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.

Table Risk of gastric neuroendocrine neoplasms (NEN) by proton pump inhibitor (PPI) exposure defined by tertiles of defined daily doses (DDD) for the entire drug history between 1996 and 2020.
PPI (DDD)*	Crude odds ratio (95% confidence interval)**	Adjusted odds ratio (95% confidence interval)***
None	1.00 (reference)	1.00 (reference)
Tertile 1	1.46 (1.25-1.70)	1.34 (1.14-1.58)
Tertile 2	1.54 (1.30-1.81)	1.37 (1.15-1.64)
Tertile ​3	1.92 (1.65-2.24)	1.83 (1.56-2.15)
* Tertiles: 1 ≤56 DDDs; 2 >56-385 DDDs; 3 >385 DDDs. ** Matched for sex, age, calendar year, and country. *** Matched for sex, age, calendar year, and country, and adjusted for chronic atrophic gastritis, NEN in duodenum or pancreas, 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

Endoscopic gastroplasty (EG) is a minimally invasive endoscopic treatment aimed at reshaping the gastric body to manage obesity. This approach is now applicable across all obesity grades. Currently, three EG techniques are commonly used in clinical practice: endoscopic sleeve gastroplasty (ESG), endoluminal vertical gastroplasty (EVG), and distal primary obesity surgery endoluminal (POSE-2).

Aims & Methods

This randomized, single-center clinical trial (ClinicalTrials.gov NCT04854317) included obese individuals undergoing EG using one of the three methods (ESG, EVG, or POSE-2). A subgroup analysis based on obesity classes was performed to determine which technique yields the most favorable outcomes within each class, aiming to support a more tailored, patient-specific treatment approach for obesity. The primary outcomes assessed were weight loss efficacy, improvement in obesity-related comorbidities, and enhancement of quality of life (QoL) across obesity categories.

Results

Between July 2020 and April 2023, 183 patients with obesity (mean BMI 36.3±2.9 kg/m²; mean age 45±10 years; 89.1% female; 57.4% in class II obesity; hepatic steatosis present in 83%) underwent EG using ESG, EVG, or POSE-2. Follow-up adherence was 56.3% at 6 months, 32.8% at 12 months, and 15.8% at 18 months. At these time points, total body weight loss (TBWL) averaged 15.5±6.0%, 14.5±8.5%, and 17.1±10.2%, respectively, while excess weight loss (EWL) was 39.3±15.5%, 36.7±21.3%, and 43.0±26.6%. No significant differences were observed among the three techniques in either TBWL (p=0.92) or EWL (p=0.93) at 18 months.
When stratified by obesity class, there were no significant differences in TBWL (p=0.92) or EWL (p=0.62) among the techniques. However, analyzing technique performance within each obesity class revealed that POSE-2 was superior in class I obesity (p=0.03 for TBWL; p=0.006 for EWL), but less effective in class III (p=0.003). In contrast, EVG showed the best results in class III (p=0.048 for TBWL; p=0.02 for EWL), but underperformed in class I (p=0.034). No significant differences were noted between techniques in class II obesity. Improvements in fatty liver disease, hypertension, hyperlipidemia, diabetes, and obstructive sleep apnea were noted across all groups. Additionally, QoL, as assessed by the BAROS score, significantly improved over 18 months (p<0.001), with no variation across obesity classes.

Conclusion

Endoscopic gastroplasty proved effective in managing obesity. POSE-2 was most beneficial for patients with class I obesity, while ESG and EVG showed greater efficacy in higher obesity classes during mid-term follow-up. These results may support a more personalized therapeutic strategy for obesity.

Disclosure

Consultant for Apollo Endosurgery, EndoTools Therapeutics and USGI Medical.

Introduction

Functional dyspepsia (FD) is associated with duodenal eosinophilia and gut microbiota dysbiosis. Proton pump inhibitors (PPIs), as a first-line therapy, can suppress duodenal eosinophilic inflammation to ameliorate symptoms, yet the symptom relief rate is low. Rifaximin (RIF), an antibiotic known to modulate the gut microbiota, may offer an alternative therapeutic avenue. It is hypothesized that combining RIF with PPIs could more effectively alleviate FD symptoms and duodenal inflammation by targeting the gut microbiota.

Aims & Methods

A single-center, open-label, randomized controlled clinical trial was conducted on subjects who met the inclusion and exclusion criteria (Trial registration: ChiCTR2300069313). Ninety-six patients were randomly assigned in a 1:1 ratio to either the PPI+RIF group or the PPI group. The follow-up period extended to 4 weeks post-treatment cessation. The primary endpoint was the symptom relief rate, while secondary endpoints included symptom response rate, duodenal eosinophil counts, and changes in the microbiota. The study hypothesis was that the clinical efficacy of PPI+RIF would be superior to that of PPI monotherapy.

Results

	PPI+RIF	PPI	Z value	P value	PPI+RIF	PPI	Z value	P value
Abbreviations: PPI+RIF: Proton Pump Inhibitor plus Rifaximin; PPI: Proton Pump Inhibitor; ITT: the intention-to-treat analysis;PP: the per-protocol analysis.
Symptom relief rate	ITT				PP
Week 2	54.2%（26/48）	54.2%（26/48）	0.000	0.500	53.7%（22/41）	53.3%（24/45）	0.030	0.488
Week 4	72.9%（35/48）	58.3%（28/48）	1.522	0.064	76.7%（33/43）	56.8%（25/44）	2.020	0.022
4 weeks post-treatment	77.1%（37/48）	47.9%（23/48）	3.095	0.001	78.6%（33/42）	48.9%（22/45）	3.036	0.001
Symptom response rate	ITT				PP
Week 2	70.8%（34/48）	72.9%（35/48）	-0.227	0.590	68.3%（28/41）	73.3%（33/45）	-0.514	0.696
Week 4	81.3%（39/48）	77.1%（37/48）	-0.503	0.307	83.7%（36/43）	75.0%（33/44）	1.012	0.156
4 weeks post-treatment	85.4%（41/48）	68.8%（33/48）	1.982	0.024	85.7%（36/42）	71.1%（32/45）	1.688	0.046

A total of 96 patients were enrolled in the randomized controlled study. There were no statistically significant differences in baseline demographic data and clinical characteristics between the two groups. According to the intention-to-treat (ITT) analysis, the PPI+RIF group showed significantly higher rates of symptom relief (P = 0.001) and symptom response (P = 0.024) at 4 weeks post-treatment. These findings were supported by the per-protocol (PP) analysis, which revealed a superior symptom relief rate for the combination group at both 4 weeks of treatment (P = 0.022) and 4 weeks post-treatment (P = 0.001), as well as a superior symptom response rate at 4 weeks post-treatment (P = 0.046). Combination therapy also led to a greater reduction in duodenal eosinophil infiltration (P = 0.036) and significantly decreased peak hydrogen sulfide (H₂S) levels (P < 0.001), indicating a reduction in small intestinal bacterial load. Oral microbiota analysis revealed that β-diversity of the oral flora increased following the PPI+RIF intervention, with an increased relative abundance of Enterococcus (P = 0.004). Conversely, the PPI intervention led to the enrichment of the potentially pathogenic bacterium Catonella (P = 0.006). Notably, treatment responders in the PPI+RIF group showed a specific enrichment of the Eubacterium_yurii_group (P = 0.037), an alteration associated with the amelioration of duodenal eosinophilic inflammation and the enhancement of pathways related to preventing bacterial invasion of the epithelium.

Conclusion

In patients with FD, combining a PPI with Rifaximin is superior to PPI monotherapy, improving both symptoms and duodenal eosinophil infiltration. This effect is linked to a reduction in H₂S-producing bacteria and a beneficial shift in the oral microbiota. The oral abundance of Eubacterium_yurii_group may serve as a biomarker for treatment response.

Disclosure

The authors declare that they have no conflicts of interest.

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.

Day	Statistics	25 mg LG QD (N=12)	50 mg LG QD (N=12)	75 mg LG QD (N=13)	25 mg LG BID (N=9)	50 mg LG BID (N=11)	75 mg LG BID (N=10)
Day 1 pH >4 HTR	n	12	12	12	9	11	9
	Mean (SD)	48.0 (23.23)	64.6 (13.33)	68.1 (23.48)	76.0 (13.52)	87.4 (8.62)	94.5 (4.18)
Day 1 (1.5-24h) pH >4 HTR	n	12	12	12	9	11	9
	Mean (SD)	51.0 (24.91)	68.9 (14.02)	73.7 (24.78)	80.5 (14.12)	91.5 (8.98)	98.1 (3.10)
Day 14 pH >4 HTR	n	12	12	11	9	11	8
	Mean (SD)	48.5 (30.62)	63.9 (20.09)	87.2 (11.44)	76.9 (20.13)	95.7 (5.55)	99.0 (1.54)

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

Human transglutaminase 2 (TG2) plays a key role in celiac disease (CeD) pathogenesis, spurring development of the oral TG2 inhibitor ZED1227. In the phase 2a CEC-003/CEL study in CeD patients on a gluten-free diet (GFD), once-daily treatment with ZED1227 with gluten challenge (3 g/day) for 6 weeks led to significant improvement in the ratio of intestinal villous height to crypt depth (VH:CrD) versus placebo.¹ Despite adherence to a gluten-free diet, up to half of CeD patients report persistent symptoms often combined with varying degrees of small intestinal injury. Hence, potential treatments for CeD should ideally address these symptoms and improve mucosal injury.

Aims & Methods

The aim of the present study was a dose-ranging trial of ZED1227 in CeD patients with residual symptoms and villous atrophy despite a GFD. This was a double-blind, randomized, placebo-controlled phase 2b study. It enrolled adult CeD patients who had followed a GFD for at least one year and who experienced at least one moderate or severe gastrointestinal (GI) symptom in the month prior to baseline. All patients underwent an initial 5-week placebo run-in phase, followed by endoscopy and 1:1:1:1 randomization of patients with VH:CrD ≤2.5. Treatment was placebo thrice-daily (TID) or ZED1227 at doses of 10 mg TID, 25 mg TID, or 50 mg once-daily (QD) for 12 weeks. No gluten challenge was carried out. The primary endpoint was the rate of patients with both improvement by ≥ 0.4 in VH:CrD and improvement by ≥ 15% in either of two symptom scores (non-stool GI or diarrhea severity) on the celiac disease symptom diary (CDSD) from the end of the run-in phase to week 12. Key secondary endpoints included the change in VH:CrD, change in CDSD GI total severity score, and safety.

Results

A total of 397 patients were randomized to the 4 arms, of whom 92.7% completed treatment. The primary endpoint was achieved by 27.1% of patients receiving 10 mg ZED1227 TID, 16.9% for 25 mg TID, 25.3% for 50 mg QD, and 19.3% for placebo, with no significant differences between any treatment arm and placebo. The mean change in VH:CrD ratio from baseline was 0.21 for 10 mg ZED1227 TID, 0.17 for 25 mg TID, and 0.26 for 50 mg QD versus 0.12 for placebo. Within-group changes from baseline to week 12 were statistically significant within each arm, while the between-group difference in changes was significant only for 50 mg ZED1227 QD versus placebo (p<0.05). Similarly, mean changes in the CDSD GI total severity score were -0.96 with 10 mg ZED1227 TID, -0.95 with 25 mg TID, -1.20 with 50 mg QD, and -1.05 with placebo. Improvements within each arm were again statistically significant, with no significant differences between any treatment arm and placebo. There were no notable differences in the rates of adverse events or serious adverse events (SAEs) between the study arms, and no SAEs related to the study drug were reported.

Conclusion

The CEC-004/CEL study did not meet its primary endpoint of combined improvement in histology and symptoms. However, changes in the VH:CrD ratio achieved with 50 mg ZED1227 QD were statistically superior to placebo, consistent with the results of the prior CEC-003/CEL study. Significant within-group improvement from baseline to week 12 in both histologic and symptom outcomes within the placebo group underscored the challenges of clinical trials without deliberate gluten exposure in patients with the heterogeneous symptom and histology typical of partially treated CeD. The favorable safety profile of ZED1227 was confirmed, and no new safety concerns were identified.

References

1. Schuppan D, Maki M, Lundin KEA, Isola J, Friesing-Sosnik T, Taavela J, et al. A Randomized Trial of a Transglutaminase 2 Inhibitor for Celiac Disease. N Engl J Med. 2021;385(1):35-45.

Disclosure

Sponsor of the trial: Dr. Falk Pharma GmbH
Acknowledgement: This research was supported by Takeda.