RPC4046, a Monoclonal Antibody Against IL13, Reduces Histologic and Endoscopic Activity in Patients With Eosinophilic Esophagitis

Abstract

Primary Outcome Esophageal eosinophil count: P < .0001 for both dose groups Key Secondary Outcome Dysphagia clinical symptom frequency and severity (DSD): Not statistically significant for both dose groups Safety Assessment AEs All low frequency Headache Upper respiratory tract infection Arthralgia Nasopharyngitis Diarrhea Nausea SAEs All unrelated to treatment RPC4046 180 mg or 360 mg treatment for 16 weeks See editorial on page 545. BACKGROUND & AIMS: Eosinophilic esophagitis (EoE) is a chronic, esophageal, type 2 inflammatory response associated with increased serum levels of interleukin 13 (IL13), which might contribute to its pathogenesis. RPC4046, a recombinant humanized monoclonal antibody against IL13, prevents its binding to the receptor subunits IL13RA1 and IL13RA2. We performed a phase 2 trial to evaluate the efficacy and safety of RPC4046 in patients with EoE. METHODS: We performed a multicenter, double-blind trial of 99 adults with active EoE randomly assigned (1:1:1) to groups given RPC4046 (180 or 360 mg) or placebo once weekly for 16 weeks, from September 2014 through December 2015. Patients were seen at day 1 (baseline) and weeks 2, 4, 8, 12, and 16. They underwent esophagogastroduodenoscopy and biopsies were collected at baseline and week 16. Patients completed a daily dysphagia symptom diary through week 16 and patient-reported outcome data were collected. The primary outcome was change in mean esophageal eosinophil count in the 5 high-power fields (hpfs) with the highest level of inflammation. RESULTS: At week 16, mean changes in esophageal eosinophil count per hpf were a reduction of 94.8 ± 67.3 in patients who received 180 mg RPC4046 (P < .0001) and a reduction of 99.9 ± 79.5 in patients who received 360 mg RPC4046 (P < .0001) compared with a reduction of 4.4 ± 59.9 in patients who received placebo. The 360-mg RPC4046 group, compared with the placebo group, showed significant reductions in validated endoscopic severity score at all esophageal locations (P < .0001), validated histologic grade and stage scores (both P < .0001), and clinician's global assessment of disease severity (P ¼ .0352); they had a numerical reduction in scores from the dysphagia symptom diary (P ¼ .0733). Significant reductions in esophageal

Molecular, endoscopic, histologic, and circulating biomarker-based diagnosis of eosinophilic gastritis: Multi-site study

“…The prominent role of type 2 immunity-related responses provides the scientific basis for therapeutic intervention with dupilumab (anti-IL-4 receptor a, which inhibits IL-4 receptor a/IL-13Ra1), anti-IL-13Ra1, and/or anti-IL-13 (eg, RPC4046 inhibiting IL-13 interactions with both IL-13Ra1 and IL-13Ra2). 26 Increased expression levels of type 2 immune/eosinophil-associated pathways can be seen in patients with other atopic disorders associated with nodularity, such as chronic rhinosinusitis with nasal polyps, suggesting that they were not to be EG specific but might function to generate these histologic features in certain tissue/conditions. Interestingly, endoscopic changes, such as friability and erythema, were associated with downregulation of IL33 (epitheliumderived, proinflammatory alarmin), SLC26A7 (anion exchange transporter), and ATP4A (proton pump; gastric H, K-ATPase alpha subunit).…”

Single-cell RNA sequencing identifies inflammatory tissue T cells in eosinophilic esophagitis

“…We focused on analyzing a model, tissue-specific, allergic disease termed eosinophilic esophagitis (EoE), as this is a food antigen-driven disease involving adaptive T cell memory (2). EoE is dependent on cytokines likely derived from T cells (e.g., , as evidenced by recent successful clinical trials with anti-IL-13 and anti-IL-4Rα antibody therapy (3)(4)(5). Importantly, human tissue samples enriched in T cells were readily available via endoscopy, providing an opportunity to probe human tissue T cells at the single-cell level ( Figure 1A).…”

Mechanisms of gastrointestinal allergic disorders

“…Anti-IL-5 antibodies (mepolizumab, reslizumab) have been FDA-approved for treating eosinophilic asthma (161), and several clinical trials support their effectiveness for EoE, although while esophageal eosinophilia improved, clinical symptoms were only modestly improved compared with typical improvements seen with topical glucocorticoids or dietary elimination therapy (162)(163)(164). Treatment of EoE with anti-IL-13 antibodies (QAX576 and RPC4046) produced favorable early results (165)(166)(167). Early phase II trials of anti-IL-4Rα (dupilumab) also yielded positive results (168), substantiating preclinical models based on IL-13-driven EoE-like responses (169,170).…”