Anti-interleukin-5 antibody treatment (mepolizumab) in active eosinophilic oesophagitis: a randomised, placebo-controlled, double-blind trial

Abstract

Objective: Eosinophilic oesophagitis (EoO) is a clinicopathological condition defined by proton pump inhibitorrefractory oesophageal symptoms combined with oesophageal eosinophilia. The pharmacodynamic effect of mepolizumab (a humanised anti-interleukin-5 monoclonal antibody) in EoO was evaluated. Methods: Eleven adults with active EoO (.20 peak eosinophil number/high power field (hpf) and dysphagia) were randomised to 750 mg of mepolizumab (n = 5) or placebo (n = 6) and received two intravenous infusions, 1 week apart. Those not in complete remission (,5 peak eosinophil number/hpf) after 8 weeks received two further doses 4 weeks apart, 1500 mg of mepolizumab or placebo. The effect of mepolizumab was assessed clinically, endoscopically, histologically, and via blood and tissue biomarkers. Results: As assessed by immunofluorescence, a marked reduction of mean oesophageal eosinophilia (p = 0.03) was seen in the mepolizumab group (254%) compared with the placebo group (25%) 4 weeks after initiation of treatment. No further reduction of eosinophil numbers was observed in response to the two additional infusions in either group. Mepolizumab reduced tenascin C (p = 0.033) and transforming growth factor b1 (p = 0.05) expression in the oesophageal epithelial layer 13 weeks after initiation of treatment. Clinically, limited improvement of symptoms was seen, although a trend was seen between 4 and 13 weeks after initiation of mepolizumab treatment. Mepolizumab was well tolerated. Conclusions: Mepolizumab significantly reduced eosinophil numbers in oesophageal tissues in adult patients with active EoO, and changes in the expression of molecules associated with oesophageal remodelling were reversed. Minimal clinical improvement was achieved in a subgroup of patients with EoO. Mepolizumab had an acceptable safety profile, even at the high 1500 mg dose level. Trial registration number: NCT00274703Eosinophilic oesophagitis (EoO) is an emerging disease with a constantly increasing prevalence.

Systematic review of histological remission criteria in eosinophilic esophagitis

“…Among the interventional trials (randomized controlled trial studies [RCTs] or trials with historical controls), 80 (80%) compared treatment effect using histological remission as values within the range of 0 to ≤5 eosinophils/hpf. Among studies that examined the effectiveness of monoclonal antibody treatment in EoE subjects, 80% defined histological remission as peak esophageal eosinophil counts within the range of 0 to ≤5 24, 25, 26, 27, 28. Approximately 26% (N = 15) of the eligible studies examined remission among EoE patients who received only the diet elimination treatment formula (SFED, FFGED, ELED) compared to other forms of treatment, with the most common definitions falling within 0 to ≤5 eosinophils/hpf 29, 30, 31, 32, 33, 34 or 11 to ≤15 eosinophils/hpf 35, 36, 37, 38, 39, 40.…”

“…Of the 22 studies selected from European centers, 12 studies (55%) considered values within the range 11 to ≤15 eosinophils/hpf 17, 36, 37, 38, 39, 46, 47, 53, 54, 55, 56, 57, 58 as histological remission, and 4 studies (23%) defined histological remission as less than 5 or ≤ 5 eosinophils/hpf 30, 33, 42, 45. Strikingly, all studies conducted in Switzerland used a more stringent and consistent end‐point of <5 eosinophils /hpf to identify cases of histological remission 28, 59, 60…”

Eosinophilic Esophagitis–More than Two Decades of Progress

“…An initial open labeled trial of 4 patients in 2006 receiving mepolizumab, showed both a reduced esophageal eosinophilic count and improvement in symptoms. Two larger trials including a RCT of 59 children receiving mepolizumab, showed a decrease in eosinophilic count, however not a significant change in symptoms [64][65][66]. In a 2012 study, 226 children and adolescents with EoE were given reslizumab with significant improvement in intraepithelial esophageal eosinophil counts.…”

The Impact of Therapeutic Antibodies on the Management of Digestive Diseases: History, Current Practice, and Future Directions

“…Although the monoclonal antibody against IL-5, mepolizumab is approved for asthma with an eosinophilic phenotype, and studies have considered its use for eosinophilic esophagitis [111]. Limited studies demonstrate that mepolizumab reduces intraepithelial eosinophils in children and adults, though efficacy with reducing symptoms is lacking [112,113].…”