Introduction

Tenascin-X (TNX) is a glycoprotein involved in the regulation of the tissue structure via anti-adhesive interactions with collagen in the extracellular matrix. Deficiency often manifests as hypermobility Ehlers–Danlos syndrome involving joint hypermobility, skin hyperelasticity, pain and gastrointestinal dysfunction. TNX gene localizes to the major histocompatibility complex (MHC) class III region on chromosome 6. TNX deficient mice have accelerated gastric emptying and markedly increased vagal afferent responses to gastric distension. These observations in knockout mice correlated closely with gastrointestinal symptoms in genetically confirmed TNX-deficient patients with EDS, including disrupted motility and bowel habit and visceral pain

Aims & Methods

We explore the type and frequency of identified TNX variants in a set of whole genome sequencing data based on samples obtained from gastroparesis patients.

Results

In the current study, we replicate this enrichment of TNX variants in the largest set of whole genome sequencing set of gastroparesis cases (n>1700). We focused on all coding/splicing variants in the TNX with a minor allele frequency (MAF)<0.05. Together we see 83 non-synonymous variants with at least 2-fold enrichment in this dataset. Several of these variants have been previously reported in association with EDS in CLINVAR and the functional role of the remaining ones is to be confirmed. One of the TNX variants is in identified in our cohort the TNX:NM_019105:exon26:c.A9044G:p.K3015R, with a high (CADD score of 23.3 is seen in two patients with EDS and idiopathic gastroparesis). We have also identified a subset of patients with CNVs specifically with TNX microdeletions and this analysis is ongoing on the full set of samples.

Conclusion

These results suggest a statistically significant enrichment of moderate to rare TNX non synonymous variants in the idiopathic gastroparesis set of patients. Furthermore, these results suggest an enrichment of such gene variants in the entire idiopathic cohort of patients with idiopathic gastroparesis not only with individuals with confirmed EDS status. TNX appears to be associating with and stabilizing the newly produced collagen fibrils, which suggests that all recessive forms of EDS affect post-translational modification of collagens. This finding would not be delineated with a classic GWAS approach yet may explain a proportion of underlying pathophysiology manifesting as gastroparesis.

Disclosure

Authors are employees of Vanda Pharmaceuticals Inc.

Introduction

Gastroparesis is a severe medical condition characterized by delayed gastric emptying and symptoms of nausea, vomiting, bloating, fullness after meals, and abdominal pain. Thus far, little is known about the underlying genetic risk factors for nausea in gastroparesis patients. We explored the association of genetic variants with nausea severity in a set of WGS data from a clinical gastroparesis study.

Aims & Methods

Blood samples were obtained from adults with a diagnosis of diabetic or idiopathic gastroparesis, having evidence of delayed gastric emptying, and moderate to severe nausea, daily average nausea score of >2.5, at least one episode of vomiting, PAGI-SYM nausea score of ≥2 at screening, and controlled blood glucose levels. WGS was conducted with 30x read depth using whole blood samples. Nausea score was assessed from a daily symptom dairy with a range from 0 mild to 5 severe. GWAS using linear model was conducted on variants with MAF ≥0.01 with adjustment of the subject’s age, sex, BMI, etiology, and the first 3 PCs.

Results

Variant clusters from multiple genes are significantly associated with baseline nausea score at p=1e-5 level. Among the top scoring variants are loci within ATF3, PP2D1, CNTN4, BMP2, ABL1, CTNNA3 and KIF6. Interestingly, upon comparing our results with a published transcriptomic analysis that included both diabetic and idiopathic gastroparesis subjects, we found that ATF3 and BMP2 were overlapping with genes differentially expressed in both diabetic and idiopathic gastroparesis when compared with controls. ABL1 was however differentially expressed in diabetic cases whereas CNTN4 was differentially expressed in idiopathic controls.
We expanded the analysis with single gene tests which shows that ATF3 is significant especially for MAF>0.05 variants (SKAT p=0.02). The top variant in ATF3 is rs79151334 (beta= 0.68, p=5.76e-6), whose minor allele associates with higher nausea score.

Conclusion

Additionally, we report new potential associations CTNNA3, PP2D1, and KIF6 as well as a cluster of variants between CDH2 and MIR302F, that associated with baseline nausea score. Among those, both CTNNA3 and CDH2 encode cadherin related proteins, suggesting this type of junction could play a role in the underlying mechanism.

Disclosure

I am an employee at Vanda Pharmaceuticals Inc.

Introduction

Tradipitant is a novel NK1R antagonist studied in diabetic and idiopathic gastroparesis. This report presents the analysis from the open-label arm of a multicenter, randomized, double-blind, placebo-controlled study (VP-VLY-686-3301) assessing the efficacy of tradipitant in relieving symptoms of gastroparesis.

Aims & Methods

N=531 idiopathic and diabetic gastroparesis patients with delayed gastric emptying received open label 85mg tradipitant BID for 12 Weeks. Nausea was assessed using the 5-point Gastroparesis Core Symptom Daily Diary. An exposure response analysis was performed to control for low drug exposure. We used a threshold of ≤140ng/ml tradipitant blood concentration at any visit to classify participants in the High (n=309) and Low (n=218) PK Populations.

Results

Patients improved the average nausea score significantly from baseline after 12 weeks tradipitant (improvement of -1.01 vs 2.14 at baseline, p<0.0001). A significant improvement was also seen in the percent of nausea free days (an addition of 51.76% of days for tradipitant vs. 19.62% at baseline, p<0.0001).

Patients in the High PK group significantly improved average nausea score compared to the Low PK group at Week 12 (improvement of -1.19 vs -0.78, p<0.0001). A significant improvement was also seen in the percent of nausea free days (an addition of 35.6% of days for High PK versus 22.6% for Low PK, p=0.0002).

Conclusion

Tradipitant demonstrated statistically significant improvement from baseline in average nausea severity and percentage of nausea-free days in this 12 week open label study in both idiopathic and diabetic gastroparesis subjects. Additionally, a strong exposure response in nausea improvement was observed when comparing subjects with high drug exposure vs low drug exposure.

Disclosure

Study was sponsored by Vanda Pharmaceuticals. Inc. Authors are employees of Vanda Pharmaceuticals, Inc.

Introduction

To assess the exposure response of NK-1 receptor antagonist tradipitant in the reduction of gastroparesis symptoms in patients with idiopathic gastroparesis in the open label arm of phase 3 study (VP-VLY-686-3301).

The four etiologies of gastroparesis are diabetic, post-surgical, drug-induced, and idiopathic. The idiopathic etiology of gastroparesis is least common, presenting in about 11.3% of patients, which amounts to about 90,000 patients in the United States. Standards set by the FDA define a rare disease or condition as one that affects less than 200,000 people in the United States. This establishes idiopathic gastroparesis as a rare condition, as well as one with a high unmet need for treatment. Patients with gastroparesis have decreased quality of life associated with severe and chronic symptoms and no treatment is currently approved for idiopathic gastroparesis specifically. Tradipitant previously demonstrated efficacy in idiopathic gastroparesis in reducing gastroparesis symptoms in a phase 2 study (VP-VLY-686-2301).

Aims & Methods

The open label arm of Study 3301 enrolled n=531 idiopathic and diabetic gastroparesis patients with delayed gastric emptying, moderate to severe nausea, and at least 1 vomiting episode. Patients received 85 mg tradipitant twice a day for 12 weeks. Nausea was assessed daily using the 5-point Gastroparesis Core Symptom Daily Diary (GCSDD). Overall gastroparesis symptoms were assessed every 2 weeks in clinic using the Gastroparesis Cardinal Symptom Index (GCSI).

An exposure response analysis was performed on a subgroup of patients to control for low drug exposure. We used a threshold of ≤140ng/ml tradipitant blood concentration at any visit to classify participants in the High (n=309) and Low (n=218) PK Populations. Results were further stratified to compare average nausea severity and gastroparesis symptoms at baseline nausea severity scores of ≥2 and ≥2.5 for Low (n=129 and n=89, respectively) and High (n=170 and n=110, respectively) PK subgroups.

Results

Patients in the High PK subgroup had statistically improved nausea severity at Week 12 compared to the Low PK subgroup (-1.19 vs. -0.78, respectively; p<0.0001), including at baseline nausea severity scores of ≥2 (-1.61 vs. -0.98, respectively; p<0.0001) and ≥2.5 (-1.77 vs. -1.03, respectively; p<0.0001). The High PK subgroup also had statistically significant improvement in nausea-free days at Week 12 compared to Low PK (+35.65% vs. +22.56%, respectively; p=0.0002), including at baseline nausea scores of ≥2 (+36.36% vs. 18.15%, respectively; p=0.0002) and ≥2.5 (+33.44% vs. 14.11%, respectively; p=0.0009).

Conclusion

A significant exposure response was seen in idiopathic gastroparesis patients receiving open label tradipitant for 12 weeks. Patients with higher blood levels of tradipitant significantly improved in average nausea severity and in endpoints measuring overall gastroparesis symptoms compared to subjects with low drug blood levels.

Disclosure

Study was sponsored by Vanda Pharmaceuticals, Inc. Authors are employees of Vanda Pharmaceuticals, Inc.

Introduction

Idiopathic gastroparesis (IG) remains a challenging condition, with few effective therapeutic options available. Despite recent European and international consensuses, some management modalities are still different in the French practice (1).

Aims & Methods

We aimed to develop French recommendations on the diagnosis and management of IG in adults and paediatric patients, highlighting the similarities and differences with recent consensuses. A Delphi process was conducted among a panel of 16 French neurogastroenterology experts, including gastroenterologists and paediatricians. A first list of statements was drafted with a literature summary. After revisions and clarifications, 3 voting rounds were conducted and consensus statements were identified (defined as ≥ 80% agreement).

Results

Consensus was reached for 39 out of 46 statements. Definition and diagnostic modalities were similar to recent guidelines. IG was defined as symptoms associated with delayed gastric emptying (GE), in the absence of a mechanical obstruction. The panel agreed that nausea and vomiting are cardinal symptoms, with postprandial distress symptoms frequently overlapping. Variable presentations according to age were highlighted in paediatric patients.
Delayed GE can be confirmed by either scintigraphy or a GE breath test, using a solid meal, and a 4-hour measurement. Food retention at endoscopy was not considered a diagnostic criterion. Pyloric EndoFlip was not considered a diagnostic or pretherapeutic tool. A blood test and screening for Helicobacter pylori were supported before diagnosing IG.
Regarding the management, like in recent guidelines, the panel supported a first-line therapy using dietary advice and dopamine antagonists (metoclopramide or domperidone). The panel supported the efficacy of intravenous erythromycin, but not oral erythromycin. Agreement on the efficacy of other drugs, including prucalopride, antiemetics, or neuromodulators, was not reached. The use of nutritional support was recommended if deemed necessary for refractory vomiting and malnutrition, with enteral post-pyloric nutrition recommended as the first option.
The consensus supported different strategies for the management of refractory gastroparesis. Stopping opioids, or drugs inducing delayed GE, and the treatment of associated constipation were recommended before considering more invasive procedures. The efficacy of pyloric toxin injection was not agreed upon. Gastric endoscopic pyloromyotomy and gastric electrical stimulation were considered effective therapies for refractory IG. Finally, surgical procedures were not supported.

Conclusion

This consensus shows that the diagnostic modalities for IG are similar in France as compared to international guidelines, but highlights differences in the management of refractory gastroparesis, supporting endoscopic pyloromyotomy or the implantation of gastric electrical stimulation.

References

1. Schol J, Wauters L, Dickman R, Drug V, Mulak A, Serra J, et al. United European Gastroenterology (UEG) and European Society for Neurogastroenterology and Motility (ESNM) consensus on gastroparesis. United European Gastroenterol J. 2021 Apr;9(3):287–306.
2. Schol J, Huang IH, Carbone F, Fernandez LMB, Gourcerol G, Ho V, et al. Rome Foundation and international neurogastroenterology and motility societies’ consensus on idiopathic gastroparesis. Lancet Gastroenterol Hepatol. 2025 Jan;10(1):68–81.

Disclosure

HS received lecture fees from Enterra Medical, and Viatris.

Introduction

This report presents the results of a multicenter, randomized, double-blind, placebo-controlled phase 3 study (VP-VLY-686-3301) assessing the efficacy of tradipitant in relieving symptoms of gastroparesis. Tradipitant, a novel NK-1 receptor antagonist, previously demonstrated efficacy in diabetic and idiopathic gastroparesis in reducing gastroparesis symptoms in a phase 2 study (VP-VLY-686-2301).

Aims & Methods

N=201 idiopathic and diabetic gastroparesis patients with delayed gastric emptying, moderate to severe nausea, and at least 1 vomiting episode were included in the ITT (Intent-to-Treat) population. Subjects were randomized to receive 85 mg tradipitant twice a day (n=102) or placebo (n=99) for 12 weeks. Nausea was assessed daily using the 5-point Gastroparesis Core Symptom Daily Diary (GCSDD). Overall gastroparesis symptom improvement was evaluated using the Patient Global Impression of Change (PGI-C) and the Overall Patient Benefit (OPB) scales. Sensitivity analyses were also performed to control for confounders that may have masked the true treatment effect size.

Results

At the primary endpoint of change in nausea from baseline as measured by the GCSDD at week 12, both tradipitant and placebo showed significant and similar reductions from baseline at 1.55 and 1.49 respectively. Comparison between treatment arms did not reach statistical significance in this measure. However, in the PGI-C scale, more tradipitant treated patients demonstrated response as compared to placebo both at week 2 (74% v. 58%, p=0.019) and at week 12 (78% v. 66%, p=0.065). Similarly, in the OPB scale, more tradipitant treated patients demonstrated response as compared to placebo both at week 2 (81% v. 62%, p=0.0003) and week 12 (86% v. 71%, p=0.011).
Sensitivity analysis adjusting for rescue medication use further confirmed the ITT findings in both the PGI-C and OPB analysis at both week 2 and week 12.

Conclusion

Significant but similar improvements from baseline for tradipitant and placebo may have masked the true treatment effect size at the primary endpoint of the study of change in nausea severity as measured by daily diary at week 12 leading to no statistically significant difference between treatments. Despite this large placebo effect, tradipitant was shown to be significantly better than placebo in global measures of patient improvement including the Patient Global Impression of Change (PGI-C) and the Overall Patient Benefit (OPB) scales.

Disclosure

Study was sponsored by Vanda Pharmaceuticals, Inc. Authors are employees of Vanda Pharmaceuticals, Inc.

Introduction

MAPS III redefined the risk of gastric cancer and provides a well-defined screening and surveillance protocol for patients with precancerous lesions [1]. It represents an updated guideline, emphasizing the importance of evaluation of gastric mucosa and targeted biopsy. To date, the role of magnification endoscopy has become increasingly significant for the accurate assessment of gastric mucosal patterns.

Aims & Methods

The aim of this study is to compare magnified-endoscopy and standard (non-magnified) endoscopy in terms of their effectiveness in detecting dysplastic lesions and the concordance between endoscopic grading of gastric intestinal metaplasia (EGGIM) [2] and histological findings (operative link on gastritis assessment or gastric intestinal metaplasia OLGA/OLGIM).
A retrospective, single-center study was conducted, enrolling patients who had undergone upper GI-endoscopy for surveillance according with MAPS III. The procedures were performed using high-definition endoscopes, with or without magnification, following adequate mucosal preparation [3]. Only endoscopic reports containing at least five images of the antrum, body, and incisura (minimum of 15 images) both using WLI and BLI chromoendoscopy, were included. The endoscopic records were retrospectively reviewed to assess EGGIM classification on each region of interest (0-2) and the total score (0-10). During all exams targeted biopsies were performed, and histological analyses were also collected. Image review was carried out by three expert endoscopists, blinded to the histological reports.

Results

A total of 96 patients were enrolled (40 males, 41.6%; median age 66.1 years, IQR 56.6–73.4). Fifty-four patients (56.2%) underwent standard upper-GI endoscopy (Group A), while 42 patients (43.8%) received magnifying endoscopy (Group B). Upon re-evaluation of endoscopic images, 42 out of 54 patients in Group A (77.7%) showed an EGGIM score of 0–4, while 12 patients (22.3%) had an EGGIM score ≥5. A higher proportion of patients in Group B showed EGGIM ≥5 (19 patients, 45.2%; p=0.01). Histological analysis revealed that 18 of 96 patients (18.7%) had advanced stages (OLGA/OLGIM III–IV), with a significantly higher prevalence in Group B (15 patients) compared to Group A (3 patients; p<0.001). Linear regression analysis between EGGIM and OLGA/OLGIM scores demonstrated a statistically significant correlation in both groups, which was higher in Group B (p=0.02 and p<0.001, respectively). Dysplastic lesions were identified in two cases, both of them were detected using magnifying endoscopy.

Conclusion

EGGIM shows good correlation with the OLGA/OLGIM staging systems, particularly in examinations performed with magnification. Despite a potential selection bias due to the retrospective nature of the study, our findings demonstrate that the use of magnification during surveillance of upper-GI precancerous conditions is highly effective.

References

1. Dinis-Ribeiro, M. et al. MAPS III: ESGE/EHMSG/ESP guideline update 2025. Endoscopy, 2025
2. Esposito G, et al. Endoscopic grading of gastric intestinal metaplasia (EGGIM): a multicenter validation study, Endoscopy, 2019
3. Manfredi G, et al. Premedication with simethicone and N-acetylcysteine for improving mucosal visibility during upper gastrointestinal endoscopy in a Western population. Endosc Int Open, 2021