And they get response automatically as well. Is there a benefit of sending biopsies out to a GI pathology lab versus just a general pathology lab? Yeah, we use that a lot for Barrett esophagus. So when you go see Dr. Chan, I always tell my patients, you're buying him and his pathologist. And so when you're coming to see us, you're also doing that as well. That's really important, I think, for pre-cancerous conditions. Eosinophils are really easy to find. So I wouldn't be as worried about someone missing it. We also rely on biopsies, but we also are using our eyes. So if you have a low performer of endoscopy and a bad pathologist where you're in trouble, I can tell you automatically, I don't need a biopsy. It just helps me know if you're gonna go to remission long-term as well too. So if you are a provider and you do the endoscopy and you don't use eREF score in your notes and you just send biopsies willy-nilly throughout and your pathologist is kind of lazy as well too, that's pretty uncommon though. But Barrett's, they'll always refer patients back to us to get that overread. But for eosinophils, that's pretty rare to miss. They're easy to find. Even I can look at them and tell you. You'll find them tomorrow. You'll find them easily as well. Yeah. In your clinical experience, what percentage of patients don't respond to PPI therapy? Yeah, we studied this. So 80% of our patients do respond to PPI who have reportedly failed it. So if you come see one of us, you've already been in the community practice and already failed either PPI or reportedly failed it. So that data from E. coheranos though is less. It's about 50% of response instead. But we're a little bit higher. And it's probably just timing of the patient walking to the compliance, are you taking it? There's also dissolvable tablets you can take instead of the pills. Maybe they're not taking the pills and swallow the pills down as well. So there's things that are just logistically there that we find high response to us. So I really had to go to Platica so many more. I used to go more younger at this point. But now most are responsive to PPI for us. Or dilations. They have a stricture that's present for them as well too. Yeah. How long have you been checking for eosinophil counts in the esophagus? You mean as a society? Yeah, so this is what our chance showed. So we didn't know if this was a misdiagnosis for a long time, or it was a new diagnosis as well too. So we always counted it and we thought all the eosins were GERD. So I get a lot of referrals for eosinophil esophagitis. It's just GERD. So we don't put them on a biologic for just GERD symptoms as well. But the pathologists have been looking at this for over 30, 40 years for this one. Yeah. All right, thanks guys. Wow. Thank you.

eosinophilic esophagitis

personalized medicine

biologic therapies

Dupixent

patient monitoring