Eosinophilic esophagitis (EoE) is an allergic condition of the esophagus that is on the rise throughout the United States. Patients with the condition typically have inflammation throughout their esophagus and trouble swallowing food – known as dysphagia.
Without proper treatment, the lining of the esophagus becomes fibrous, and the passage becomes so narrowed, or strictured, that food can lodge in the esophagus, requiring medical attention.
Historically, obtaining treatment has been difficult for U.S. physicians. There is one approved treatment for EoE in several other countries, but it is not available for use in the United States.
This left physicians to rely on food elimination diets, off-label treatments, such as stomach acid reducers or asthma steroid medications (which are swallowed to coat the esophagus rather than inhaled), and stretching the esophagus with dilation during endoscopy. However, for many patients these methods were either not available or may not have been very effective.
To fulfill this need, Evan Dellon, MD, MPH, a professor of medicine at the UNC School of Medicine and director of the Center for Esophageal Diseases and Swallowing, worked with colleagues on a clinical trial that led to approval of dupilumab for treatment in adults and adolescents with eosinophilic esophagitis.
The drug was approved by the United States Food and Drug Administration in May 2022 based on a three-part, phase 3 clinical trial. The results of which were published in the New England Journal of Medicine in late December.
“This study was designed to be a pivotal study for drug approval,” said Dellon, who was both the co-lead and corresponding author on the study. “Dupilumab was approved for eczema several years ago, and then was approved for asthma, and then for chronic rhinosinusitis with nasal polyposis. Eosinophilic esophagitis is now its fourth indication.”
Scientifically speaking, EoE is caused by an accumulation of white blood cells, called eosinophils, in the esophagus – a place where they are not normally located. Typically, eosinophils can be found in the stomach, small bowel, and colon, where they are involved in fighting off parasites and infections. But when eosinophils are abnormally present in the esophagus, they release toxic chemicals, causing swelling, irritation, and ultimately the formation of scar tissue.
Dupilumab is an antibody that blocks, or inhibits, a receptor called interleukin (IL)-4 receptor alpha. As a result, allergic factors IL-13 and IL-4, which are important in the inflammation that EoE patients experience, are suppressed when the receptor is blocked. This kind of drug cannot be taken orally; instead, it is injected under the skin once a week.
The clinical trial was funded and sponsored by Regeneron Pharmaceuticals, the developer of dupilumab, and recruited 321 patients who were at least 12 years of age and weighed at least 40 kg (88 pounds), had a documented diagnosis of EoE through an endoscopic biopsy, and had not responded to eight weeks of high-dose stomach acid reducer therapy. The patients were separated into different groups to determine dosing and the overall effectiveness in resolving their symptoms and eosinophilic inflammation in the esophagus.
The study had three parts. In part A, patients were randomized to either weekly dupilumab dosing or weekly placebo shots for 24 weeks. In part B, patients were randomized to one of two dose groups (weekly or every-other-week dupilumab) or to placebo, again for 24 weeks. Patients who completed parts A and B could continue on to part C, where they received open label dupilumab. This allowed the study of two different doses, as well as treatment up to 52 weeks.
The study successfully met its pre-specified co-primary endpoints. Researchers witnessed a reduction in the eosinophil counts via esophageal biopsy (termed “histologic response”), as well as significant improvement in symptoms of dysphagia. In addition, there was better endoscopic healing with the medication than with placebo. Symptoms were only observed to improve more than placebo with the weekly dose than with a biweekly dose, so the medication was ultimately approved for once-weekly use.
“In addition to the improvements with the eosinophil counts and symptoms, we also saw that the overall histologic severity, which includes all aspects of inflammation and pathologic changes in the biopsy improved with the Dupilumab,” said Dellon. “There was also evidence of normalization of the molecular changes associated with EoE. In basically every way disease activity was measured in this study, we saw improvements with dupilumab.”
Because prior treatment guidelines were published prior to the FDA-approval of dupilumab, providers are still working out when it should be used for EoE in clinical practice. For example, should it be reserved for use after attempting other treatments first or should it be provided to patients who have more severe disease features. Dellon believes that initially most doctors will prescribe the therapy for their more severe patients who weren’t responding to prior therapies.
“All of the patients in this study were non-responsive to proton pump inhibitors,” said Dellon, “So at the present time, this medicine should probably not be used as first-line treatment in most patients, and we are waiting for more data for how dupilumab would work in newly diagnosed EoE patients who have never been treated before.”
To provide some guidance for use of dupilumab in clinical practice, Dellon worked with colleagues and the American College of Allergy, Asthma, and Immunology to develop what is known as a “yardstick”, which has just been published in the journal Annals of Allergy, Asthma, and Immunology. Essentially, this is a rapid communication that helps doctors choose the best course of treatment, given the patient’s individual situation, clinical severity, and prior treatments, while more formal treatment guidelines are under development. (KSN/Newswise)