A Pilot Study of Omalizumab in Eosinophilic Esophagitis

<div><p>Eosinophilic disorders of the gastrointestinal tract are an emerging subset of immune pathologies within the spectrum of allergic inflammation. Eosinophilic Esophagitis (EoE), once considered a rare disease, is increasing in incidence, with a rate of over 1 in 10,000 in the US, for unknown reasons. The clinical management of EoE is challenging, thus there is an urgent need for understanding the etiology and pathophysiology of this eosinophilic disease to develop better therapeutic approaches. In this open label, single arm, unblinded study, we evaluated the effects of an anti-IgE treatment, omalizumab, on local inflammation in the esophagus and clinical correlates in patients with EoE. Omalizumab was administered for 12 weeks to 15 subjects with long standing EoE. There were no serious side effects from the treatment. Esophageal tissue inflammation was assessed both before and after therapy. After 3 months on omalizumab, although tissue Immunoglobulin E (IgE) levels were significantly reduced in all but two of the subjects, we found that full remission of EoE, which is defined as histologic and clinical improvement only in 33% of the patients. The decrease in tryptase-positive cells and eosinophils correlated significantly with the clinical outcome as measured by improvement in endoscopy and symptom scores, respectively. Omalizumab-induced remission of EoE was limited to subjects with low peripheral blood absolute eosinophil counts. These findings demonstrate that in a subset of EoE patients, IgE plays a role in the pathophysiology of the disease and that anti-IgE therapy with omalizumab may result in disease remission. Since this study is open label there is the potential for bias, hence the need for a larger double blind placebo controlled study. The data presented in this pilot study provides a foundation for proper patient selection to maximize clinical efficacy.</p><p>Trial Registration</p><p>ClinicalTrials.gov <a href="https://clinicaltrials.gov/ct2/show/NCT01040598" target="_blank">NCT01040598</a></p></div

Effect of omalizumab on esophageal eosinophil counts, symptom scores and overall endoscopic score.

<p>The x-axis represents symptoms scores, the y-axis eosinophil counts, and right side of the graph represents post therapy with omalizumab. Individual patient data are shown as circles connected with a dashed line to allow comparison between pretreatment and post treatment. The size of the circle represents endoscopy score (also shown as a number inside the circle).</p

Eosinophil FcR1 expression in EoE.

<p>Eosinophils were identified by a combination of FSC/SSA and expression of CD9 and CD16 as CD9⁺CD16^- cells. Evaluation of FcεR1 and CD69 were compared versus IgG1 as an isotype control.</p

Effect of omalizumab on tissue IgE.

<p>Immunohistochemical staining for IgE was performed at baseline and 3 months into omalizumab therapy. Positive stain is shown in per high power field.</p

Study Subjects and Baseline Characteristics.

<p>M: mid; d: distal, m/d: mid and distal.</p><p>*Represents the peak count either in distal or mid esophagus.</p><p>Study Subjects and Baseline Characteristics.</p

Study flow diagram and design.

<p>24 subjects consented to participate in the study, 17 enrolled and completed all study visits. A total of 15 subjects who fully met inclusion and exclusion criteria, completed all study visits and drug administration, and underwent pre-and post-treatment endoscopic examinations were included in the data analysis. After a 2-week screening period, subjects received omalizumab subcutaneously every 2 weeks (6 patients) or 4 weeks (9 patients) for a total of 12 weeks. Safety and efficacy continued to be monitored during the follow-up period (weeks 12 through 16). The end of study endoscopy was performed between week 20 and 24.</p

Summary of the statistics of the comparison of pre and post omalizumab data points: Wilcoxon Signed-Rank Test (2-tailed).

<p>Summary of the statistics of the comparison of pre and post omalizumab data points: Wilcoxon Signed-Rank Test (2-tailed).</p

Comparison of blood AEC to symptom score.

<p>The x-axis represents symptoms scores before (left) and after (right) omalizumab, the y-axis represents AEC in peripheral blood.</p

Mechanisms of eosinophilic esophagitis.

<p>Conventional hypothesis: esophageal epithelial cells mediate eosinophil influx into esophagus. Alternative hypothesis: IgE mediated secretion of eosinophilic factors from mast cells.</p

Change in tissue eosinophil counts/hpf in response to omalizumab therapy in patients with low and high peripheral blood absolute eosinophil counts.

<p>Patients were classified as having high (>450 cell/mcl) and low (<450 cells/mcl) peripheral blood eosinophil counts and the tissue eosinophil counts/hpf before and after omalizumab were compared using t-test (p = 0.0027).</p