Is FDA approval in sight for emerging EoE therapies?
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Over the years, there have been many advances in the pathologic understanding of eosinophilic esophagitis, but FDA-approved treatment options have lagged.
In a review published in the Journal of Allergy and Clinical Immunology, researchers noted that current treatments are considered off-label and include the three Ds: drugs, dietary elimination and endoscopic dilation.
Source: Sandeep K. Gupta, MD.
“There is a large amount of drug development for EoE currently, based on the expanding knowledge of the pathogenesis of the disease, so it is a very exciting and promising time for EoE therapeutics,” co-author of the review Evan S. Dellon, MD, MPH, professor of gastroenterology and hepatology and director of the Center for Esophageal Diseases and Swallowing at the University of North Carolina School of Medicine, told Healio Gastroenterology. “There are novel topical steroid formulations, biologics (antibodies) targeting cytokines, cytokine receptors and other cellular receptors, and novel small molecules targeting other aspects of the EoE pathogenic pathway. One possibility is that we will identify different subgroups of EoE patients (ie, different phenotypes) who will be best suited for one or another of these treatments.”
Sandeep K. Gupta, MD, a pediatric gastroenterologist at Indiana University School of Medicine and Community Health Network in Indianapolis, IN, echoed Dellon, explaining that although some alternate therapies are currently in phase 2 or phase 3 trials, there is concern about whether they will be approved.
“It is definitely exciting times, but I do worry that if we do not get FDA approvals, it will dampen ongoing efforts,” Gupta told Healio Gastroenterology. “It could be because it is a tough call or because people conducting the studies are not meeting goals, or the goals are shifting. It could be for any reason, but for consumers and providers like us, we are stuck in the middle, because we do not know where this will go.”
Over the past few years, patients are becoming aware of and inquiring about available drugs and medications, Gupta said, but without FDA approval, physicians are not able to provide them.
“This makes life quite challenging, as we also know that the drugs are out there,” Gupta continued. “It is just hoping for this FDA approval.”
Healio Gastroenterology spoke with experts about emerging therapies, recent research, the lack of FDA approvals and what is next in the management of EoE.
Off-Label Treatments
Dilation
Dilation is both highly effective and safe, Scott Gabbard, MD, a gastroenterologist at the Digestive Disease & Surgery Institute at Cleveland Clinic, said, but in normal cases, patients should have an esophageal diameter of at least 20 mm — and patients with EoE often have a very narrow esophagus.
“We see patients, not uncommonly with esophageal diameter less than 8 mm, who have had longstanding disease and have not sought medical therapy,” Gabbard said. “Patients who have a severely narrow esophagus may require repeated dilations on a serial basis.”
These patients may still have symptoms until their esophageal diameter meets a target of 16 to 18 mm in diameter, Gabbard said, even if the inflammation is treated.
“In my personal practice, I have a very low threshold to empirically dilate patients carefully and then go back with a scope and look for mucosal disruption to see if I actually dilated the esophagus.”
The AGA does not recommend dilation for maintenance therapy as it does not treat the underlying inflammation.
Dietary Therapy
Jonathan Spergel, MD, PhD, chief of the allergy program at Children’s Hospital of Philadelphia, said that one fear with diet therapy is poor nutritional status and quality of life. For all patients, nutritional status can be easily managed. The quality of life can vary from individual to individual and depends on exactly what diet is chosen. A simple 1-2 food diet has a good quality of life. A variety of dietary modifications exist, the most common being the fixed-food elimination diet, in which wheat, dairy, soy, nuts, legumes, shellfish and eggs are removed from a patient’s diet.
Gabbard noted various studies showed the response rates from diet management are between 50 to 70%.
“The downside to diet management is it can be quite challenging for the patient. Generally, the most common triggers are wheat and dairy, which are pretty hard things to avoid,” Gabbard said. “It requires numerous endoscopies to try to pinpoint what a patient is allergic to.”
However, Spergel said endoscopies are only necessary if you are doing a six-food diet. If you are doing a one-food or two-food diet, the number of endoscopies is 2 or 3 (1 for diagnosis of EoE and 1 or 2 to check if the foods that were removed are correct).
According to Spergel, IgE-based allergy tests have shown limited accuracy in the prediction of food triggers in EoE as EoE is not IgE mediated disease. Therefore, empiric elimination diets are currently preferred over allergy testing-directed diets.
The two most common elimination diets are the six-food group (milk, wheat, soy, egg, fish, peanut, tree nuts and shellfish) or four-food group (milk, egg, soy and wheat), according to research. Both have similar effectiveness in the range of 54% to 64%. Interesting, a simple elimination of milk had similar histologic remission rates vs. four-food elimination and is now the most common diet, which has only 2 endoscopies to identified the culprit food.
Researchers also have discussed the two-four- six-food elimination approach, which showed patient remission rates of 43% after elimination of two foods.
Proton Pump Inhibitors
Gabbard noted PPIs work about 50% of the time with regard to clinical remission symptom improvement, pathologic improvement and reduction of eosinophils.
Topical Corticosteroids
Gabbard noted that studies evaluating topical corticosteroids for EoE have shown that nearly 75% of patients achieve remission.
FDA Approvals
The FDA in late 2021 rejected Takeda’s new drug application for budesonide to treat EoE.
“I am looking forward to an FDA-approved medication for the treatment of EoE to get our patients safe and effective medications that are covered,” Gabbard, who was involved in the phase 3 clinical trials ORBIT1 and ORBIT2 for TAK-721 (budesonide oral suspension), said.
According to a Takeda press release, the FDA completed review of the new drug application for budesonide oral suspension but stated the treatment could not be approved in its present form. The FDA suggested the biopharmaceutical company perform an additional clinical study to resolve FDA feedback.
“We are disappointed by the outcome of the FDA’s review of TAK-721, and that EoE patients will still be without a treatment option that the FDA has approved as safe and effective,” Ramona Sequeira, president of Takeda’s U.S. business unit and global portfolio commercialization, said in the release. “Takeda is assessing the details of the [complete response letter] and evaluating a regulatory path forward.”
Spergel doesn’t fully understand why budesonide wasn’t approved by the FDA, but he has looked at surveys from Europe where it has been approved and expects it will eventually be approved in the U.S.
The FDA focuses more on symptom scores, he said, which do not associate well with what physicians consider the “gold standard” — histology and endoscopy improvements.
“I would rather see improvement in histology and endoscopy findings or EndoFlip (Medtronic) findings than just patient findings, because patients are not the best when reporting symptoms,” Spergel said.
Other Emerging EoE Therapies
According to Dellon, with budesonide dissolvable tablets currently only approved in Europe, Canada and Australia, physicians in the U.S. must look to other treatment options.
“The current guidelines position PPIs, topical steroids and dietary elimination as acceptable first-line treatments, and the decision to use one over another is based on a shared decision-making framework between the patient and provider, since there are no direct comparative trials,” he said. “Of note, if esophageal strictures are present, then esophageal dilation is also a reasonable treatment to use in parallel. But because dilation does not treat the underlying inflammation (it only mechanically addresses fibrosis), an anti-inflammatory treatment is also needed.”
Previous research has highlighted other emerging therapies being studied for EoE, some of which have been evaluated in clinical trials. They include:
- Biological agents, such as IL-4, IL-5 and IL-13, as well as IgE and TNF;
- Anti-IL-5 antibodies mepolizumab and reslizumab;
- Benralizumab, an eosinophil-depleting antibody targeting the IL-5 receptor;
- QAX576 and RPC4046, which target IL-13;
- Dupixent (dupilumab; Regeneron, Sanofi), an mAb that antagonizes the IL-4 and IL-13 pathway by targeted IL-4ra;
- AK002, an antibody targeting the Siglec-8 receptor;
- Losartan, an angiotensin II receptor antagonist; and
- CALY-002, an anti-IL-15 antibody.
Guidelines for EoE Therapies
The AGA and the joint task force on allergy-immunology practice parameters published guidelines in 2020 on the management of eosinophilic esophagitis, as reviewed by Hirano et al in Gastroenterology.
“During the past two decades, EoE has emerged as a dominant cause of dysphagia worldwide,” Ikuo Hirano, MD, professor of gastroenterology and hepatology at Northwestern University Feinberg School of Medicine, and colleagues wrote. “In concert with the rise in disease prevalence, an increasingly robust evidence base has provided insights into effective management strategies that are summarized in this guideline. At the same time, EoE is an evolving field with many unknowns and areas of controversy.”
Key recommendations include:
- In patients with symptomatic EoE, PPIs should be used over no treatment;
- Topical glucocorticosteroids should be used over no treatment;
- Topical glucocorticosteroids are preferred over oral glucocorticosteroids;
- An elemental diet should be used over no treatment;
- An empiric, six-food elimination diet should be used over no treatment;
- An allergy testing-based elimination diet should be used over no treatment;
- In patients with EoE in remission after short-term use of topical glucocorticosteroids, continuation of topical glucocorticosteroids is preferred over discontinuation of treatment;
- In adult patients with dysphagia from a stricture associated with EoE, endoscopic dilation is preferred over no dilation;
- Anti-IL-5 therapy should be used only in the context of a clinical trial;
- Anti-IL-13 or anti-IL-4 receptor-alpha therapy should only be used in the context of a clinical trial;
- Anti-IgE therapy should not be used; and
- Montelukast, cromolyn sodium, immunomodulators and anti-TNF should only be used in the context of a clinical trial.
Recent Research
At the 2021 North American Society for Pediatric Gastroenterology, Hepatology and Nutrition annual meeting, Gupta presented a poster demonstrating the efficacy and safety of budesonide oral suspension (BOS) in pediatric patients with EoE.
In a post-hoc analysis of two clinical trials, Gupta and colleagues evaluated data from 76 patients, aged 11 to 17 years, with EoE and dysphagia who were treated for 12 weeks with twice daily 2 mg BOS (n = 45) or placebo (n = 31). Researchers assessed histologic, symptomatic and endoscopic outcomes via peak eosinophil count, the Dysphagia Symptom Questionnaire and the EoE Endoscopic Reference Score (EREFS).
Results showed pediatric patients treated with BOS had greater histologic response (P < .001) and symptom response. In addition, more BOS-treated patients had a full (combined histologic and symptom) response (P = .003), similar to observations from each individual clinical trial. Further, patients treated with BOS also achieved a greater reduction in mean EREFS from baseline to week 12 (–4.1 vs. –2.1). Researchers reported no significant differences in adverse events in BOS- vs. placebo-treated patients.
“BOS 2 mg twice daily significantly improved histologic, endoscopic and combined outcomes, as measured using stringent endpoints, compared with placebo,” Gupta and colleagues concluded. “In addition, BOS 2 mg twice daily was well tolerated in this pediatric population with EoE.”
At the 2022 American Academy of Allergy, Asthma and Immunology annual meeting, Dellon presented results from part B of the LIBERTY EoE TREET study, which examined the effects of weekly dupilimab 300 mg in adult and adolescent patients with EoE.
“This study confirms that dupilumab is effective and well-tolerated in a larger group of patients than in the similarly-designed “Part A” of the phase 3 program,” Dellon said. “It is important to see the result extended in this larger cohort, with highly clinically meaningful improvements in both histology and symptom severity with dupilumab compared with placebo.”
Researchers analyzed results from 159 patients, who were randomly assigned to dupilumab (n = 80) or placebo (n = 79). The primary study endpoints included histological remission and improvement in dysphagia. At week 24, 58.8% of patients given dupilumab achieved histological remission vs. 6.3% given placebo. Rates of adverse events were similar for both groups and included injection-site reactions and fever.
“Weekly dupilumab vs. placebo demonstrated statistically significant, clinically meaningful improvements in symptoms in adults and adolescents, with greater proportion of patients achieving histological remission,” Dellon and colleagues concluded.
Without FDA Approval, What’s Next?
The reality of EoE management is that physicians are considering where they currently are and where they need to be to properly care for patients. Ultimately, physicians must continue to adapt, because EoE management doesn’t fit the classic picture of GI disease treatment and control.
“We are hopeful that we will get some approved therapies in the upcoming year,” Spergel said. “That will bring excitement to everyone. We are also looking for new ways to monitor things, and we are hoping that we will have some less invasive ways to monitor patients, which I think will make patients happy.”
- References:
- Budesonide improves histologic, symptom response in pediatric EoE. www.healio.com/news/gastroenterology/20211216/budesonide-improves-histologic-symptom-response-in-pediatric-eoe. Published Dec. 16, 2021.
- Dellon ES, et al. Abstract L02. Presented at: American Academy of Allergy, Asthma and Immunology Annual Meeting; Feb. 25-28, 2022; Phoenix.
- FDA rejects new drug application from Takeda for budesonide for EoE. www.healio.com/news/gastroenterology/20220104/fda-rejects-new-drug-application-from-takeda-for-budesonide-for-eoe. Published Jan. 04, 2022.
- Greuter T, et al. J Allergy Clin Immunol. 2019;doi:10.1016/j.jaci.2019.10.027.
- Gupta SK, et al. Poster 271. Presented at: North American Society for Pediatric Gastroenterology, Hepatology and Nutrition Annual Meeting; Dec. 12-18, 2021 (virtual meeting).
- Hirano I, et al. Gastroenterology. 2020;doi:10.1053/j.gastro.2020.02.038.
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