Introduction

Linaprazan glurate (LG) is a next generation P-CAB, a prodrug to linaprazan, with an excellent clinical efficacy in erosive esophagitis (1-2).
The acid control properties of LG were assessed by the holding time ratio (HTR) i.e., percentage of time with intragastric pH>4, during Day 1 and 14 of LG administered once daily (QD) or twice daily (BID) at 3 dose levels.
Pharmacokinetic (PK) profiles for LG and Linaprazan were determined and PK parameters, area under the plasma concentration time profile (AUC) and peak plasma concentration (C_max) derived.

Aims & Methods

73 healthy subjects randomized into six dosing groups and received LG, a total of 67 subjects completed the study and had at least one evaluable pH measurement (Table 1).
Measurement of intragastric pH was performed during 24 hours on Day 1 and on Day 14, by means of a pH‑measuring electrode in the stomach inserted by the nasogastric route. Intragastric pH was measured every second. The pH>4 HTR is presented as the mean of the 10 min median per dose group and day. Blood samples for PK parameters were also collected.

Results

There was a rapid onset of intragastric acid control achieved already within 90 min after the intake of the first dose of LG, irrespective of dose level, with a clear dose response. The HTRs presented in Table 1 show a dose response with pH>4 HTR similar at Day 1 and Day 14. Already on Day 1, the pH>4 HTR reached approximately 90% in the two highest dosing groups (50 mg and 75 mg BID), with a minor difference in acid control between these doses, particularly at steady state (Table 1).
Linaprazan AUC and C_max increased approximately in proportion to dose and were comparable on Day 1 and Day 14. AUC and C_max for LG was approximately 10-fold lower than for linaprazan.
A post-hoc analysis of the pH>4 HTR excluding the initial 90 min after first dosing (pH>4 HTR 1.5-24h) showed that the pH>4 HTR 1.5-24h was close to the Day 14 pH>4 HTR in all dosing cohorts, suggesting a pH-control near steady state already 1.5 hours after the first dosing. It is noteworthy that a pH>4 HTR 1.5-24h above 90% is seen, not only in the 75 mg BID group as noted in the primary endpoint, but also in the 50 mg BID group (Table 1).
Comparing 50 mg QD and 25 mg BID, a more sustained pH>4 HTR was seen with BID dosing, with more than 10-15 percentage points higher pH>4 HTR already from the start, indicating a better pharmacodynamic yield when dividing the dose.
There was one serious adverse event in the study, a concussion that occurred before the first dose of LG. The most observed treatment emergent adverse event (TEAE) was headache. There was no dose related increase in TEAEs or other findings as assessed by physical examinations, vital signs, ECG, and laboratory parameters.

Table 1: Descriptive statistics of percentage of time within intragastric pH categories- based on 10-minute medians of pH.

Conclusion

A rapid onset of pH>4 HTR was seen with LG with a clear dose response. The two highest dosing groups achieved above 90% pH>4 HTR excluding the initial 90 min after the first dose.
Repeated oral doses of LG 25, 50 and 75 mg QD and BID for 14 days were safe and well tolerated.

References

1. LINAPRAZAN GLURATE IS HIGHLY EFFECTIVE IN TREATING MODERATE TO SEVERE EROSIVE ESOPHAGITIS: A DOUBLE-BLIND, RANDOMIZED, DOSE FINDING STUDY. Sharma P et al, United European Gastroenterology Journal 2023; 11 (Supplement 8).

1. LINAPRAZAN GLURATE IS WELL TOLERATED IN THE TREATMENT OF PATIENTS WITH EROSIVE ESOPHAGITIS: A DOUBLE-BLIND, RANDOMIZED, DOSE FINDING STUDY, Sharma P et al, United European Gastroenterology Journal 2023; 11 (Supplement 8)

Disclosure

Kajsa Larsson, Kjell Andersson, Gunilla Huledal, Elham Yektaei and Kristofer Katkits are employees of Cinclus Pharma. Peter Unge is a consultant and senior advisor at Cinclus Pharma.

Introduction

Hypergastrinemia, caused by chronic atrophic gastritis or Helicobacter pylori (H. pylori) associated pangastritis, is associated with an increased risk of non-cardia gastric cancer. Recent studies have also found an increased risk of gastric cancer in long-term proton pump inhibitor (PPI) users. Patients with chronic atrophic gastritis also have an increased risk of neuroendocrine neoplasms (NEN) due to hypergastrinemia. However, whether long-term PPI use increases the risk of gastric NEN has not been assessed in the general population.

Aims & Methods

The aim of the present study was to assess the risk of gastric NEN among long-term PPI users in a multinational population-based study from the Nordic countries (Denmark, Finland, Iceland, Norway, and Sweden). The study was based on the Nordic Gastric and Esophageal Tumor Study (NordGETS), which is a population-based multinational sex, age, calendar year, and country matched case-control study including all adults (≥18 years of age) with a diagnosis of gastric or esophageal tumor in the Nordic countries. In the present study, the cases were incident gastric NEN identified in the cancer registries and the exposure was long-term use of PPI categorised into three equal-sized groups (tertiles) of defined daily doses (DDDs) from the medication registries of the Nordic countries between 1996 and 2020. Multivariable logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs), adjusted for chronic atrophic gastritis, NEN in the duodenum or pancreas, and H. pylori infection identified in the patient registries and medication registries.

Results

In total, 1,790 gastric NEN case patients were compared to 17,897 control participants. After a one-year run-in period, the median follow-up was 11.8 years. The risk of incident gastric NEN increased in PPI users compared to non-users in a dose-dependent manner. The adjusted OR for incident gastric NEN was 1.83 (95% CI 1.56 to 2.15) in the highest tertile of PPI use (>385 DDDs, entire drug history) compared to no PPI use (Table). The risk was higher in the younger age group (<65 years) than the older age group (≥65 years) and the estimates were consistent when excluding individuals with chronic atrophic gastritis, other NENs, and H. pylori.

Conclusion

In this population-based study from the five Nordic countries the risk of gastric NEN was increased in PPI users compared to non-users of PPI in a seemingly dose-dependent manner. The risk was higher in younger age groups of PPI users compared to older age groups.

Disclosure

No conflicts of interest

Introduction

Spasmolytic polypeptide expressing metaplasia (SPEM) is a cell repair lineage and is a very important phenotype of gastric mucosal injury and precancerous lesion.
Previously, parietal cells loss is considered as the first step and followed with chief cells transdiffernation to induce SPEM. But whether chief cells initial loss cause SPEM
needs to be further investigation. Acidic mammalian chitinase (CHIA) belongs to the 18 glycosidase family and is highly expressed in the chief cells. Our previous study showed that CHIA deficiency in the chief cells is the key event to induce SPME to progress to gastric cancer (Liu et al., DDW 2023 and 2024). However, the molecular role of CHIA in the development of SPEM is need further investigated.

Aims & Methods

Electron microscopy, qRT-PCR and single-cell sequencing (scRNA-seq) technology, as well as histopathological and immunofluorescence (IF) stainning with specific markers were performed in chief cells specific CHIA knockout mouse model (CHIA^rox/rox-GIF-Dre) and wild-type mice(CHIA^rox/rox), and in CHIA over - expression mice (CHIA ^rox/rox - GIF - Dre + rAAv - CHIA) and the control group (CHIA ^rox/rox - GIF - Dre + rAAv - control).

Results

Compared with CHIA^rox/rox mice, histological analysis and scRNA-seq technology data showed that loss of chief cells with increased M2 macrophage infiltration and final SPEM formation, but remaining of parietal cells in CHIA^rox/rox-GIF-Dre mice. Electron microscopy showed CHIA deficiency in mice resulted in endoplasmic reticulum was dilated and swollen, as well as the mitochondrial membrane was discontinuous of chief cells, followed with the accumulation of endoplasmic reticulum stress marker, including PERK, XBP-1, eIF2α/P-eIF2α, and GRP78, together with upregulation of pyroptosis-related marker, including NLRP3, ACS, GSDMD, NEK7, Caspase1, Caspase11, IL-1β, and IL-18, which was detected by qRT-PCR. These data indicating that target CHIA deletion caused chief cells pyroptosis. Furthermore, qRT-PCR analysis showed that CHIA deficiency caused the activation of IL33/IL-13 circuit in the mucosa of mice. Moreover, double immunofluorescence staining confirmed that upregulation and colocalization of IL-33 induced M2 macrophage polarization markers, including F4/80 and CD163⁺ with NLRP3 in the base of gastric mucosal of CHIA^rox/rox-GIF-Dre mice when compared with CHIA^rox/rox mice.Notably, CHIA ^rox/rox - GIF - Dre + rAvv - CHIA mice reversed the above process compared with controls.

Conclusion

Chief cells specific CHIA deficiency resulted in endoplasmic reticulum stress mediate NLRP3 inflammasome activation to induce chief cells proptosis.
Chief cells initial loss is sufficient and the key step to activate IL-33/ST2-M2 macrophage polarization axis to induce SPEM, which is independent of parietal cells loss.