Melanie Cole, MS (Host): Welcome to Better Edge, a Northwestern Medicine podcast for physicians. I'm Melanie Cole. And today, we're highlighting eosinophilic gastritis, or EOG. Joining me is Dr. Nirmala Gonsalves. She's a Professor of Medicine in the Division of Gastroenterology and Hepatology at Northwestern Medicine.

Doctor, thank you so much for joining us today. So, I'd like you to start by explaining a little bit about eosinophilic gastrointestinal disorders. What are the current challenges with diagnosis and treatment of these conditions?

Dr. Nirmala Gonsalves: Thanks, Melanie, and thanks for having me today for the podcast. So, really important question to just understand what we're talking about. So, eosinophilic gastrointestinal disorders are thought to be immune-mediated conditions of the GI tract. They're food allergy-driven conditions that in response to food antigens, eosinophils and other inflammatory cells traffic to the GI tract, whether it's the esophagus, stomach, small intestine, and colon. And as a result, there's lots of inflammation in the tissue, and that can result in end-organ damage and the clinical symptoms that we see in our patients

. So, the umbrella term for these disorders are eosinophilic gastrointestinal disorders. And under that umbrella, we have eosinophilic esophagitis, which affects the esophagus, eosinophilic gastritis, which affects the stomach, eosinophilic enteritis, the intestine, and eosinophilic colitis of the colon.

Now, eosinophilic esophagitis is the most common of these disorders, and it presents with difficulty swallowing in patients with food impaction. And we think it affects about 500,000 patients in the US. Eosinophilic gastritis is significantly more rare, about tenfold more rare. We think about it affecting about three to six per 100,000 patients.

And that really is what presents challenges for diagnosing these disorders because they are rare. Eosinophilic gastritis typically presents with symptoms of abdominal pain, nausea, vomiting, feeling full more quickly, early satiety, bloating, and diarrhea.

Melanie Cole, MS: Well, thank you for that and for those clear distinctions. So, what did we know about the pathophysiology about EOG prior to the study we're going to talk about, and how did this study reinforce or advance this knowledge, particularly in the role of type 2 dysregulation?

Dr. Nirmala Gonsalves: So unlike EoE, where there was a really good link to food antigens and Th2 immune dysregulation, we didn't know as much about non-EoE agents, which are all the other things I mentioned, but specifically EoG, because of the fact that they are rare disorders. And we really just had case reports of these conditions before. But there were some prior studies that were very informative. One other study through the CEGIR Consortia, which is the Consortia of Eosinophilic GI Researchers, in collaboration with Northwestern, was a study we did called the ELEMENT Study, which showed a direct link of food antigens in eosinophilic gastritis, or EoG. So, that was one of the first similarities with EoE and EoG.

The next was another study done through CEGIR, which showed that there are certain genetic transcriptome or signature that was similar in EoE and EoG, so a similar Th2 signature. However, prior clinical studies other than the ELEMENT study, studies looking at other cytokines and blocking cytokines such as IL-5 or IL-13 or even anti-Siglec-8, they did not meet important endpoints of those studies.

So, there was really a huge unmet need in understanding pathophysiology of EoE and also developing treatments. Treatments had typically hinged on oral steroids, some cases topical corticosteroids, and even significant dietary elimination. So, all things that could affect quality of life.

Melanie Cole, MS: Yeah, that's so interesting. Now, when we think of the trial rationale and design, as one of the first randomized placebo-controlled trials in eosinophilic gastritis, what were the biggest challenges in designing this study, particularly patient selection, which we know is so important in establishing validated endpoints? How did the OMEGA framework help overcome them?

Dr. Nirmala Gonsalves: So, the study was called the DEGAS study, which was dupilumab versus placebo in adults and adolescents with eosinophilic gastritis. It was a collaboration with the CEGIR group, the Consortia of Eosinophilic GI Researchers, and the Rare Disease Network through the NIH. And so, this study really was a pivotal study trying to understand whether or not dupilumab was effective in treatment for patients with eosinophilic gastritis.

The biggest challenge when we think about researching or treating rare diseases is recruitment of these patients. Because these are rare diseases, trying to find the right patient population can be a challenge. So, working in collaboration with CEGIR, it was a collaboration with 11 different centers, helped to aid in that patient recruitment.

We looked at a study called OMEGA, which is a longitudinal assessment of eosinophilic GI disease across the ages, another collaboration with CEGIR. We had some really good information about the outcomes we wanted to look at when we designed this trial. So, that initial information was really pivotal in trying to identify what were the important endpoints, who were the patients we were looking for, and really what were the meaningful outputs that would help improve knowledge about this condition so we can ultimately get better treatments for our patients

Melanie Cole, MS: Well, that certainly is the end goal. And so, as we think about interpreting the primary outcome, the study met its primary endpoint and multiple secondary endpoints as well. So, which of these do you believe, Doctor, are the most clinically meaningful for practicing gastroenterologists? Take us from bench to bedside here when they're managing EOG, and why is that so important?

Dr. Nirmala Gonsalves: I think this is really the most important theme here that we're discussing is how can this be meaningful for the practicing gastroenterologist? When we think about inflammation in eosinophilic gastritis, EOG, we think about eosinophil levels.

And one of the big challenges was how many eosinophils were too high and how many were normal. And so, we really landed on a number of 30 there. Realizing data that we got from the OMEGA study, it helped to understand that an absolute number of eosinophils after treatment was probably not the ideal endpoint, but an overall reduction of those eosinophils were really a critical, meaningful endpoint.

So, that was really the primary outcome, the percentage of drop of eosinophils after treatment, because we think that eosinophils are associated with inflammation. They are associated with macroscopic inflammation of the gut tissue, and that was a very meaningful endpoint. So when we think about a practicing gastroenterologist, what do we really want to see in clinical trials?

We want to see a drop in those inflammatory cells, which we did in this study. We want to see improvement in that endoscopic change. As gastroenterologists, we see all the critical features of these conditions like ulcers, strictures, erythema, erosions. And the secondary endpoint was looking at that, a tool called the EG-REFS, which is a marker of endoscopic inflammation in the gut, in the stomach specifically. And we did see a significant reduction in the EG-REFS in addition to the eosinophil level.

Other things that we saw were on the histology. There are other tools called the EG-HSS. It's a histologic assessment looking at mucosal healing. We saw significant improvement there. And another novel thing that this study looked at was transcriptomics, looking at the genetic signature of patients with EOG before and after treatment. And after treatment, their genetic signature really did move towards normalization, meaning going back to what we would see in a patient without EOG or with treated EOG.

Melanie Cole, MS: So, Doctor, as we think of clinical implementation of off-label use, and based on your data, how should clinicians think about patient selection for dupilumab in real-world practice today? Again, take us from that bench to bedside and what practical considerations you want them to know should guide that off-label use.

Dr. Nirmala Gonsalves: I think the most important thing is the study showed that eosinophils dropped, endoscopic improvement occurred, histologic healing happened. Patients certainly did feel better as well, and the transcriptomics got better. So, how do we navigate this in a real-world practice? Now, dupilumab is FDA-approved for EoE and certainly other atopic conditions. It's not yet approved for non-EoE EGID. However, we did see such a profound improvement in our patients. I think this really sheds light on the need to do larger scale trials in this area, but it also sheds light on challenges. Because this is a rare disease, information from this trial should help us, at least in the more immediate sense, have other tools to treat our patients.

And I think in this case, if you had a patient with non-EoE EGID that you were really having a difficult time controlling, use of dupilumab can be reasonable in this setting, understanding certainly that it is off-label use at this time.

Melanie Cole, MS: Well, based on that then and the lessons that we're learning from, as you said, eosinophilic esophagitis or EoE. So, given dupilumab's success in that, what similarities and differences in response do you observe in EOG? And what does that tell us about treating that broader EGID spectrum?

Dr. Nirmala Gonsalves: When we look at the trials for EoE, their histologic endpoint was different, and they made that endpoint in about 70% compared to placebo. In this study, the numbers are less, 50%. But the endpoints were very different. So, it's very hard to compare. It's not apples to apples, so to speak.

I would say that non-EoE EGIDs, so eosinophilic gastritis compared to EoE, it is much more difficult to treat. It typically requires much more extensive dietary elimination or even oral steroids as opposed to topical corticosteroids. So, having the use of dupilumab here where it can really reset that inflammation and normalize or improve that transcriptomics makes a huge impact on these disorders.

Melanie Cole, MS: This is such an interesting topic, and although rare, you seem to be really learning more and more. It's an exciting time in this field. And as we think of the next steps toward FDA approval, looking ahead, what are the key design elements and unanswered questions that the next generation trials will really need to address to support regulatory approval and long-term disease management?

Dr. Nirmala Gonsalves: I mean, I think this trial was very, very informative. It was very informative to actually make such a significant difference with the doses that were presently used in the study. Now, one thing I didn't mention in the trial design is that the doses used for this trial were dupilumab 300 milligrams every other week.

And the reason for that was when this trial was designed, that was the FDA-approved dose for other atopic conditions. Now, this has subsequently been approved for EoE, and the dose for that is dupilumab 300 milligrams every week.

So, I think a real critical trial would be looking at this at a weekly dosing. We think that the patients who didn't meet the endpoints could actually meet those endpoints if that study design was a weekly dosing as opposed to every other week dosing. So, I think there are critical things that the study has shown evidence that dupilumab has been helpful, evidence that Th2 signature is really important, and that endoscopic improvements are really a critical endpoint for this condition.

So, I do think that there's a lot of potential here moving forward. I think we have to temper this all with, you know, when we have rare diseases, it's aspirational to think that we can have large scale, large number of patients in a trial. But with rare diseases, we really think that even with our trial which had 41 patients, this is very meaningful considering the baseline number of patients with this disease.

Melanie Cole, MS: Thank you so much, Doctor, for joining us and telling us about that study and really sharing your incredible expertise for other providers. And to refer your patient or for more information, please visit our website at breakthroughsforphysicians.nm.org/gastroenterology to get connected with one of our providers.

And that concludes this episode of Better Edge, a Northwestern Medicine podcast for physicians. I'm Melanie Cole.