Society: AGA

Background: Novel treatment options for eosinophilic esophagitis (EoE) are needed. Previous studies have assessed mepolizumab (mepo), a monoclonal antibody against IL-5, with mixed results in EoE, and the efficacy of mepo in an adult and adolescent population has yet to be fully examined.

Aim: To determine whether mepo is more effective than placebo for improving symptoms of dysphagia and decreasing esophageal eosinophil counts in EoE.

Methods: We conducted a multicenter, randomized, double-blind, placebo-controlled, investigator-initiated clinical trial comparing mepo to placebo (PBO) (NCT03656380). Patients aged 16-75 with EoE, PPI non-response, ≥15 eos/hpf on biopsy at screening, and active symptoms of dysphagia (EoE Symptom Activity Index [EEsAI] score ≥27) were eligible. Key exclusion criteria were: inability to pass a standard endoscope due to severe stricturing, and esophageal dilation or systemic steroids within 8 weeks, or topical steroids (tCS) within 4 weeks, of baseline endoscopy. Patients were randomized 1:1 to 3 months of either mepolizumab 300mg SQ monthly or matching PBO SQ, after stratification for prior tCS non-response. Primary outcome was change in dysphagia as measured by EEsAI from baseline to month 3 (M3). Secondary outcomes included change in peak eosinophil counts, histologic response thresholds, change in EoE Endoscopic Reference Score (EREFS), EEsAI thresholds, and safety.

Results: Of 66 patients randomized, 64 completed M3 and were analyzed. Baseline characteristics were generally similar between study groups (Table 1). Of note, >80% of subjects had been treated with tCS, 50% had not responded, and >70% had previously had dilation. At M3, EEsAI decreased 15.4±18.1 points with mepo and 8.3±18.0 with PBO (p=0.14; Fig 1A). While 6% in each group had a M3 EEsAI score ≤20 (clinical remission; p=0.95), 35% on mepo had an EEsAI score decrease ≥20 (clinical response) vs 21% with PBO (p=0.20). At M3, the peak eosinophil count decreased with mepo (113±77 to 36±43) and increased (146±94 to 160±133) with PBO (p<0.001 for post-treatment comparison; Fig 1B). With mepo, 42% and 34% achieved histologic responses of <15 and ≤6 eos/hpf compared to 1% and 3% respectively, with PBO (p<0.001 and 0.02; Fig 1C). The change in EREFS at M3 was also larger with mepo than PBO (1.0±1.1 vs 0.4±1.3; p=0.03; Fig 1D). Mepo was generally well-tolerated, with no medication-related SAEs or new safety signals; the most common AEs were injection site reactions.

Conclusions: In this population of previously difficult to treat EoE patients, mepo as stand-alone therapy for 3 months led to a numerical but not statistically significant improvement in dysphagia symptoms, and significant improvements in eosinophil counts and endoscopic severity, as compared to PBO. Longer-term treatment effects and predictors remain to be assessed.

Background: Short-term use of mepolizumab (mepo), a monoclonal antibody against IL-5, has been previously assessed in eosinophilic esophagitis (EoE). However, the optimal dose and length of treatment for mepo in EoE has not been extensively investigated.

Aim: To determine the durability of symptomatic and histologic response to mepo after 6 months of treatment in patients initially randomized to active medication, and to assess response to 3 months of a lower mepo dose in those initially randomized to placebo.

Methods: In the first phase of a multicenter, randomized, double-blind, placebo-controlled, investigator-initiated clinical trial, we compared mepo 300mg SQ monthly (mepo300) to placebo and assessed outcomes after 3 months of treatment (NCT03656380). In the second phase, patients initially randomized to mepo continued 300mg monthly dosing for an additional 3 months, and those initially on placebo started mepo 100mg monthly (mepo100) for 3 months; allocation remained blinded. Eligible patients were aged 16-75 with EoE, had PPI non-response, ≥15 eos/hpf on biopsy at screening, and active symptoms of dysphagia (EoE Symptom Activity Index [EEsAI] score ≥27). The primary outcome for the first phase was change in dysphagia as measured by EEsAI from baseline to month 3 (M3). For the second phase, this same outcome was assessed at month 6 (M6). Other outcomes assessed at M6 included change in peak eosinophil counts, histologic response thresholds, change in EoE Endoscopic Reference Score (EREFS), EEsAI thresholds, and safety.

Results: Of 64 patients who completed M3, 59 entered phase 2, and 56 completed M6 and were analyzed (28 in each group). At M6, EEsAI decreased 18.6±19.2 points from study baseline with mepo100 and 18.3±18.1 with mepo300 (p=0.85), a change of 10.1 and 3.1 points from M3 baseline, respectively (Table). Rates of clinical remission and response at M6 were the same in each group (18% and 46%, respectively). From study baseline to M6, the peak eosinophil count decreased to 50±42 eos/hpf with mepo100 and 26±20 with mepo300 (p=0.008 for post-treatment comparison), but the absolute change was slightly larger with mepo100 (-102±83 vs -88±77; p=0.04). At M6, 21% and 32% had histologic responses of <15 eos/hpf in mepo100 and mepo300, respectively (p=0.37; Table). The change in EREFS at M6 was similar with mepo100 and mepo300 (0.9±1.1 vs 0.5±1.5; p=0.26). Mepo was generally well-tolerated with longer use, with no medication-related SAEs or new safety signals.

Conclusions: Use of 300mg monthly of mepo for 6 months did not lead to additional symptom, endoscopic, or histologic improvement compared to 3 months of use, but responses were generally maintained. Use of 100mg monthly of mepo for 3 months yielded similar improvements to the higher dose. Future studies can investigate how mepo is best positioned in EoE treatment algorithms.

Swathi Eluri

University of North Carolina at Chapel Hill School of Medicine

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