Introduction: Interleukin-13 (IL-13) has been implicated in the pathogenesis of eosinophilic esophagitis (EoE). RPC4046 prevents the binding of IL-13 to both the IL-13Ra1 and IL-13Ra2 receptors. This study evaluated the efficacy and safety of 2 dose levels of RPC4046 compared to placebo (PBO). Methods: Subjects were randomized 1:1:1 to receive either RPC4046 180 mg [LD] (n=31), RPC4046 360 mg [HD] (n=34), or PBO (n=34). An IV dose on Day 1 was followed by weekly subcutaneous doses. Esophageal biopsies, read by a central blinded pathologist, were obtained at baseline (BL) and Wk 16 to assess change in mean eosinophil count, the primary endpoint. Secondary endpoints included symptom improvement measured by a Daily Symptom Diary (DSD), improvement in endoscopic features as measured by the EoE Endoscopic Reference Score (EREF), and Subject's Global Assessment of Disease Severity. Safety was also assessed. Results: Ninety subjects completed the 16 Wk double-blind period. Demographic/disease characteristics were generally comparable between treatment arms. At BL, mean esophageal eosinophil counts (cells/hpf) were 92.4 (PBO), 116.6 (LD), and 122.6 (HD). At Wk 16, the mean count was significantly reduced from BL for both RPC4046 dose levels compared to PBO (mean change: PBO -4.4, LD -94.8, and HD -99.9 [both p < 0.0001 vs PBO]). There was a greater improvement in dysphagia symptoms as measured by the DSD with HD compared to PBO, but this did not achieve statistical significance (PBO -6.4, LD -5.3 [p=0.996 vs PBO], and HD -13.3 [p=0.073 vs PBO]). There were significant improvements in endoscopic features as determined by the reduction in the total mean EREF score with both RPC4046 dose levels (mean change: PBO -0.9, LD -4.2, and HD -4.8 [both p < 0.0004 vs PBO]). There was a significant improvement in Subject's Global Assessment of Disease Severity at the HD (PBO ?1.5, LD ?2.0, HD ?2.8 [HD p=0.0107 vs PBO]). The rates of overall adverse events (AEs) were 64.7% (PBO), 64.5% (LD), and 85.3% (HD). The most frequent AEs were headache (PBO 14.7%, LD 16.1%, HD 20.6%), upper respiratory infection (PBO 8.8%, LD 16.1%, HD 14.7%), and arthralgia (PBO 0%, LD 12.9%, HD 5.9%). Conclusion: RPC4046 demonstrated significant reductions in esophageal eosinophilic inflammation and improvements in endoscopic features at both dose levels. Subjects receiving the HD had greater symptom improvement than those on LD. These phase 2 data support the further study of RPC4046 as a novel treatment for EoE. (clinicaltrials.gov ID: NCT02098473).