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Introduction

Tradipitant is a NK-1 receptor antagonist that showed efficacy in improving nausea, vomiting and gastroparesis symptoms in a phase 2 study (VLY-2301) of diabetic and idiopathic gastroparesis. Efficacy was further evaluated in a phase 3 study (VLY-3301). A large placebo effect may have masked the true size of tradipitant benefit. Large placebo responses can be driven by Baseline Severity Inflation (BSI) especially on parameters used for inclusion into the study.

Aims & Methods

Idiopathic and diabetic gastroparesis patients with delayed gastric emptying, moderate to severe nausea, and at least 1 vomiting episode were randomized to tradipitant or placebo for 12 weeks. Nausea was assessed using the 5-point Gastroparesis Core Symptom Daily Diary. Overall gastroparesis symptoms was evaluated using the Patient Global Impression of Change (PGI-C) and the Overall Patient Benefit (OPB) scales. The BSI analysis subgroup included ITT subjects with at least 1 but less than 7 average vomiting episodes and excluded subjects whose vomiting severity was zero or highest severity. This baseline threshold allows for censoring of patients with minimal or very high frequency of vomiting and uses a symptom scale for censoring other than the primary endpoint scale. This is an accepted strategy to minimize placebo effect, and allows for a less biased estimation of true treatment effect.

Results

A responder analysis of PGI-C and OPB Score in the BSI subgroup showed a larger proportion of tradipitant treated patients improved versus placebo at start (Week 2) and end (Week 12) of study. Similarly, at the same timepoints nausea was improved. For the primary endpoint of change in nausea from baseline at week 12, tradipitant treated patients reported a greater reduction in nausea than placebo treated patients (-1.98 v. -1.28, p=.028). Improvement in tradipitant treated patients versus placebo was also seen at week 2 (-.99 v. -.50, p=.013). In the PGI-C scale more tradipitant treated patients demonstrated improvement as compared to placebo at week 2 (86% v. 53%, p=.002) and at week 12 (84% v. 65%, p=.056). For the OPB scale, more tradipitant treated patients demonstrated benefit compared to placebo at week 2 (95% v. 68%, p=.003) and week 12 (92% v. 68%, p=.009).

Conclusion

Tradipitant treatment in the Baseline Severity Inflation Analysis subpopulation resulted in improvements in nausea, PGI-C, and OPBS both the earliest (Week 2) and last (Week 12) timepoints.

Disclosure

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

A BASELINE SEVERITY INFLATION ANALYSIS IN STUDY VP-VLY-686-3301 OF TRADIPITANT IN GASTROPARESIS

Jesse L. Carlin 1, Christos Polymeropoulos 1, Changfu Xiao 1, Gunther Birznieks 1, Mihael H. Polymeropoulos 1

1 Vanda Pharmaceuticals, Inc., Washington, United States

Conference

UEG Week Copenhagen 2023

Topics

Oesophagus

Submission format

Abstract

Session

PP 01 Oesophageal, gastric and duodenal disorders (Posters)

Citation

United European Gastroenterology Journal 2023; 11 (Supplement 8)

Published

2023

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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.

EFFICACY ANALYSIS OF TRADIPITANT IN IDIOPATHIC AND DIABETIC GASTROPARESIS IN STUDY VP-VLY-686-3301

Jesse L. Carlin 1, Christos Polymeropoulos 1, Michaela Fisher 1, Paula Moszczynski 1, Garrett Johannsen 1, Changfu Xiao 1, Gunther Birznieks 1, Mihael H. Polymeropoulos 1

1 Vanda Pharmaceuticals, Inc., Washington, United States

Conference

UEG Week Copenhagen 2023

Topics

Oesophagus

Submission format

Abstract

Session

PP 01 Oesophageal, gastric and duodenal disorders (Posters)

Citation

United European Gastroenterology Journal 2023; 11 (Supplement 8)

Published

2023

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Introduction

Tradipitant is a novel NK-1 receptor antagonist studied in diabetic and idiopathic gastroparesis for short-term relief of nausea. This report presents the pooled analysis from 2 multicenter, randomized, double-blind, placebo-controlled studies (VP-VLY-686-3301 and VP-VLY-686-2301) assessing the efficacy of tradipitant in relieving symptoms of gastroparesis.

Aims & Methods

N=342 idiopathic and diabetic gastroparesis patients with delayed gastric emptying, moderate to severe nausea were included in the pooled ITT (Intent-to-Treat) population. Subjects were randomized to 85mg tradipitant twice a day (n=175) or placebo (n=167) and endpoints were assessed at Week 4. Nausea was assessed with the 5-point Gastroparesis Core Symptom Daily Diary (GCSDD). Overall gastroparesis symptom improvement was evaluated with the Patient Global Impression of Change (PGI-C) and Overall Patient Benefit (OPB) scales. Sensitivity analyses were performed to control for confounders.

Results

In a pooled analysis of double-blind subjects in the ITT population of Study 1 and Study 2, tradipitant demonstrated a clinically meaningful and statistically significant improvement in average nausea at week 4 (-1.15 for tradipitant v. -0.85 for placebo, p=0.0138). Significant improvement was seen in the number of nausea free days (20.96% improvement for tradipitant v. 12.52% for placebo, p=0.0085). Tradipitant also showed improvement in other gastroparesis symptoms as measured by the GCSI total score (-0.99 for tradipitant v. -0.76 for placebo, p=0.0265). Responder rates for PGI-C were 79.3% on tradipitant versus 69% on placebo at week 4 (p value = 0.036). For the Overall Patient Benefit, more patients improved on tradipitant versus placebo with 85.3% v. 71.2% at week 4 (p= 0.002). Sensitivity analysis adjusting for drug compliance confirmed the PK population (tradipitant blood levels ≥ 140ng/mL) in the pooled data set (n=284). In the pooled PK Population, tradipitant significantly improved average nausea at week 4 with -1.38 for tradipitant v. -0.85 for placebo (p=0.0001).

Conclusion

Pooling the data provided an opportunity to analyze a much larger data set, increase statistical power, and confirm results and subpopulations from the two separate studies. In the pooled analysis, we observed a clinically meaningful and significant effect on change of nausea severity at week 4. Improvements were also seen across core gastroparesis symptoms and overall measures of gastroparesis.

Disclosure

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

POOLED EFFICACY ANALYSIS OF TRADIPITANT IN IDIOPATHIC AND DIABETIC GASTROPARESIS STUDY VP-VLY-686-3301 AND VP-VLY-686-2301

Jesse L. Carlin 1, Christos Polymeropoulos 1, Michaela Fisher 1, Paula Moszczynski 1, Garrett Johannsen 1, Changfu Xiao 1, Gunther Birznieks 1, Mihael H. Polymeropoulos 1

1 Vanda Pharmaceuticals, Inc., Washington, United States

Conference

UEG Week Copenhagen 2023

Topics

Oesophagus

Submission format

Abstract

Session

Gastroparesis, dyspepsia, and beyond (Posters)

Citation

United European Gastroenterology Journal 2023; 11 (Supplement 8)

Published

2023

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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.

EXPOSURE-RESPONSE ANALYSIS OF OPEN LABEL TRADIPITANT IN IDIOPATHIC GASTROPARESIS IN STUDY VP-VLY-686-3301

Jesse L. Carlin 1, Christos Polymeropoulos 1, Michaela Fisher 1, Paula Moszczynski 1, Garrett Johannsen 1, Changfu Xiao 1, Gunther Birznieks 1, Mihael H. Polymeropoulos 1

1 Vanda Pharmaceuticals, Inc., Washington, United States

Conference

UEG Week Vienna 2024

Topics

Oesophagus

Submission format

Abstract

Session

OESOPHAGEAL, GASTRIC AND DUODENAL (Posters)

Citation

United European Gastroenterology Journal 2024; 12 (Supplement 8)

Published

2024

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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.

OPEN LABEL EFFICACY ANALYSIS OF TRADIPITANT IN IDIOPATHIC AND DIABETIC GASTROPARESIS

Jesse L. Carlin 1, Christos Polymeropoulos 1, Michaela Fisher 1, Paula Moszczynski 1, Garrett Johannsen 1, Changfu Xiao 1, Gunther Birznieks 1, Mihael H. Polymeropoulos 1

1 Vanda Pharmaceuticals, Inc., Washington, United States

Conference

UEG Week Vienna 2024

Topics

Oesophagus

Submission format

Abstract

Session

OESOPHAGEAL, GASTRIC AND DUODENAL (Posters)

Citation

United European Gastroenterology Journal 2024; 12 (Supplement 8)

Published

2024

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MOTION SERIFOS: TRADIPITANT EFFECTIVE IN THE PREVENTION OF VOMITING IN MOTION SICKNESS DURING SEA TRAVEL

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Introduction

Motion sickness has altered the course of history, including afflicting the sailors in the Battle of the Red Cliffs potentially leading to the fall of the Han Dynasty. Motion sickness remains a signficant challenge for both professional and leisure travelers, including during spaceflight where motion sickness affects 60-80% of astronauts. Neurokinin-1 receptors (NK1) are widely expressed in the body with important locations in the emetic pathway in the network of brainstem nuclei and the gut. In the intestine NK1 receptors are widely distributed, regulating motility, pain, and inflammation. Tradipitant is a novel NK1 receptor antagonist being studied for the treatment of motion sickness. In two previous studies in the coastal waters of the United States with 491 total participants, tradipitant significantly prevented vomiting as compared to placebo. In this study we sought to further understand the effects of tradipitant 170mg and tradipitant 85mg in motion sickness.

Aims & Methods

The Motion Serifos study was a multicenter, randomized, double-blind, placebo-controlled study where 316 participants embarked on boat trips under varied sea conditions and received 1:1:1 tradipitant 170mg, tradipitant 85mg, or placebo. Participants evaluated their symptoms at thirty-minute intervals during the approximately four-hour expedition, with questionnaires evaluating instances of vomiting and severity of nausea.

Results

Both dosing arms of tradipitant (170mg and 85mg) were superior to placebo in the prevention of vomiting (p = 0.000002, p = 0.0014). Tradipitant was superior to placebo in the prevention of severe nausea and vomiting across varied sea conditions (p = 0.00003).

Conclusion

Tradipitant could be of significant utility for motion sickness affected travelers in both civilian and military settings across air, land, and sea. Given the adverse effects and incomplete efficacy of currently available therapies, there remains a need for a novel efficacious therapeutic with a desirable tolerability profile.

Disclosure

All authors are employees of Vanda Pharmaceuticals. The study was sponsored by Vanda Pharmaceuticals.

MOTION SERIFOS: TRADIPITANT EFFECTIVE IN THE PREVENTION OF VOMITING IN MOTION SICKNESS DURING SEA TRAVEL

Vasilios Polymeropoulos 1, Margaret Bushman 1, Leah Kiely 1, Tanner Davis 1, Abigail Giles 1, Dane Morgan 1, Raina Mourad 1, Changfu Xiao 1, Christos Polymeropoulos 1, Gunther Birznieks 1, Mihael Polymeropoulos 1

1 Vanda Pharmaceuticals, Washington, DC, United States

Event

UEG Week Vienna 2024

Topics

Endoscopy IBD Mechanisms & Personalised Medicine Oesophagus

Submission format

Late-Breaking Abstract

Session

From IBS and IBD: Late-breaking abstracts

Citation

United European Gastroenterology Journal 2024; 12 (Supplement 8)

Published

2024

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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.