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Anti–Siglec-8 Antibody for Eosinophilic Gastritis and Duodenitis
In this panel discussion, Dr. Ikuo Hirano and Dr. Nirmala Gonsalves join the show to share details about a recent study published in the The New England Journal of Medicine that examined the use of a novel anti–Siglec-8 antibody known as AK002 for Eosinophilic Gastritis and Duodenitis.
Featured Speakers:
Learn more about Ikuo Hirano, MD
Nirmala Gonsalves, MD is a Professor of Medicine in the Division of Gastroenterology and Hepatology at Northwestern Medicine.
Learn more about Nirmala Gonsalves, MD
Ikuo Hirano, MD | Nirmala Gonsalves, MD
Dr. Hirano is Professor of Medicine at Northwestern University Feinberg School of Medicine. He attended college at Yale University, medical school at the University of Pennsylvania and completed his medical residency and GI fellowship at Beth Israel Hospital in Boston.Learn more about Ikuo Hirano, MD
Nirmala Gonsalves, MD is a Professor of Medicine in the Division of Gastroenterology and Hepatology at Northwestern Medicine.
Learn more about Nirmala Gonsalves, MD
Transcription:
Anti–Siglec-8 Antibody for Eosinophilic Gastritis and Duodenitis
Melanie Cole (Host): Welcome to Better Edge, a Northwestern Medicine podcast for physicians. I'm Melanie Cole and joining me today are Dr. Ikuo Hirano and Dr. Nirmala Gonsalves. They are both Professors of Medicine in the Division of Gastroenterology and Hepatology at Northwestern Medicine. They're here with us today to share details about a recent study published in the New England Journal of Medicine that examined the use of novel Anti–Siglec-8 antibody for eosinophilic gastritis and duodenitis. Welcome to the show doctors. I'm so glad to have you join us today, Dr. Gonsalves, I'd like to start with you. Tell us a little bit about the clinical manifestations of eosinophilic gastritis and duodenitis. What are some of the common symptoms associated with these disorders? and has lack of recognition of these disorders lead to misdiagnoses and delay in diagnosis and treatment?
Nirmala Gonsalves, MD (Guest): Good morning, Melanie. Thank you for that question. Eosinophilic gastrointestinal disorders are chronic immune mediated inflammatory conditions of the gut. And by that, I mean, inflammatory cells called eosinophils infiltrate or go to the gut tissue and create inflammation, which leads to gut dysfunction, and that can contribute to the symptoms that develop. The disorders are typically named based on the organ involved. So, when the eosinophils go to the stomach in higher numbers, this typically has been called eosinophilic gastritis. When it involves the duodenum, it was called eosinophilic enteritis or more recently eosinophilic duodenitis.
So, patients who have these conditions, present with an array of symptoms, including abdominal pain, nausea, vomiting, bloating, feeling full when they eat, diarrhea and malnutrition. And depending on the severity of the disease, patients may either have mild symptoms or may have severe complications including weight loss, malnutrition, gastrointestinal bleeding, and even bowel obstruction or perforation. You raise an important point about the diagnostic criteria, because there really haven't been firm diagnostic guidelines; but what is currently used, includes having a certain threshold of eosinophils in the tissue and also having these characteristic symptoms. They are considered rare disorders on the order of six to eight per a hundred thousand patients.
But recent studies suggest that these disorders may be under-recognized and therefore increasing in incidence. Diagnosis, therefore is hinged on suspecting these disorders, referring a patient to a gastroenterologist and then obtaining adequate biopsy samples, during an endoscopic procedure in order to make the diagnosis. Due to these complications that I mentioned earlier, awareness, early diagnosis and treatment of these disorders is essential to prevent complications of these diseases.
Host: Well, thank you for that. So, Dr. Hirano, what's the current standard of care. And tell us a little bit about what has been done and how it's evolved over the years as you've learned more.
Ikuo Hirano, MD (Guest): Yeah, thank you, Melanie. I think it's really important to acknowledge that there really is no standard of care for either eosinophilic gastritis or duodenitis. Moreover, there are currently no medications approved for the treatment of eosinophilic GI disease by the US FDA. While systemic steroids are very effective for both the symptoms and signs of eosinophilic gastritis and duodenitis that Dr. Gonsalves mentioned, their long-term use is limited by obvious well-known systemic adverse effects. Diet therapies can be very effective, but are difficult to adhere to and can have negative effects on a patient's quality of life. Other therapies are often tried and these include cromolyn sodium and anti-histamines, but are at best modestly effective in clinical practice. Thus, there is a huge unmet need for the treatment of eosinophilic GI disease.
Host: I'd like you to expand Dr. Hirano on why these treatments that you've mentioned; you mentioned that dietary guidelines for this are tough to follow. So, you're speaking to other providers, tell them why some of these treatments that have been tried, have been inadequate and there is such a need for these improved therapies.
Dr. Hirano: Yeah. So, in terms of the available therapies again, the steroids, whether it's systemic or topical steroids are highly effective for eosinophilic gastritis, particularly, less so for enteritis or colitis, but the problem with steroids are the well-known toxicities for long-term use. So, they're great short-term induction therapies, but not so great for long-term maintenance therapies. As Dr. Gonsalves mentioned, these disorders are chronic disorders. They need some form of maintenance therapy the majority of times. The other therapies, I mentioned diet therapy. It sounds appealing to get rid of food allergens, but when you talk of getting rid of these foods from patients' diets, there's usually multiple foods and getting rid of very commonly ingested foods like milk and wheat and soy and egg and from patients' diets can have an adverse effect on their quality of life.
Host: So, then Dr. Gonsalves, let's discuss your phase two trial that examined AK002 for treatment of eosinophilic gastritis and duodenitis. Explain the initial purpose of the research and the methods and trial designs that you used during this study.
Dr. Gonsalves: Sure Melanie. The phase two Enigma study examined AK002 for the treatment of eosinophilic gastritis and duodenitis in adult patients ages 18 to 80. Just as background, Siglec-8 is an inhibitory receptor that is selectively expressed on mature eosinophils and mast cells and AK002 is a molecule that was developed against that receptor, that depletes eosinophils through, certain cytotoxic mechanisms and results in decrease of the eosinophils in the tissue. This was a multicenter randomized placebo controlled study, which was recently published in the New England Journal of Medicine, as you mentioned. The background for the study was that as Dr. Hirano just went through, current available treatment options for eosinophilic gastrointestinal disease are not ideal, and there's a great need for improved therapies.
The study was designed to assess the advocacy and the safety of this drug in treating eosinophilic gastritis and duodenitis in adults. And the study design was that patients with characteristic symptoms of eosinophilic gastritis and gastroenteritis, as well as a necessary threshold numbers of eosinophils in the gut were randomized in a one-to-one-to-one fashion to get either a low dose or high dose AK002 or a placebo. Patients received the medication in these doses or placebo for a total of four months during the study.
Host: Well then Dr. Hirano, share some of the findings and speak about some of the meaningful end points of the study.
Dr. Hirano: Sure. The principle finding and primary endpoint of the trial was that both low dose and high dose AK002 led to profound and significant reduction in both gastric and duodenal eosinophils in patients with eosinophilic gastritis and duodenitis. The reduction was 86% with AK002 compared to a 9% increase in the tissue eosinophils in the placebo treated patients. Even more impressive in my mind, was a significant improvement in symptoms in patients treated with AK002, compared to placebo. There was a 48% reduction in symptoms with AK002 compared to a 22% reduction with placebo.
Host: Wow. That's really promising. So Dr. Gonsalves, given those promising results that Dr. Hirano just shared, what's next for your research in the area? Where do you see this going in the next bunch of, years?
Dr. Gonsalves: So, what is coming down the pike is that based on these results, there has been a second study called Enigma two, which is sponsored by Allakos. And this has been initiated as a phase three study investigating AK002 in adults with eosinophilic gastritis and duodenitis to determine the reproducibility of these incredible study results in a broader patient population. This study really highlights the need for development of better treatments of these unique and difficult disorders. It also highlights the need for better diagnostic criteria, diagnostic guidelines, and understanding the natural history of these conditions to better understand the outcomes of the disease and treatment impact.
In addition to industry sponsored studies, Dr. Hirano and I are involved in many investigator initiated studies. We are also both principal investigators of CEGIR, which is the consortium of eosinophilic gastrointestinal researchers, a U54 rare disease network grant funded by several branches of the NIH and led by the lead investigators, Drs. Rothenberg and Fruita. One of the key missions of this grant is to better understand eosinophilic gastrointestinal disorders and their impact on patients to improve their lives and their quality of life. Our hope is that by developing formal consensus guidelines and developing diagnostic guidelines, earlier diagnosis and treatment of these conditions will be made and help improve the quality of life of our patients.
Host: Well, that's certainly the goal and what an interesting topic and study we're discussing here today. So, Dr. Hirano, why don't you take the last word? What would you like other providers to take away from this segment and from your studies? Anything you'd like them to know about treating patients with eosinophilic gastritis and duodenitis?
Dr. Hirano: I think the central take home message is that eosinophilic GI disorders are rare, but clinically important diseases that cause substantial morbidity for patients. Currently, there are no FDA approved therapies for these diseases. And the current trial of AK002 addresses a huge unmet need by offering a novel biologic therapy shown in this trial to be highly efficacious for both the symptoms and manifestations of eosinophilic gastritis and duodenitis.
Furthermore, this trial represents the first placebo control trial ever conducted for eosinophilic GI disease outside of the esophagus, and has certainly increased disease awareness and interest in a previously largely neglected disease state. It should be noted that Bruce Bochner, who's a Professor at Northwestern in the Division of Allergy and Immunology, helped to discover and characterize Siglec-8. Thus, this trial represents a wonderful example of bench to bedside success story.
Host: Thank you doctors for coming on and telling us about your studies and sharing your expertise with us for other providers. To refer your patient, or for more information, please visit nm.org/dhc to get connected with one of our providers. That concludes this episode of Better Edge, a Northwestern Medicine podcast for physicians. Please always remember to subscribe, rate and review these podcasts and all the other Northwestern Medicine podcasts. I'm Melanie Cole,
Anti–Siglec-8 Antibody for Eosinophilic Gastritis and Duodenitis
Melanie Cole (Host): Welcome to Better Edge, a Northwestern Medicine podcast for physicians. I'm Melanie Cole and joining me today are Dr. Ikuo Hirano and Dr. Nirmala Gonsalves. They are both Professors of Medicine in the Division of Gastroenterology and Hepatology at Northwestern Medicine. They're here with us today to share details about a recent study published in the New England Journal of Medicine that examined the use of novel Anti–Siglec-8 antibody for eosinophilic gastritis and duodenitis. Welcome to the show doctors. I'm so glad to have you join us today, Dr. Gonsalves, I'd like to start with you. Tell us a little bit about the clinical manifestations of eosinophilic gastritis and duodenitis. What are some of the common symptoms associated with these disorders? and has lack of recognition of these disorders lead to misdiagnoses and delay in diagnosis and treatment?
Nirmala Gonsalves, MD (Guest): Good morning, Melanie. Thank you for that question. Eosinophilic gastrointestinal disorders are chronic immune mediated inflammatory conditions of the gut. And by that, I mean, inflammatory cells called eosinophils infiltrate or go to the gut tissue and create inflammation, which leads to gut dysfunction, and that can contribute to the symptoms that develop. The disorders are typically named based on the organ involved. So, when the eosinophils go to the stomach in higher numbers, this typically has been called eosinophilic gastritis. When it involves the duodenum, it was called eosinophilic enteritis or more recently eosinophilic duodenitis.
So, patients who have these conditions, present with an array of symptoms, including abdominal pain, nausea, vomiting, bloating, feeling full when they eat, diarrhea and malnutrition. And depending on the severity of the disease, patients may either have mild symptoms or may have severe complications including weight loss, malnutrition, gastrointestinal bleeding, and even bowel obstruction or perforation. You raise an important point about the diagnostic criteria, because there really haven't been firm diagnostic guidelines; but what is currently used, includes having a certain threshold of eosinophils in the tissue and also having these characteristic symptoms. They are considered rare disorders on the order of six to eight per a hundred thousand patients.
But recent studies suggest that these disorders may be under-recognized and therefore increasing in incidence. Diagnosis, therefore is hinged on suspecting these disorders, referring a patient to a gastroenterologist and then obtaining adequate biopsy samples, during an endoscopic procedure in order to make the diagnosis. Due to these complications that I mentioned earlier, awareness, early diagnosis and treatment of these disorders is essential to prevent complications of these diseases.
Host: Well, thank you for that. So, Dr. Hirano, what's the current standard of care. And tell us a little bit about what has been done and how it's evolved over the years as you've learned more.
Ikuo Hirano, MD (Guest): Yeah, thank you, Melanie. I think it's really important to acknowledge that there really is no standard of care for either eosinophilic gastritis or duodenitis. Moreover, there are currently no medications approved for the treatment of eosinophilic GI disease by the US FDA. While systemic steroids are very effective for both the symptoms and signs of eosinophilic gastritis and duodenitis that Dr. Gonsalves mentioned, their long-term use is limited by obvious well-known systemic adverse effects. Diet therapies can be very effective, but are difficult to adhere to and can have negative effects on a patient's quality of life. Other therapies are often tried and these include cromolyn sodium and anti-histamines, but are at best modestly effective in clinical practice. Thus, there is a huge unmet need for the treatment of eosinophilic GI disease.
Host: I'd like you to expand Dr. Hirano on why these treatments that you've mentioned; you mentioned that dietary guidelines for this are tough to follow. So, you're speaking to other providers, tell them why some of these treatments that have been tried, have been inadequate and there is such a need for these improved therapies.
Dr. Hirano: Yeah. So, in terms of the available therapies again, the steroids, whether it's systemic or topical steroids are highly effective for eosinophilic gastritis, particularly, less so for enteritis or colitis, but the problem with steroids are the well-known toxicities for long-term use. So, they're great short-term induction therapies, but not so great for long-term maintenance therapies. As Dr. Gonsalves mentioned, these disorders are chronic disorders. They need some form of maintenance therapy the majority of times. The other therapies, I mentioned diet therapy. It sounds appealing to get rid of food allergens, but when you talk of getting rid of these foods from patients' diets, there's usually multiple foods and getting rid of very commonly ingested foods like milk and wheat and soy and egg and from patients' diets can have an adverse effect on their quality of life.
Host: So, then Dr. Gonsalves, let's discuss your phase two trial that examined AK002 for treatment of eosinophilic gastritis and duodenitis. Explain the initial purpose of the research and the methods and trial designs that you used during this study.
Dr. Gonsalves: Sure Melanie. The phase two Enigma study examined AK002 for the treatment of eosinophilic gastritis and duodenitis in adult patients ages 18 to 80. Just as background, Siglec-8 is an inhibitory receptor that is selectively expressed on mature eosinophils and mast cells and AK002 is a molecule that was developed against that receptor, that depletes eosinophils through, certain cytotoxic mechanisms and results in decrease of the eosinophils in the tissue. This was a multicenter randomized placebo controlled study, which was recently published in the New England Journal of Medicine, as you mentioned. The background for the study was that as Dr. Hirano just went through, current available treatment options for eosinophilic gastrointestinal disease are not ideal, and there's a great need for improved therapies.
The study was designed to assess the advocacy and the safety of this drug in treating eosinophilic gastritis and duodenitis in adults. And the study design was that patients with characteristic symptoms of eosinophilic gastritis and gastroenteritis, as well as a necessary threshold numbers of eosinophils in the gut were randomized in a one-to-one-to-one fashion to get either a low dose or high dose AK002 or a placebo. Patients received the medication in these doses or placebo for a total of four months during the study.
Host: Well then Dr. Hirano, share some of the findings and speak about some of the meaningful end points of the study.
Dr. Hirano: Sure. The principle finding and primary endpoint of the trial was that both low dose and high dose AK002 led to profound and significant reduction in both gastric and duodenal eosinophils in patients with eosinophilic gastritis and duodenitis. The reduction was 86% with AK002 compared to a 9% increase in the tissue eosinophils in the placebo treated patients. Even more impressive in my mind, was a significant improvement in symptoms in patients treated with AK002, compared to placebo. There was a 48% reduction in symptoms with AK002 compared to a 22% reduction with placebo.
Host: Wow. That's really promising. So Dr. Gonsalves, given those promising results that Dr. Hirano just shared, what's next for your research in the area? Where do you see this going in the next bunch of, years?
Dr. Gonsalves: So, what is coming down the pike is that based on these results, there has been a second study called Enigma two, which is sponsored by Allakos. And this has been initiated as a phase three study investigating AK002 in adults with eosinophilic gastritis and duodenitis to determine the reproducibility of these incredible study results in a broader patient population. This study really highlights the need for development of better treatments of these unique and difficult disorders. It also highlights the need for better diagnostic criteria, diagnostic guidelines, and understanding the natural history of these conditions to better understand the outcomes of the disease and treatment impact.
In addition to industry sponsored studies, Dr. Hirano and I are involved in many investigator initiated studies. We are also both principal investigators of CEGIR, which is the consortium of eosinophilic gastrointestinal researchers, a U54 rare disease network grant funded by several branches of the NIH and led by the lead investigators, Drs. Rothenberg and Fruita. One of the key missions of this grant is to better understand eosinophilic gastrointestinal disorders and their impact on patients to improve their lives and their quality of life. Our hope is that by developing formal consensus guidelines and developing diagnostic guidelines, earlier diagnosis and treatment of these conditions will be made and help improve the quality of life of our patients.
Host: Well, that's certainly the goal and what an interesting topic and study we're discussing here today. So, Dr. Hirano, why don't you take the last word? What would you like other providers to take away from this segment and from your studies? Anything you'd like them to know about treating patients with eosinophilic gastritis and duodenitis?
Dr. Hirano: I think the central take home message is that eosinophilic GI disorders are rare, but clinically important diseases that cause substantial morbidity for patients. Currently, there are no FDA approved therapies for these diseases. And the current trial of AK002 addresses a huge unmet need by offering a novel biologic therapy shown in this trial to be highly efficacious for both the symptoms and manifestations of eosinophilic gastritis and duodenitis.
Furthermore, this trial represents the first placebo control trial ever conducted for eosinophilic GI disease outside of the esophagus, and has certainly increased disease awareness and interest in a previously largely neglected disease state. It should be noted that Bruce Bochner, who's a Professor at Northwestern in the Division of Allergy and Immunology, helped to discover and characterize Siglec-8. Thus, this trial represents a wonderful example of bench to bedside success story.
Host: Thank you doctors for coming on and telling us about your studies and sharing your expertise with us for other providers. To refer your patient, or for more information, please visit nm.org/dhc to get connected with one of our providers. That concludes this episode of Better Edge, a Northwestern Medicine podcast for physicians. Please always remember to subscribe, rate and review these podcasts and all the other Northwestern Medicine podcasts. I'm Melanie Cole,