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

IntroductionAutoimmune 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.AimTo assess the effect of netazepide on tumour biomarkers, number and size in patients with type I gastric NETs.MethodsWe 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.ResultsNetazepide 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.ConclusionThe 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 RegistrationEuropean Union EudraCT database 2007-002916-24 https://www.clinicaltrialsregister.eu/ctr-search/search?query=2007-002916-24 ClinicalTrials.gov NCT01339169 http://clinicaltrials.gov/ct2/show/NCT01339169?term=yf476&rank=5

Somatostatin analogs for gastric carcinoids: For many, but not all

“…Another pharmacological therapeutic option is represented in the near future by netazepide, an orally administered highly selective active gastrin/CCK-2 receptor antagonist, recently described as an effective treatment in animal models of ECL-cell tumours induced by hypergastrinemia [80] . Its use over a 12-wk period in a recent non-randomized trial was associated with a significant reduction in both the number of GC1s and the size of the largest tumour, of about 30%, and with the normalization of CgA levels, but not of gastrin values [81] . Nevertheless, randomized controlled trials involving longer-term treatment and larger cohorts of patients, are required to confirm these results.…”

Gastric neuroendocrine tumors: management and challenges

“…22,23,40,42 Furthermore, the oral gastrin receptor antagonist netazepide (YF476) is under study as an alternative therapeutic option for patients with type I gastric NETs and has been shown to cause tumor regression and normalize chromogranin A levels in 2 small prospective studies. 43,44 As in type I and II gastric NETs, systemic therapy in type III is warranted only in locoregional disease that is unresectable or metastatic. Management in these cases is identical to that of all unresectable or metastatic gastrointestinal NETs and is based on a multitude of factors, including the patient's symptoms, tumor grade, tumor burden, and progression of disease during imaging-guided surveillance.…”

Nowotwory neuroendokrynne żołądka i dwunastnicy z uwzględnieniem gastrinoma (zasady postępowania rekomendowane przez Polską Sieć Guzów Neuroendokrynnych)

“…This therapy may be the right option for patients with metastatic disease and proven SSTR2 expression, as well as low Ki-67 value. Studies without control groups revealed that netazepid, an antagonist of the gastrin/cholecystokinin receptor, demonstrates antiproliferative properties in g-NEN [63,64]. However, it cannot be universally recommended, and further assessment of this therapy in controlled randomised studies is necessary (*evidence level 5).…”

“…Discontinuation of PPI and resulting rebound hypersecretion may result in severe complications, such as perforation or gastrointestinal stenosis [68]. However, in some patients PPI doses may be reduced during the follow-up [64].…”