Anti-interleukin-5 antibody treatment (mepolizumab) in active eosinophilic oesophagitis: a randomised, placebo-controlled, double-blind trial
- A Straumann1,
- S Conus2,
- P Grzonka2,
- H Kita3,
- G Kephart3,
- C Bussmann4,
- C Beglinger5,
- D A Smith6,
- J Patel7,
- M Byrne7,
- H-U Simon2
- 1Department of Gastroenterology, Kantonsspital, Olten, Switzerland
- 2Institute of Pharmacology, University of Bern, Bern, Switzerland
- 3Allergic Diseases Research Laboratory, Mayo Clinic, Rochester, Minnesota, USA
- 4Institute for Clinical Pathology Viollier, Basel, Switzerland
- 5Department of Gastroenterology, University Hospital Basel, Basel, Switzerland
- 6GlaxoSmithKline, Research Triangle Park, North Carolina, USA
- 7GlaxoSmithKline, Stockley Park, Uxbridge, UK
- Correspondence to Professor H-U Simon, Institute of Pharmacology, University of Bern, Friedbuehlstrasse 49, CH-3010 Bern, Switzerland;
- Revised 13 July 2009
- Accepted 17 July 2009
- Published Online First 13 October 2009
Objective: Eosinophilic oesophagitis (EoO) is a clinicopathological condition defined by proton pump inhibitor-refractory 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 (−54%) compared with the placebo group (−5%) 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 β1 (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: NCT00274703
▸ Additional figures, tables and supplementary information are published online only at http://gut.bmj.com/content/vol59/issue1
Funding This study was supported by GlaxoSmithKline (GSK), Greenford, UK. The trial was conducted under GSK protocol number MEE103226.
Competing interests Declared (the declaration can be viewed on the Gut website at http://www.gut.bmj.com/supplemental).
Ethics approval The study was conducted according to ICH/GCP guidelines and was approved by the Ethics Committee of the Kantonsspital Olten, Olten, and the Swissmedic regulatory authority, Bern, Switzerland.
Contributors: The study was planned and designed by AS, MB and HUS. Data collection and analysis was performed by the authors, who took final responsibility for manuscript content and the decision to submit for publication. AS, MB and HUS wrote the manuscript.
Provenance and Peer review Not commissioned; externally peer reviewed.