Pharmacodynamics, Pharmacogenetics, Clinical Efficacy and Safety of Tradipitant for Functional Dyspepsia

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ABSTRACT 30 lines (currently 30) Upper gastrointestinal symptoms may result from gastric dysfunction including reduced gastric accommodation and gastric hypersensitivity, and may cause functional dyspepsia (FD), a very common cause of substantial morbidity estimated to affect 10% of the population. FD manifests as abdominal pain/discomfort for at least three days per week which may be associated with eating. An estimated 40% of patients with this symptom complex consult their physicians, negatively influencing their workplace attendance and productivity with overall economic impact of more than $18 billion in 2009. Development of effective treatments of these disorders is desirable, given significant unmet medical need. Systematic reviews and meta-analyses of the literature have shown low levels of efficacy with current treatments which include proton pump inhibitors, H pylori eradication, prokinetics, and central neuromodulators. There is currently no approved treatment for functional dyspepsia. We have developed a noninvasive imaging method to simultaneously measure gastric accommodation and gastric emptying, one or both of which are reported to be altered in up to 75% of patients with functional dyspepsia. The approved NK 1 receptor (NK1R) antagonist aprepitant has been shown to increase fasting gastric volume and postprandial accommodation in healthy participants without deleteriously affecting gastric emptying. The novel NK1R antagonist, tradipitant, was previously shown to reduce symptoms in patients with gastroparesis although the precise mechanism, overall effects, and benefit-risk ratio of this medication unclear. Our general hypothesis is that tradipitant relieves symptoms in patients with functional dyspepsia as well as enhances postprandial gastric accommodation without deleterious effects on gastric emptying. Our aims are: 1. To compare the pharmacodynamics and clinical effects of tradipitant vs. placebo on satiation, fasting and fed gastric volume, gastric accommodation, gastric emptying, and symptoms in patients with functional dyspepsia (and non-delayed gastric emptying at baseline) based on Leuven Dyspepsia scale and Nepean Dyspepsia Index 2. To assess prevalence of NKR-SNP rs881 genetic variant and the pharmacogenetics effects of this variant in NK1 gene on the pharmacodynamics of tradipitant compared to placebo on fasting and accommodation gastric volumes, gastric emptying and satiation. In an exploratory analysis, we shall assess the correlation between gastric accommodation and emptying in functional dyspepsia and to compare the relationship with those previously reported in health volunteers. Anticipated Results and Significance: We expect these studies will lead to understanding the mechanisms of action of tradipitant in improving gastrointestinal functions and patient reported outcomes, including pain, in patients with functional dyspepsia, addressing unmet needs of millions of American citizens.