Novel Diagnostic Tools and Emerging Therapies for Esophageal Diseases: Highlights From ACG 2022

Gary W. Falk, MD, MS
University of Pennsylvania Perelman School of Medicine, Philadelphia

Key Takeaways

  • Research presented in the plenary session at the American College of Gastroenterology (ACG) 2022 Annual Scientific Meeting and Postgraduate Course focused on improving the diagnosis and management of esophageal diseases.
  • A group from The Netherlands successfully applied a tissue biomarker-based test known as the TissueCypher Barrett’s Esophagus Assay to improve management decisions for patients who have Barrett’s esophagus with low-grade dysplasia.
  • A phase 3 trial of dupilumab in patients with eosinophilic esophagitis found that dupilumab significantly improved dysphasia symptoms and endoscopic features at week 24. Dupilumab is now the first drug that the US Food and Drug Administration (FDA) has approved for eosinophilic esophagitis.
  • Vonoprazan was found to be more effective than placebo for rapid and sustained relief of heartburn episodes in patients with nonerosive reflux disease.
  • A large Veterans Affairs Achalasia Cohort study found that patients with achalasia had a fivefold increased risk for esophageal cancer compared with patients without achalasia.

Gastroenterologists from around the world gathered for the American College of Gastroenterology (ACG) 2022 Annual Scientific Meeting and Postgraduate Course to share insights about the latest research advances in the field of gastroenterology. The conference was held on October 21 to October 26, 2022, in Charlotte, North Carolina.
 
Gastroenterologist Gary W. Falk, MD, MS, is a professor of medicine at the University of Pennsylvania Perelman School of Medicine in Philadelphia. He was also the co-chair of the plenary session on esophageal diseases at ACG 2022. Dr Falk shared key takeaways from the ACG 2022 presentations that covered management decisions for patients with Barrett’s esophagus, use of dupilumab in patients with eosinophilic esophagitis, and results of on-demand vonoprazan in patients with nonerosive reflux disease.

Can you highlight the main findings from some of the studies presented in the plenary session on esophageal diseases? Were there any important breakthroughs?

The first study that was part of the presidential plenary session was titled “An objective spatialomics test standardizes management decisions with potential to improve health outcomes for Barrett’s esophagus patients.”1 This work came out of The Netherlands in conjunction with a collaborating company here in North America. The aim of this study was to ascertain if the TissueCypher biomarker platform could improve management decisions for patients who have Barrett’s esophagus with low-grade dysplasia. They performed 500 simulations on each of 154 patients with known outcomes and found that this test increased the likelihood of a proper management decision for people who either progressed to higher-level lesions or did not progress to higher-level lesions.
 
I thought that this was a very interesting paper, as it amplified work that has already been done. The key message here is that we need better risk stratification in all patients with Barrett’s esophagus, and especially for those in low-grade dysplasia; patients could benefit if there was an accurate tool to predict who will progress vs who will not progress to higher-level lesions, thereby determining who would benefit from ablative therapy vs who would likely not benefit. This paper provides a piece of the puzzle that may help improve management decisions for these patients in the future.

How were the lesions in this study classified?

All patients in this study were classified as low-grade dysplasia based on a pathology reading. The problem with pathology is that there is considerable interobserver variability among pathologists around the world, and this biomarker assay attempts to provide a more objective marker of progression risk.

Did any studies from this session report on novel therapies?

Yes, there were reports on 2 new compounds. The first study was presented by Evan Dellon on the phase 3 study results of dupilumab in eosinophilic esophagitis over 24 weeks of therapy.2 This is the first drug approved by the US Food and Drug Administration (FDA) for eosinophilic esophagitis.3 The findings were very striking in that the study met both co-primary endpoints of histology and symptoms with a histologic response rate of 59% if you use a threshold of less than 6 eosinophils/hpf and 77% if you use a threshold of less than 15 eosinophils/hpf.2 It also significantly improved endoscopic features at week 24.
 
The problem so far in getting drugs approved for eosinophilic esophagitis is that while they invariably improve the eosinophil counts, they have not been shown to consistently improve symptoms. Dupilumab improved both histologic and symptomatic endpoints, which has subsequently led to its FDA approval earlier this year.  Additionally, the safety profile was excellent.

The problem so far in getting drugs approved for eosinophilic esophagitis is that while they invariably improve the eosinophil counts, they have not been shown to consistently improve symptoms. Dupilumab improved both histologic and symptomatic endpoints, which has subsequently led to its FDA approval earlier this year.

Can you explain how dupilumab works?

Dupilumab is a human monoclonal immunoglobulin G4 (IgG4) antibody that inhibits interleukin-4 (IL-4) and interleukin-13 (IL-13) signaling to the interleukin-4 receptor alpha (IL-4Rα) subunit shared by the IL-4 and IL-13 receptor complexes. Both cytokines are important drivers in eosinophilic esophagitis.

You mentioned another study reporting on a novel agent. Can you elaborate on the findings from that study?

The second study looked at the safety of on-demand vonoprazan vs placebo in the treatment of heartburn.4 Gastroesophageal reflux disease (GERD) is a chronic problem that requires long-term therapy, making compliance an issue. Patients will often use drugs on an as-needed basis instead of how they are prescribed, which is on a daily basis. Proton pump inhibitors (PPIs) are often used for GERD, but PPIs take anywhere from 3 to 5 days to achieve maximal acid suppression.
 
Vonoprazan operates by a different mechanism: It is a potassium-competitive acid blocker and is potentially preferable because it works very rapidly, within the first dose. Investigators in this study looked at the efficacy and safety of different doses of vonoprazan vs placebo for on-demand therapy for individuals with heartburn episodes. The patients were randomized to 3 different doses of vonoprazan or the placebo group, and study endpoints included heartburn episodes and rescue antacid use. The most important endpoint was the percentage of heartburn episodes with complete and sustained relief.
 
All 3 doses of vonoprazan were superior to placebo in terms of complete and sustained relief in patients with nonerosive reflux disease. The 10-mg and 20-mg on-demand doses appeared to be equally efficacious, while the 40-mg dose provided limited extra benefit of unclear significance. The study supported the use of vonoprazan as an on-demand option for patients with nonerosive reflux disease.

Is vonoprazan already approved for any indication?

It is approved for use as part of Helicobacter pylori therapy, but it is not yet approved for use in reflux disease. If it does get approved, it has the potential to change practice in the future.

Are there any other interesting studies you would like to highlight?

There was also a Veterans Affairs cohort study that examined the risk for esophageal cancer in people with achalasia.5 This issue has been unresolved for many years, and it is thought that there is some increased risk for esophageal cancer in patients with achalasia. However, the optimal approach to these patients remains unclear. In this study, investigators evaluated the risk for esophageal cancer in individuals with achalasia and compared it with those without achalasia using a large Veterans Affairs Achalasia Cohort. The primary outcomes were the incidence of fatal esophageal cancers and cause-specific mortality.
 
The investigators found that in individuals with achalasia, the unadjusted hazard ratio for esophageal cancer was increased fivefold compared with those without achalasia. In a post hoc analysis, they also found that candida esophagitis seemed to be a predictor of who was going to develop esophageal cancer. What is interesting is that several esophageal cancer cases with achalasia had candida esophagitis noted prior to cancer diagnosis, indicating that candida esophagitis may be a signal for subsequent cancer. However, the authors also pointed out that the number of cancer cases was small, which impacts the conclusions. The study is provocative, and this is an area clearly in need of additional studies. At the end of the day, we do not yet know how to best approach these patients.

This Q&A was edited for clarity and length.

Disclosures

Gary W. Falk, MD, MS, reported affiliations with Castle Biosciences, Inc; Regeneron Pharmaceuticals, Inc; Sanofi-Aventis US LLC; and Phathom Pharmaceuticals.

References

1. Frei NFF, Duits LC, Khoshiwal A, et al. An objective spatialomics test standardizes management decisions with potential to improve health outcomes for Barrett’s esophagus patients. Paper presented at: American College of Gastroenterology (ACG) 2022 Annual Scientific Meeting and Postgraduate Course: Presidential Plenary Session 2; October 21-26, 2022; Charlotte, NC.

2. Dellon E, Rothenberg M, Bredenoord A, et al. Dupilumab improves clinical, symptomatic, histologic, and endoscopic aspects of EoE up to 24 weeks: pooled results from parts A and B of phase 3 LIBERTY-EoE-TREET. Paper presented at: American College of Gastroenterology (ACG) 2022 Annual Scientific Meeting and Postgraduate Course: Plenary Session 1A – Esophagus; October 21-26, 2022; Charlotte, NC.

3. FDA approves first treatment for eosinophilic esophagitis, a chronic immune disorder. News release. US Food and Drug Administration. May 20, 2022. Accessed November 16, 2022. https://www.fda.gov/news-events/press-announcements/fda-approves-first-treatment-eosinophilic-esophagitis-chronic-immune-disorder

4. Fass R, Vaezi MF, Sharma P, et al. Efficacy and safety of on-demand vonoprazan versus placebo in the treatment of heartburn in symptomatic nonerosive reflux disease (NERD) patients: a phase 2 randomized controlled trial. Paper presented at: American College of Gastroenterology (ACG) 2022 Annual Scientific Meeting and Postgraduate Course: Plenary Session 1A – Esophagus; October 21-26, 2022; Charlotte, NC.

5. Low EE, Demb J, Shah S, et al. Risk of esophageal cancer in achalasia: a matched cohort study utilizing the Veterans Affairs Achalasia Cohort (VA-AC). Paper presented at: American College of Gastroenterology (ACG) 2022 Annual Scientific Meeting and Postgraduate Course: Plenary Session 1A – Esophagus; October 21-26, 2022; Charlotte, NC.

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Reviewed November 2022