Is clinical trial data showing positive progress for the treatment of eosinophilic esophagitis?

1. Body of article

Eosinophilic gastrointestinal disorders (EGIDs) are characterized by GI tract dysfunction (dysphagia, vomiting, gastro-esophageal reflux, abdominal pain, diarrhea, etc.) and findings of increased tissue eosinophils on biopsy. These disorders can affect any segment of the GI tract, and the best characterized is eosinophilic esophagitis (EoE). Originally described as a distinct entity in the 1990s, EoE is now recognized worldwide with defined clinical, endoscopic, and histologic diagnostic criteria as well as widely accepted guidelines for management [1]. Treatment options include food elimination diets, which focus on removal of the triggering food(s), or use of medications, to induce disease remission. There are generally three categories of medications utilized: proton-pump inhibitors (PPIs), swallowed, topical corticosteroids (TCS), and biologics. In EoE, PPIs function as anti-inflammatory agents by decreasing the expression of Th2 (allergic) cytokines and improving the disrupted barrier function of the esophagus. Swallowed, topical corticosteroids and many biologics function in a similar way: downregulation of Th2 cytokines, repair of esophageal barrier function, and prevention of tissue remodeling. In trials of PPIs, between 20% and 50% of patients demonstrate clinical and histologic improvement with high-dose monotherapy and the majority maintain this with long-term use [2]. PPIs are positioned among the first-line treatments for EoE, although they are not approved by the FDA in the United States for this indication. TCS have undergone the most extensive evaluation of any therapeutic for EoE. There are currently two formulations utilized in the United States: budesonide, which is mixed into a ‘slurry,’ and fluticasone propionate, which is administered as an aerosol through an MDI device. Both formulations are swallowed, providing a topical effect in the esophagus and each is effective for both induction of clinical and histological remission of EoE as well as long-term maintenance therapy [3]. Biologics have garnered much recent attention, likely due to their success in a variety of other disorders including atopic diseases such as asthma and atopic dermatitis.

Based upon this discussion, it would seem clear that there are multiple, effective therapies for EoE; however, until recently none have been approved by the FDA for use in the United States. The reasoning behind this, at least in part, can likely trace back to how EoE is diagnosed and the challenges faced in therapeutic trials for this disease. EoE is a clinicopathologic diagnosis requiring both clinical symptoms of gastrointestinal dysfunction and histologic findings of increased eosinophils/eosinophil activity in the affected tissue [4]. Treatment outcomes have focused on reducing tissue eosinophil load and improving the clinical symptoms and endoscopic features [5]. In early clinical trials, the results were often hampered by a lack of standardized outcome measures [6–8]. In addition, there has been a lack of consensus on how to define disease ‘remission’ when evaluating changes in tissue eosinophil counts. Various cutoff points have been utilized (≤15 eos/hpf to ≤5 eos/hpf) making comparisons between trials difficult [9]. Recently, standardized measures have been validated for clinical (Pediatric Eosinophilic Esophagitis Score (PEES), PedsQL, dysphagia symptom questionnaire (DSQ), etc.), endoscopic (EoE endoscopic reference score (EREFS)), and histologic (EoE histology scoring system (HSS)) outcomes allowing for improved trial design [5]. In 2019, the FDA announced the development of guidelines for industrial trials of drugs for EoE [10]. Several key criteria were announced: all trials should be randomized, double-blind, placebo controlled and should treat for a minimum period of 24 weeks with an extension to 52 weeks to evaluate for safety and long-term efficacy. Assessment of efficacy should focus on utilization of standardized clinical outcome measures, improvement of endoscopic findings, and the ability of the treatment to reduce peak esophageal eosinophils to ≤6 eos/hpf and improve other histologic abnormalities.

Since publication of the FDA guidance, several therapeutics have completed or are nearing completion of late-phase clinical trials. In a phase 3 trial of over 300 adolescent and adult patients with EoE who were treated over 12 weeks, budesonide oral suspension (BOS) led to a reduction in tissue eosinophils to ≤6/hpf in 53.1% of treated subjects, compared to only 1% of the placebo group [11]. BOS was also associated with significant improvements in clinical symptoms and endoscopic features, compared to placebo. A follow-up study evaluating long-term outcomes was performed in subjects who completed the initial BOS trial. Subjects who were considered ‘full’ responders (≤6 eos/hpf, >30% reduction in dysphagia symptom questionnaire (DSQ)) were randomized to continue BOS (BOS-BOS) or to stop therapy (BOS-placebo) for an additional 36 weeks [12]. Subjects who were partial or non-responders or those who received placebo during the initial study were also enrolled to continue BOS for 36 weeks. The primary outcome was the proportion of subjects who relapsed (≥15 eos/hpf and ≥4 days of dysphagia over 2 weeks) in the two arms (BOS-BOS versus BOS-placebo). An additional outcome measure included the number of partial or non-responders and placebo subjects from the initial trial who became full responders after a total of 52 weeks of BOS treatment. Seventy-six percent of the initial full responders were able to maintain their response after 52 weeks of total therapy. Approximately 13% of the partial or non-responders became full responders. After 36 weeks, more BOS-placebo subjects relapsed compared to the BOS-BOS group, although this difference was not statistically significant. Unfortunately, in December 2021, the FDA denied approval of BOS for treatment of EoE in adolescent and adult patients. Similar agents, including a budesonide orodispersible tablet (BOT, Jorveza, Dr Falk Pharma GmbH), have been approved for EoE in Europe and Canada [13]. In the pivotal trial of BOT, 58% of the treated subjects achieved histologic remission (<5 eos/hpf (<16 eos/mm²)) with significant reductions in symptom severity after 6 weeks of therapy, compared to placebo. A long-term study evaluating the efficacy over 48 weeks demonstrated that BOT was able to maintain remission in 73.5–75% of subjects compared to only 4% of placebo-treated subjects [14]. A fluticasone oral disintegrating tablet has also been evaluated (APT-1011, Ellodi Pharmaceuticals) [15]. In a phase 2, dose-finding study, 86% of the 1.5 mg BID and 80% of the 3 mg BID treated group achieved histologic remission (≤6 eos/hpf) after 12 weeks. In addition, over 80% of the 1.5 mg BID treated group were able to maintain remission after 52 weeks. Each of the treatment groups demonstrated significant improvements in endoscopic scores and dysphagia scores compared to placebo. These improvements were maintained in the majority of subjects over 52 weeks. A phase 3 trial for adolescents and adults is planned (NCT05083312).

Multiple biologics have also undergone investigation. Dupilumab, a humanized monoclonal antibody that inhibits IL-4 (and IL-13), was evaluated in two phase 3 studies of adolescents and adults [16,17]. The first study enrolled 81 subjects, 12 years and older with EoE, to receive dupilumab 300 mg weekly with co-primary endpoints of histologic remission (≤6 eos/hpf) and changes in DSQ after 24 weeks of therapy [16]. Nearly 60% of treated subjects achieved the primary histologic endpoint and 70% demonstrated significant reductions in dysphagia, compared to the placebo group. A second phase 3 trial was performed and enrolled a total of 159 subjects with the same co-primary endpoints [17]. This study demonstrated similar reductions in tissue eosinophils and dysphagia scores in the treatment arm, compared to placebo. In a 28-week extension study, placebo-treated subjects from the initial trial began active treatment and those subjects who were treated with dupilumab in the initial trial continued treatment (for a total of 52 weeks) [18]. Of those who continued dupilumab, histologic remission was maintained in 56% of subjects, while 60% of the placebo rollover group achieved histologic remission with significant reductions in dysphagia. In May 2022, dupilumab was approved by the FDA for adolescents (12 years and older) and adults with EoE who weigh at least 40 kg and had been tried on at least 8 weeks of PPI therapy. Benralizumab (AstraZeneca), an anti-IL5 receptor antagonist, is currently approved for the treatment of moderate-to-severe asthma in adolescents and adults. It is under investigation in hypereosinophilic syndrome (HES) (NCT04191304), eosinophilic granulomatosis with polyangiitis (EGPA) (NCT04157348), chronic rhinosinusitis/nasal polyposis (NCT04157335), and EoE (NCT04543409). In a cohort of 7 HES patients with concomitant EGID, benralizumab was associated with complete depletion of eosinophils through the GI tract, as early as 4 weeks after initiation of therapy [19]. Another novel agent, lirentelimab (Allakos), a siglec-8 antibody that depletes eosinophils and inhibits mast cell activation, has been investigated in eosinophilic gastritis and duodenitis. In a phase 2 study, 65 subjects were randomized to receive lirentelimab or placebo monthly for 3 months [20]. Treated subjects demonstrated an 86% reduction in GI tissue eosinophil count (compared to 9% in the placebo group) with significant improvements in symptom scores. Of the enrolled subjects, 23 also had esophageal eosinophilia (14 in the treatment group and 9 in the placebo group). 93% (13/14 subjects) in the treatment group had a reduction in esophageal eosinophils to ≤6/hpf compared to only 11% (1/9 subjects) of the placebo group. A study to evaluate the efficacy of lirentelimab for EoE is currently planned (NCT04322708). Finally, an antibody against IL13, cendakimab (Bristol Myers Squibb), has also been investigated. In a phase 2 trial, 99 adults with EoE were randomized to receive cendakimab or placebo for 16 weeks [8]. Treated subjects demonstrated a significant reduction in tissue eosinophils compared to placebo as well as improvements in endoscopic severity scores, histologic scores, and disease severity. Sixty-six of these subjects completed a 52-weeks extension study [21]. Of those who rolled over from placebo to active therapy, similar improvements in histologic, endoscopic, and clinical outcomes were seen after 12 weeks. Symptom remission rates improved from 14% (extension study entry) to 67% after 52 weeks in those initially treated with placebo and from 30% to 54% in those who remained on cendakimab through both trials. A phase 3 trial is planned (NCT05175352).

2. Expert opinion

Overall, significant progress has been made in the development of therapeutics for EoE. With a more standardized approach to outcomes and clear guidelines for the performance of trials from the FDA, investigators and sponsors are better positioned to perform high-quality studies. This approach has led to the first FDA approved medication for EoE. Based upon recent trial data, several other biological agents show similar promise. However, there are still no TCS approved for treatment of EoE in the US despite approval of similar agents in Europe. While biologics have demonstrated efficacy, they are associated with significant costs. PPIs and TCS have been the mainstay of medical therapy for EoE for the past decade and have also demonstrated efficacy in both children and adults. With the FDA denial of BOS, it is unclear what path the development of TCS in the United States will be. These disorders are significantly rarer and will likely require significant collaboration amongst clinicians and researchers to develop and complete clinical trials.

Declaration of interest

S Gupta is a consultant/speaker for Abbott, Adare, Celgene, Gossamer Bio, QOL, Takeda, MedScape, ViaSkin, and UpToDate. S Gupta has research support from Allakos, Ellodi, and AstraZeneca. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.