IMPACT OF UP TO 6 MONTHS OF MEPOLIZUMAB TREATMENT FOR ADOLESCENTS AND ADULTS WITH EOSINOPHILIC ESOPHAGITIS IN THE SECOND PHASE OF A MULTICENTER, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED CLINICAL TRIAL

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.