Randomized Controlled Trial of the Gastrin/CCK2 Receptor Antagonist Netazepide in Patients with Barrett's Esophagus

Abstract

Hypergastrinemia has been associated with high-grade dysplasia and adenocarcinoma in patients with Barrett's esophagus, and experimental studies suggest proinflammatory and proneoplastic effects of gastrin on Barrett's esophagus. This is of potential concern, as patients with Barrett's esophagus are treated with medications that suppress gastric acid production, resulting in increased physiologic levels of gastrin. We aimed to determine whether treatment with the novel gastrin/CCK2 receptor antagonist netazepide reduces expression of markers associated with inflammation and neoplasia in Barrett's esophagus. This was a randomized, double-blind, placebo-controlled trial of netazepide in patients with Barrett's esophagus without dysplasia. Subjects were treated for 12 weeks, with endoscopic assessment at baseline and at end of treatment. The primary outcome was within-individual change in cellular proliferation as assessed by Ki67. Secondary analyses included changes in gene expression, assessed by RNA-sequencing, and safety and tolerability. A total of 20 subjects completed the study and were included in the analyses. There was no difference between arms in mean change in cellular proliferation (netazepide: +35.6 Ki67+ cells/mm2, SD 620.7; placebo: +307.8 Ki67+ cells/mm2, SD 640.3; P = 0.35). Netazepide treatment resulted in increased expression of genes related to gastric phenotype (TFF2, MUC5B) and certain cancer-associated markers (REG3A, PAX9, MUC1), and decreased expression of intestinal markers MUC2, FABP1, FABP2, and CDX1 No serious adverse events related to study drug occurred. The gastrin/CCK2 receptor antagonist netazepide did not reduce cellular proliferation in patients with nondysplastic Barrett's esophagus. Further research should focus on the biological effects of gastrin in Barrett's esophagus.Prevention Relevance: Treatment of patients with Barrett's esophagus with a gastrin/CCK2 receptor antagonist did not have obvious chemopreventive effects.

Conflict of interest statement

Disclosures: The authors have no conflicts of interest to declare.

©2021 American Association for Cancer Research.

Figures

Figure 1.

CONSORT diagram for randomized, double-blind, placebo-controlled trial of netazepide in patients with Barrett’s esophagus without dysplasia.

Figure 2.

Examples of immunostaining and automated analysis of Barrett’s esophagus biopsies immunostained for Ki67 (brown) and pan-cytokeratin (red). (A) Annotation of biopsy to include Barrett’s epithelium (40x magnification); (B) BE immunostained for Ki67 (brown) and pan-cytokeratin (red) (400x magnification); (C) AI algorithms used to identify Ki67-positive nuclei (red) (400x magnification).

Figure 3.

There was no significant difference in mean within-individual change in cellular proliferation in Barrett’s esophagus epithelium after 12 weeks’ treatment with netazepide compared to placebo.