Sticky steroids-In search of an approved treatment for eosinophilic esophagitis

Current therapies for eosinophilic esophagitis (EoE) include topical corticosteroids, dietary restrictions, and esophageal dilation, however no Food and Drug Administration (FDA) approved medical treatments exist¹. Although dietary therapy can be highly effective in EoE, it can negatively affect quality of life and have low adherence due to food restrictions. Swallowed topical corticosteroids are the mainstays of pharmacologic treatment in EoE. Faubion et al reported the successful use of topical steroids administered via a metered dose inhaler in 1998²; their seminal finding have been validated by a series of studies. In 2005, Aceves et al, reported the use of a novel preparation, oral viscous budesonide, in the treatment of children with EoE³. This preparation was developed to address concerns related to administration technique and mucosal coverage. To date, commercially available pre-prepared suspensions of topical steroids are still unavailable.

In this issue of JPGN, Salvatore et al report their findings from a single center, non-blinded pilot study that evaluated the efficacy and safety of a pre-prepared oral viscous budesonide suspension in 36 pediatric patients with EoE⁴. The authors demonstrate that 88.9% of patients had complete histological response after 12 weeks of pre-prepared viscous budesonide (PVB). Twenty-four weeks after cessation of PVB, most patients relapsed, but almost half maintained remission raising a question of seasonal effects or sampling bias. They found an improvement in symptoms, endoscopy scores and histology scores after treatment, indicating that pre-prepared viscous budesonide may be effective in inducing clinic-pathologic remission without untoward side effects related to adrenal suppression or infection.

In previous studies and in clinical practice, oral viscous budesonide is formulated by combining liquid budesonide, intended for nebulized administration, with a substrate, typically sucralose (Splenda)³. However, many families are hesitant to use artificial sweeteners on a daily basis. Other substrates such as Neocate Nutra⁵ and a host of other foods including applesauce, honey, hot cocoa mix, pear sauce, xanthem gum, and rice cereal⁶ have also been reported to reduce eosinophilia. However, these alternatives still require choosing the best tolerated vehicle and mixing the suspension, factors that could contribute to variability in therapeutic responses. Salvatore et al provide data that, similar to previous studies using budesonide, a pre-prepared solution is feasible to use and can reduce eosinophils in the esophageal mucosa in a safe fashion.

Consistent with previous EoE therapeutic studies, this report notes again that symptom scores poorly correlate with mucosal eosinophilia⁷. The use of co-primary endpoints has become the standard for EoE therapeutic trials in which both patient reported outcomes as well as mucosal eosinophilia are assessed⁸. Gupta et al reported their experience with a prepared oral viscous budesonide formulation and found a histological response in 52% of children with 1.4 mg/day and 94.1% response with 2.8 mg/day⁹. However, a large percentage of placebo treated subjects reported an improvement in symptoms again demonstrating a poor correlation of symptoms with mucosal eosinophilia⁹. Capturing symptoms experienced can be challenging since patients often develop compensatory behaviors due to chronic symptoms associated with EoE. In the last several years, new symptom measurement tools have been developed to measure both symptoms as well as compensatory behaviors¹⁰. For example, the Pediatric Eosinophilic Esophagitis Symptom Scores 2.0 (PEESS) correlates with histopathology¹¹. Although the symptom score used by Salvatore addressed the varied symptoms that can be seen in EoE, it did not account for many compensatory behaviors associated with EoE. Perhaps a more robust metric would have provided better correlation with histology and symptoms.

Technological advances are providing additional means to assess the patient’s response to novel therapeutics. Confocal assessments¹², mucosal impedance¹³ and Endolumenal Functional Lumen Imaging Probe (EndoFLIP)¹⁴ all may provide structural and functional outcomes in the future. In particular EndoFLIP may provide not only a structural correlate by means of measuring stiffness, but also a method to assess function and risk assessment¹⁴. The coming years will provide answers to the important question of what is the least tolerable burden of disease for a patient and family? With respect to new therapeutics, what is the best way to measure disease activity or treatment endpoints in EoE?

The authors in this study achieved similar remission rates than previous studies evaluating effectiveness of oral viscous budesonide (OVB). In the landmark study by Dohil et al, children experienced an 86.7% remission rate with 3 months of Budesonide 1–2 mg daily¹⁵. Here, Salavatore et al used higher doses of 2–4 mg daily of pre-prepared oral viscous budesonide for 3 months without identified side effects. In adolescents and adults, Straumann et al demonstrated 72.2% remission with 15 days of Budesonide 2 mg daily¹⁶.

Several limitations exist with this study including lack of untreated controls, lack of blinding to endoscopic or histologic assessments and lack of clarity as to the chemical properties that permit PVB to reduce eosinophilia. With respect to the latter concern, it is likely that proprietary issues may exist that limit disclosure, but more information as to how this vehicle differs from our currently available vehicle would be important to know. As a pilot study, we are provided with a snapshot of the impact of this, but how it differs from other topical steroids in its mechanistic properties and whether it will be more effective or safer will need to be determined in future randomized, double blinded, placebo-controlled studies.

In summary, this report provides hope for another potential topical steroid option that limits the concern about variability related to preparation technique. As our understanding of the pathogenesis of the EoE evolves and studies continue to place an emphasis on the importance of clinically relevant outcomes, we await the first FDA approved treatment for pediatric and adult EoE.