Netazepide, a gastrin receptor antagonist, normalises tumour biomarkers and causes regression of type 1 gastric neuroendocrine tumours in a nonrandomised trial of patients with chronic atrophic gastritis

PLoS One. 2013 Oct 1;8(10):e76462. doi: 10.1371/journal.pone.0076462. eCollection 2013.

Abstract

Introduction: Autoimmune chronic atrophic gastritis (CAG) causes hypochlorhydria and hypergastrinaemia, which can lead to enterochromaffin-like (ECL) cell hyperplasia and gastric neuroendocrine tumours (type 1 gastric NETs). Most behave indolently, but some larger tumours metastasise. Antrectomy, which removes the source of the hypergastrinaemia, usually causes tumour regression. Non-clinical and healthy-subject studies have shown that netazepide (YF476) is a potent, highly selective and orally-active gastrin/CCK-2 receptor antagonist. Also, it is effective in animal models of ECL-cell tumours induced by hypergastrinaemia.

Aim: To assess the effect of netazepide on tumour biomarkers, number and size in patients with type I gastric NETs.

Methods: We studied 8 patients with multiple tumours and raised circulating gastrin and chromogranin A (CgA) concentrations in an open trial of oral netazepide for 12 weeks, with follow-up 12 weeks later. At 0, 6, 12 and 24 weeks, we carried out gastroscopy, counted and measured tumours, and took biopsies to assess abundances of several ECL-cell constituents. At 0, 3, 6, 9, 12 and 24 weeks, we measured circulating gastrin and CgA and assessed safety and tolerability.

Results: Netazepide was safe and well tolerated. Abundances of CgA (p<0.05), histidine decarboxylase (p<0.05) and matrix metalloproteinase-7(p<0.10) were reduced at 6 and 12 weeks, but were raised again at follow-up. Likewise, plasma CgA was reduced at 3 weeks (p<0.01), remained so until 12 weeks, but was raised again at follow-up. Tumours were fewer and the size of the largest one was smaller (p<0.05) at 12 weeks, and remained so at follow-up. Serum gastrin was unaffected.

Conclusion: The reduction in abundances, plasma CgA, and tumour number and size by netazepide show that type 1 NETs are gastrin-dependent tumours. Failure of netazepide to increase serum gastrin further is consistent with achlorhydria. Netazepide is a potential new treatment for type 1 NETs. Longer, controlled trials are justified.

Trial registration: European Union EudraCT database 2007-002916-24 https://www.clinicaltrialsregister.eu/ctr-search/search?query=2007-002916-24ClinicalTrials.gov NCT01339169 http://clinicaltrials.gov/ct2/show/NCT01339169?term=yf476&rank=5.

Publication types

  • Clinical Trial, Phase II
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use
  • Benzodiazepinones / pharmacology
  • Benzodiazepinones / therapeutic use*
  • Biomarkers / blood
  • Biomarkers / metabolism
  • Biopsy
  • Chromogranin A / blood
  • Female
  • Gastric Mucosa / metabolism
  • Gastric Mucosa / pathology
  • Gastrins / blood
  • Gastritis, Atrophic / complications*
  • Gastroscopy
  • Humans
  • Male
  • Middle Aged
  • Neuroendocrine Tumors / complications*
  • Neuroendocrine Tumors / drug therapy*
  • Neuroendocrine Tumors / pathology
  • Phenylurea Compounds / pharmacology
  • Phenylurea Compounds / therapeutic use*
  • Receptor, Cholecystokinin B / antagonists & inhibitors*
  • Stomach Neoplasms / complications*
  • Stomach Neoplasms / drug therapy*
  • Stomach Neoplasms / metabolism
  • Stomach Neoplasms / pathology
  • Treatment Outcome
  • Tumor Burden

Substances

  • Antineoplastic Agents
  • Benzodiazepinones
  • Biomarkers
  • Chromogranin A
  • Gastrins
  • Phenylurea Compounds
  • Receptor, Cholecystokinin B
  • YF 476

Associated data

  • ClinicalTrials.gov/NCT01339169

Grant support

Trio Medicines Ltd funded the study. This report is independent research arising in part from a Biomedical Research Fellowship to ARM funded by the National Institute of Health Research (NIHR). The views expressed are those of the authors and not necessarily those of the NHS, NIHR or the Department of Health. The funders (Trio Medicines Ltd.) participated in study design, data monitoring and manuscript preparation.