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Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Conclusions
  8. Acknowledgements
  9. References

Background

Patients with chronic atrophic gastritis have long-term gastric hypoacidity, and secondary hypergastrinaemia. Some also develop gastric ECL cells carcinoids (type 1 GC). Most type 1 GC remain indolent, but some metastasise. Patients undergo surveillance, and some are treated with somatostatin analogues, endoscopic resection or surgery. Netazepide (YF476) is a highly selective, potent and orally active gastrin receptor antagonist, which has anti-tumour activity in various rodent models of gastric neoplasia driven by hypergastrinaemia. Netazepide has been studied in healthy volunteers.

Aim

To assess the effect of netazepide on type 1 GC.

Methods

Eight patients with multiple type 1 GC received oral netazepide once daily for 12 weeks, with follow-up at 12 weeks in an open-label, pilot trial. Upper endoscopy was performed at 0, 6, 12 and 24 weeks, and carcinoids were counted and measured. Fasting serum gastrin and chromogranin A (CgA) and safety and tolerability were assessed at 0, 3, 6, 9, 12 and 24 weeks.

Results

Netazepide was well tolerated. All patients had a reduction in the number and size of their largest carcinoid. CgA was reduced to normal levels at 3 weeks and remained so until 12 weeks, but had returned to pre-treatment levels at 24 weeks. Gastrin remained unchanged throughout treatment.

Conclusions

The gastrin receptor antagonist netazepide is a promising new medical treatment for type 1 gastric carcinoids, which appear to be gastrin-dependent. Controlled studies and long-term treatment are justified to find out whether netazepide treatment can eradicate type 1 gastric carcinoids.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Conclusions
  8. Acknowledgements
  9. References

Chronic atrophic gastritis (CAG) is characterised by gastric mucosal atrophy and achlorhydria leading to long-term hypergastrinaemia, which causes ECL-cell hyperplasia and in turn leads to growth of gastric tumours (type I carcinoids) in a proportion of patients.[1, 2] The annual incidence of gastric carcinoids (GC) is increasing in the Western world and ranges from 0.2 to 0.46/100.000 in Norway and the USA.[3, 4] The majority of gastric carcinoids are type I. Although most type I gastric carcinoids are relatively benign, a proportion develop into more aggressive tumours and metastasise,[5-7] which is difficult to predict in the individual patient. Patients with CAG also have an increased risk of developing gastric malignancy with an adenocarcinoma phenotype[8, 9] and these tumours have neuroendocrine differentiation.[10] It has been suggested that such carcinomas may develop through a neuroendocrine tumour–carcinoma sequence.[11]

It is generally agreed that patients with type 1 GC should undergo surveillance and some should be treated.[12] Current treatment alternatives include somatostatin analogues, endoscopic resection and antrectomy: however, less is known about which treatment strategy is best for the individual patient. Octreotide is a somatostatin analogue and has been used to treat patients with type I GC with regression of carcinoids after 1-year treatment.[13-15] The long-term efficacy of somatostatin analogue treatment is unknown, but 5 years after stopping octreotide, many patients had progression of carcinoids,[16] suggesting a possible rebound effect after stopping treatment. Type 1 GC may be removed endoscopically, but recurrence occurs in the majority of patients.[17] Radical resection may be difficult to achieve because many tumours invade the submucosa and the frequent multifocality of type 1 GC makes other treatment strategies necessary in many patients. Antrectomy removes the source of hypergastrinaemia in these patients and causes a regression of gastric carcinoids, which are still gastrin-dependent.[18-22]

Thus, there is evidence that type I carcinoids are gastrin-dependent. However, antral resection has its disadvantages, and pharmacological inhibition of gastrin seems more attractive. Administration of a gastrin receptor antagonist might obviate the need for surgical removal of gastric carcinoids. Nonclinical[23] and healthy volunteer studies[24, 25] have shown that netazepide (YF476) is a potent, orally active, highly selective and competitive antagonist of gastrin receptors. It also has anti-tumour effects in various rodent models of gastric carcinogenesis driven by hypergastrinaemia.[26-28] There have been no reports of significant adverse events in healthy volunteers. In the present study, we have examined the effect of netazepide in patients with gastric carcinoids type 1.

Materials and Methods

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Conclusions
  8. Acknowledgements
  9. References

Patient characteristics

Patient characteristics are presented in Table 1. The patients included in the study had chronic atrophic gastritis and multiple histologically verified GCs. The presence of chronic atrophic gastritis was confirmed by histological evaluation of the oxyntic mucosa and the presence of hypergastrinaemia. All patients also had elevated titres of antibodies against parietal cells: some patients also had macrocytic anaemia (n = 1) or vitamin B12 deficiency (n = 2) at the time of diagnosis. Patients with significant co-morbidity were not included in the study. Specific exclusion criteria were pregnancy, lactation, history of gastric surgery, evidence of Zollinger-Ellison syndrome or prolonged QT time (>450 ms).

Table 1. Patient characteristics
Patient numberGenderAgeCAG (year of diagnosis)Gastric carcinoid (year of diagnosis)Serum gastrin at study startPrevious SSRA treatment H. pylori
  1. CAG, chronic atrophic gastritis; H. pylori, Helicobacter pylori; SSRA, somatostatin receptor agonist.

1M662000200038712 months in 2002Neg
2F6220002000200Neg
3F5120052006349Neg
4F631999199967412 months in 2002Neg
5F5020102010220Neg
6M692002200384012 months in 2003Neg
7M6820102010215Neg
8F5420102010150Neg

Study design

The study was a single-centre, open-label, single-arm, phase 2 trial of the gastrin receptor antagonist netazepide. The primary endpoint of the study was to assess if netazepide is an effective medical treatment for type 1 GC. The secondary endpoint was to assess the tolerability and safety of netazepide, and to assess the effect of netazepide on plasma concentration and transcript profiles of biomarkers such as chromogranin A (CgA).

Patients were given netazepide 50 mg by mouth once daily for 12 weeks and were followed up for 12 weeks after cessation of treatment. The study was approved by the Norwegian Medicines Agency (NOMA) and The Regional Committee for Research Ethics. The study was registered at ClinicalTrials.gov, with identifier NCT01444014. Enrolment started in June 2011.

Endoscopic examinations

At treatment start and after 6, 12 and 24 weeks, patients were examined by upper endoscopy (Olympus GIF-H180; Olympus, Tokyo, Japan). Gastric lesions with typical carcinoid appearance were photographed, counted and their size measured during the endoscopy with an open biopsy forceps 8 mm wide (Radial Jaw 4; Boston Scientific, Natick, MA, USA) in front of the carcinoid for comparison. One biopsy was taken from the largest carcinoid before study start and after 12 weeks' treatment for histopathological examination. Biopsies were not taken from the smaller carcinoids during the study as this would physically remove entire carcinoids and preclude the evaluation of the drug effect. Two biopsies were taken from flat mucosa on the mid corpus along the major curvature for histopathological analyses at all endoscopies.

Histopathological analyses

Biopsies were fixed in 4% buffered formaldehyde for 24 h at room temperature and embedded in paraffin. From the paraffin blocks, 4-μm thick sections were cut. The sections were dewaxed, rinsed in graded alcohol and rehydrated in water. Routine staining was performed with haematoxylin and eosin before the sections were examined by a pathologist.

Immunohistochemical analyses were performed in sections dewaxed and rehydrated through graded alcohol and water. Endogenous peroxidase activity was blocked with 3% H2O2 for 10 min. Heat-induced antigen retrieval was achieved by heating the sections in 0.01 m citrate buffer pH 6 (anti-CgA and anti-Ki-67) at 900 W until boiling point, and then 15 min at 160 W using a microwave oven. The sections were then left at room temperature for 15 min and transferred to a washing buffer. As primary antibody, monoclonal anti-human CgA (M0869; Dako, Copenhagen, Denmark) at 1:2000 dilution and monoclonal anti-human Ki-67 (IR626; Dako) at 1:200 dilution were used. Visualisation was done using Dako EnVision kit (K5007; Dako, Denmark) combined with DAB+ as chromogen. Finally, the sections were rinsed in water and counterstained with haematoxylin. ECL cell growth in the flat corpus mucosa was evaluated in CgA-immunolabelled sections and classified according to Solcia et al.[29]

Blood analyses

Blood samples were collected at treatment start and after 3, 6, 9, 12 and 24 weeks for measuring gastrin and CgA. Serum analyses of gastrin were performed as previously described (normal range <40 pM)[30] and serum CgA was measured using an RIA kit (Euria-Chromogranin A; Euro-Diagnostica, Malmö, Sweden) (normal range <6.0 nmol/L). Trough and peak plasma concentrations of netazepide were measured[31] before and 1 h after administration of netazepide at 3, 6, 9 and 12 weeks.

Safety monitoring

Safety monitoring during the study (at study start and 3, 6, 9, 12 weeks after study start) consisted of measurements of blood Hb, EVF, MCV, MCH, white blood cell count with differential, thrombocytes, Na, K, creatinine, albumin, ALAT, ALP, GT, bilirubin, amylase, lactate dehydrogenase, total cholesterol and triglycerides. Urine analysis and electrocardiogram were also performed. These were performed as routine analyses at St. Olavs Hospital, Trondheim, Norway. A general symptom review was done at each visit and a physical examination at study start, and at 6 and 12 weeks.

Statistics

Descriptive data are presented as mean ± S.E. of the mean. Differences between various points of time were evaluated by a paired Wilcoxon signed rank test using GraphPad Prism 5.01 (GraphPad Software, La Jolla, CA, USA).

Results

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Conclusions
  8. Acknowledgements
  9. References

Carcinoid number and size

All patients had a reduction in the number of gastric carcinoids after 12 weeks' treatment (11.8 ± 2.4 polyps vs. 6.6 ± 2.5 polyps, P = 0.014) and there was also a reduction in size of the largest polyps (7.4 ± 0.6 mm vs. 4.2 ± 0.7 mm, P = 0.014) (Figure 1). In one patient, all carcinoids regressed completely. The typical hyperaemic appearance of carcinoids was no longer present in the remaining carcinoids after 12 weeks' treatment (Figure 2). Representative histological morphology, CgA and Ki-67 immunohistochemical labelling of a carcinoid are shown in Figure 3 and the histological appearance of the carcinoids did not change during the study.

image

Figure 1. Number of carcinoids (a) and size of the largest carcinoids in each patient (b) during treatment with netazepide for 12 weeks.

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image

Figure 2. Endoscopic appearance at start of treatment with netazepide (a) and after 12 weeks (b) in patient 1; the arrows indicate the same polyp. Carcinoids at treatment start (c) were fewer and smaller after 12 weeks (d) in patient 2; the circles indicate the same area. Larger carcinoids decreased in size from treatment start (e) to 12 weeks' treatment (f) in patient 3.

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image

Figure 3. Biopsy from a carcinoid stained with haematoxylin and eosin (a) and strong immunohistochemical positivity for chromogranin A inside the carcinoid (b). This carcinoid had a Ki-67 labelling index of about 1%, whereas the surrounding mucosa had a higher proportion of proliferating cells (c).

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ECL cell hyperplasia, dysplasia and neoplasia in the flat oxyntic mucosa

Various degrees of ECL cell hyperplasia and dysplasia were present in biopsies from flat corpus mucosa (Figure 4). However, there was no significant difference in the degree of ECL cell hyperplasia or dysplasia between treatment start and after 12 weeks' treatment with netazepide (Table 2).

image

Figure 4. ECL cell hyperplasia and dysplasia in biopsy from flat corpus mucosa before treatment start. (a) Mainly diffuse hyperplasia, (b) linear hyperplasia, (c) micronodular and linear hyperplasia and (d) dysplasia.

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Table 2. ECL cell growth in flat corpus biopsies before and during treatment with netazepide
 Number of patients with
HyperplasiaDysplasia
DiffuseLinearMicronodularAdenomatoidAll types
Baseline87731
6 weeks86410
12 weeks85602

Serum chromogranin A and gastrin

There was a significant reduction in serum CgA after 3 weeks' treatment (7.9 ± 1.0 nmol/L vs. 4.5 ± 0.4 nmol/L, P = 0.016) and a normalisation of CgA after 6 weeks, which was sustained during the remaining treatment period (Figure 5). Twelve weeks after cessation of netazepide, CgA was increased compared with levels after 12 weeks' treatment (4.2 ± 0.2 nmol/L vs. 6.6 ± 0.8 nmol/L, P = 0.016). Serum gastrin levels did not change significantly during the study (379 ± 88 pM at start vs. 301 ± 61 pM after 12 weeks' treatment, P = 0.18) (Figure 5).

image

Figure 5. Serum chromogranin A (a) and gastrin (b) in patients with type 1 carcinoids treated with YF476 for 12 weeks.

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Safety of netazepide and plasma concentrations of netazepide

There were no adverse events that could be attributed to netazepide, and no clinically relevant changes in physical examinations, blood and urine tests and electrocardiograms. Neither the peak nor trough plasma concentrations of netazepide changed significantly during the study (Table 3).

Table 3. Mean plasma netazepide concentrations (ng/mL) measured predose (trough) and 1 h after dosing (peak) at 3, 6, 9 and 12 weeks of netazepide treatment
VisitConcentration ng/mL
TroughPeak
3 weeks6.49 ± 2.2127.4 ± 31
6 weeks19.6 ± 15205.8 ± 33
9 weeks17.70 ± 11193.4 ± 65
12 weeks19.9 ± 13239.7 ± 118

Discussion

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Conclusions
  8. Acknowledgements
  9. References

Gastrin has a general trophic effect on the oxyntic mucosa, but has a specific trophic effect on the ECL cell.[32, 33] There is also extensive evidence that hypergastrinaemia is pivotal in the development of ECL cell-derived gastric neoplasia. In animal models of hypergastrinaemia and gastric carcinogenesis, rats,[34, 35] mice,[36, 37] Mongolian gerbils,[38, 39] Mastomys[40] and Japanese cotton rats[41, 42] develop either ECL cell carcinoids, adenocarcinomas in the oxyntic mucosa or both. Animals with hypergastrinaemia have an increased risk of developing ECL cell carcinoids accompanied by either increased or decreased gastric acidity. In humans, hypergastrinaemia due to chronic atrophic gastritis predisposes to the development of type 1 GC, but also increases the risk of developing gastric adenocarcinomas,[8] with a neuroendocrine differentiation.[10] A proportion of patients with gastrinomas develop type 2 GC whether the gastrinomas are associated with MEN1[43] or sporadic.[44] Conversely, the surgical removal of the source of hypergastrinaemia by antrectomy in patients with chronic atrophic gastritis or by excision of gastrinomas results in regression of type 1[18, 22] and type 2 GCs,[45] respectively. With this evidence in mind, gastrin and the gastrin receptor seem to be a compelling target for anti-tumour therapy. Many gastrin receptor antagonists of varying affinity and oral bioavailability have been described.[46] One of these antagonists, netazepide,[23] has been shown to be potent, selective and orally-active in healthy subjects.[47]

In this study, we have examined the effect of 12 weeks' oral administration of the gastrin receptor antagonist netazepide on type 1 GC. We found that all patients had some reduction in carcinoid number and size, and in one patient, all carcinoids regressed completely. Netazepide also caused a reduction in serum CgA, which is a marker of ECL cell mass and activity.[48] The observed reduction in serum CgA is most likely explained by an effect of netazepide on the large ECL cell mass in the oxyntic mucosa, and not primarily an effect on the ECL carcinoids. CAG patients with type 1 GC do not have significantly higher blood CgA levels compared with CAG patients without carcinoids, but a similar degree of ECL cell hyperplasia/dysplasia.[49]

If netazepide is to eradicate type 1 GC, treatment for longer than 12 weeks seems to be required in most patients. The half-life of the ECL cell mass in humans is uncertain, but ECL cell hyperplasia seems to last 2–4 months after long-term proton pump inhibition with subsequent rebound acid hypersecretion.[50, 51] The time to regression of type 1 GCs after antrectomy varies, but most tumors have been reported to regress completely after 4–7 months.[18, 20, 52, 53] Treatment with a somatostatin analogue seems to have an effect on GC regression after 3 months similar to our observations in the present study.[13, 15] The results from these studies suggest that it is feasible to eradicate type 1 GC with longer term netazepide treatment, but the approval from the Norwegian Medicines Agency limited the length of this pilot study to 12 weeks. The favourable safety profile of netazepide supports longer term dosing.

Netazepide increases serum gastrin in rodents[26] and in healthy subjects[47] via suppression of gastric acid secretion. That netazepide did not affect serum gastrin in our patients is explained by the presence of CAG and acholorhydria. Peak concentrations of plasma netazepide after dosing healthy subjects is about 1 h[25, 47] and netazepide concentrations in CAG patients were similar to those in healthy subjects. Thus, CAG patients appear to absorb orally administered netazepide as well as healthy subjects.

We did not detect a significant reduction in ECL cell hyperplasia or dysplasia in the surrounding flat mucosa during netazepide treatment. This may be related to intraindividual variation of histopathology seen in chronic atrophic gastritis and two biopsies at each point of time may have been insufficient to detect potential treatment-induced changes. However, although antrectomy has been reported to cause regression of carcinoids in the majority of patients, the ECL cell hyperplasia in the oxyntic mucosa persisted in a large proportion of patients after a mean observation time of 34 months.[52] Furthermore, a high proportion of patients still have gastric acid hypersecretion and ECL cell hyperplasia several years after curative surgery of gastrinomas with subsequent normalisation of serum gastrin. The mechanism is unknown.

Conclusions

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Conclusions
  8. Acknowledgements
  9. References

Targeted treatment of hypergastrinaemia-induced type 1 GC with the orally active gastrin receptor antagonist netazepide seems promising. All patients in this phase 2 study had a reduction in carcinoid number and size after 12 weeks' treatment and netazepide was well tolerated. Long-term administration of netazepide may be an effective and safe treatment alternative for this group of patients.

Acknowledgements

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Conclusions
  8. Acknowledgements
  9. References

We thank Bjørn Munkvold, Britt Schulze and Tonje Grande Storhaug for technical assistance. Declaration of personal interests: Malcolm Boyce is the Managing Director of Hammersmith Medicines Research and holds the licence for netazepide. Declaration of funding interests: Hammersmith Medicines Research has supplied the study drug (netazepide) and paid for the netazepide assays. The study was otherwise funded by St. Olavs Hospital, Trondheim, Norway, and Raagholtstiftelsen, Oslo, Norway.

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  2. Summary
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Conclusions
  8. Acknowledgements
  9. References
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