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.

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.

• Authors: Andrew R Moore, Malcolm Boyce, Islay A Steele, Fiona Campbell, Andrea Varro, D Mark Pritchard
• Journal: PloS one (PLoS One) Vol. 8 Issue 10 Pg. e76462 ( 2013) ISSN: 1932-6203 [Electronic] United States
• PMID: 24098507 (Publication Type: Clinical Trial, Phase II, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

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

Topics

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