Okay. Hopefully, you're all seeing my second talk. It's on medical anti-therapy for eosinophilic esophagitis. And I did not include in my first talk because I wasn't talking about therapeutics beyond dilation. My disclosures, which are listed here, I do have a number of consulting positions, and I've been involved with multiple clinical trials in eosinophilic esophagitis. I will be discussing off-label use of medications, as well as Dupixent, which I've been a consultant and involved with the clinical trials for Dupixent. So, this update on the management of eosinophilic esophagitis is simplified. I'm just going to talk about two things. Just first, look at what's new with commonly used therapeutics. And secondly, talk about the role for biologics, which have now emerged on the scene for eosinophilic esophagitis. So, prior to May of last year, our therapeutic options for eosinophilic esophagitis were the three Ds. We call this drugs, diet, and dilation. I've already talked about dilation. For drugs, we had proton pump inhibition and swallowed topical corticosteroids. And for dietary therapy, we had elimination diets. We had the elemental diet, and we had the algae testing directed diets. So, for proton pump inhibition, you guys are all very familiar with this. PPIs are no longer required for the diagnosis of EOE prior to 2018. PPIs were incorporated into the diagnostic evaluation, but they've now been removed. We don't need a PPI trial any longer. Instead, PPIs are now considered to be a first-line treatment option for the management of EOE. PPIs were recommended in the 2020 AGA Joint Task Force on Algae Immunology Guidelines, with an overall histologic effectiveness of 42%. The effectiveness, widespread availability, ease of administration, and high degree of safety position PPIs as a popular first-line treatment option. In fact, in my own clinical practice, I almost always start with PPI therapy before I go on to other forms of diet therapy or medical therapeutic options. Most studies that have looked at PPI therapy in the clinical trial space have used either a double dose given once daily or standard dose given twice daily. Practically speaking, you know, these are mostly 20 to 40-year-old patients who have trouble remembering to take a medication. So, I find it much more practical to give them a single dose, I'm sorry, a double dose once a day because they're going to have a hard time taking BID dosing. There has been a loss of histologic response described in a few case reports and case series, but this appears to be uncommon. Under 20% of patients described having this loss of histologic response to prolonged PPI therapy. Now, what about swallowed topical corticosteroids? There have now been well over a dozen double-blind placebo-controlled trials that have shown the efficacy of swallowed topical corticosteroids, both in children and adults that have eosinophilic esophagitis. This was the only therapeutic class that got a strong recommendation in the 2020 AGA Joint Task Force Guideline, overall histologic response of 65%. Side effects really dominated by candidiasis, either in the esophagus or in the oral pharynx. And although the numbers look high, 4 to 16%, what I find in clinical practice is it seldom causes symptoms. It's something that you notice when you do the endoscopy or if you examine the patient's oral pharynx in the office, but it rarely produces symptoms that require treatment. When it does occur, you can, of course, try lowering the dose of the steroid, or if you need to, you can use antifungal therapy. Potential long-term systemic adverse effects such as adrenal insufficiency, growth suppression, osteoporosis, no significant safety signals have been demonstrated in prospective randomized trials, but of course, we're looking very carefully at these side effects in ongoing clinical trials. In terms of regulatory approval, the European Medicines Agency, which is the European equivalent of the FDA, did approve a budesonide tablet formulation in January of 2018. However, this formulation is not available in the United States. It's only available in Europe and in Canada, but not in the US. In the US, we did have completion of a phase 3 clinical trial program using a liquid formulation of budesonide, but the FDA denied the new drug application in 2021 and requested that the company perform additional studies to show its efficacy. The company indicated discontinued development of the product at this time. There is, however, some hope that we have a phase 3 clinical trial of a fluticasone oral disintegrating tablet that is ongoing at this time. So hopefully, in the US, in the not too distant future, we will have an FDA-approved esophageal optimized formulation of swallowed topical corticosteroids. At this time, we still have to resort to off-label use of swallowed topical steroids. In terms of dietary therapy, you're all aware that there are different forms of dietary therapy. There's the elemental diet, the empiric elimination diet, and the algae testing directed diet. All three forms of diet therapy did get conditional recommendations in the AGA-JTF guideline, but what you'll notice is that the quality of evidence that informed this recommendation and also the histologic response rates did vary between the different dietary approaches. If you compare the published data on the different dietary approaches, and this is looking at the histologic effectiveness of the different diet approaches, clearly the most effective dietary approach is the elemental diet. That's the formula diet that gets rid of all dietary protein and gives your patient only amino acids. These formula diets are not very palatable. Most patients do not want to continue on a formula-based diet only. Even though it has the greatest histologic efficacy, very, very rarely is it used in clinical practice. In terms of the empiric elimination diets, the six-food elimination diet is the most effective than the four-food elimination diet, which gets rid of only milk, wheat, soy, and egg. A two-food elimination diet comes in fourth place with milk and wheat, and a single-food elimination diet getting rid of only dairy products was the sixth most effective dietary therapy. You'll notice that tying the place for last place was the allergy-testing-directed diet, and that's the approach of having the patient go to the allergist, get the skin prick and patch tested, and try to decide which foods the patient will react to. It turns out the allergy-testing-directed diet is way too inaccurate, way too many false positives and false negative results from allergy-testing-directed diets. This has pretty much fallen out of favor, and the empirical elimination diet is the primary dietary approach that's recommended in most centers in 2023. Now one piece of data I want to share with you, which is now online at Lancet Gastroenterology and Hepatology, just accepted for publication, is the first prospective diet study that was ever completed. It compared a six-food elimination diet to a single-food elimination diet. This was the SOFEED study, randomized multi-center trial, that compared milk alone to a six-food elimination diet, and this was an adult study that compared these two different dietary approaches. Now if I had to ask you which dietary approach would work, which would be the most successful, I would bet those of you who have not read the article would bet that the six-food elimination diet should win out over the single-food elimination diet. And that was what was predicted, that's the way the study was powered. However, this is why we do prospective randomized trials. It turns out that when you looked across outcomes, histologic efficacy, symptom efficacy, or endoscopic activity using ERAFs, identical results for a single-food elimination diet compared to a six-food elimination diet. Now a lot of us are now stretching our heads looking at why this occurred, but this is the data as it stands now. So I think this adds a lot of credence to the idea that maybe less is more, maybe we should be shifting more to less restrictive diets to manage our patients with dietary therapy for eosinophilic esophagitis. So just to summarize dietary therapy for EOE, what to do, the emerging data does support the effectiveness of these less restrictive diets, whether you're doing milk alone or a two-food or four-food approach, or in some cases a step-up approach. I think it's very important to obtain a consultation with a dietician, involve an allergist for concomitant IgE-mediated food allergy, outline the commitment for multiple endoscopies that are required during the elimination reintroduction process, and finally, review with your patient the allowed foods. I think it's easy to say, well, eliminate six foods, but you should tell the patient what foods they can eat. This is basically a meat and potato lover's dream. They can have all the meat and rice and potatoes they want, all the vegetables and alternative grains that they like. And emphasize that the long-term goal of the dietary approach is the elimination of only one or two foods. It's not the elimination of all different foods from the patient's diet. I'm going to just skip over this slide here. Finally, I want to conclude with the role of biologic therapy for eosinophilic esophagitis. Biologic therapies are approaches that are using monoclonal antibodies that are targeting specific allergic cytokines involved in the pathogenesis of eosinophilic esophagitis. And some of the key cytokine mediators for eosinophilic esophagitis are the allergic cytokines IL-4, IL-5, and IL-13. Dupilumab is a monoclonal antibody that's directed against IL-4 receptor. It inhibits signaling of both IL-4 and IL-13. It's already been FDA approved for over five years for the treatment of moderate to severe atopic dermatitis. It then got approved for moderate to severe asthma, and most recently got approval for chronic rhinosinusitis with nasopolyposis. That's a mouthful. So, the concept here is this particular monoclonal antibody has already been approved for multiple other type 2 or atopic diseases, and most recently was studied in a phase 3 clinical trial program for efficacy for eosinophilic esophagitis. This was a three-part phase 3 clinical trial program. I'm summarizing here the induction data from the Part B randomized placebo-controlled trial, 24 weeks of Dupilumab compared to placebo. The co-primary endpoints in the phase 3 clinical trial program focused on histologic efficacy and symptom efficacy. So, in the Part B program, 159 adult and adolescent patients were randomized to Dupilumab or placebo, and here you're seeing on the left-hand side the histologic efficacy driving down the eosinophil counts to less than or equal to 6 eosinophils per hyperalveolar field. This was achieved in 59% with Dupilumab compared to 6% with placebo, and for symptom efficacy using a validated PRO tool called the DSQ, significantly greater proportions achieved symptom benefit or symptom reduction in dysphagia with Dupilumab compared to placebo. So, the study robustly met the co-primary endpoints and therefore led to the FDA approval. Endoscopic activity was a secondary endpoint for this clinical trial using eREFs, and again, you're seeing a substantial endoscopic activity reduction here, 66% reduction endoscopic activity with Dupilumab compared to an 8% reduction in endoscopic activity with placebo. So, based on this, the FDA did approve Dupilumab just at the time of DDW last year. It's now been approved for children and adults aged 12 years and older who weigh at least 40 kilograms based on the success of the phase 3 clinical trial program. Keep in mind that this phase 3 clinical trial program only enrolled patients who were PPI non-responders. And in fact, about half the patients who had been tried on steroids for this clinical trial had failed swallow topical corticosteroid use. So, considerations for who might be candidates for Dupilumab in 2023, they might be patients who have concomitant atopic conditions for which they already have an indication for Dupilumab. I've been focusing my own use of Dupilumab for patients who are refractory to other first line therapies like PPIs, swallow topical steroids, or dietary therapy. There is also a group of patients who are intolerant to steroids or unable to tolerate an elimination diet. And consideration, again, for patients who are requiring multiple forms of therapy for multiple atopic diseases at the same time. There may be a role for severe disease phenotypes, but these are relatively uncommon. Before I conclude here, I just want to acknowledge that there are a number of advanced therapeutics other than Dupilumab that are in the pipeline that are in current phase 2 and phase 3 clinical trial program. And these span the gamut from other biologic therapies to small orally delivered immunomodulator therapies. So to conclude this tour of the update on the management of EOE, shared decision making is important in the selection of whether you're going to choose PPIs, swallow topical corticosteroids, or elimination diet as initial therapy for EOE. And Dupilumab has now emerged on the scene as an FDA approved therapy that addresses unmet therapeutic needs for EOE, and several other biologics or immunomodulators are now in development for both EOE and eosinophilic GI disease. With that, I'll conclude, and I think we'll be transitioning to a Q&A and case discussion. Thank you very much for your attention.

eosinophilic esophagitis

biologics

therapeutics

shared decision making

Dupilumab