Su1427 Gastric Electrical Stimulation of the Antrum Evokes Compound Cervical Vagal Nerve Action Potentials in Rodents

Abstract

Purpose: Patients with diabetic or idiopathic gastroparesis have delayed gastric emptying (GE) time. Velusetrag (VEL) is an oral, once-daily, investigational, highly-selective 5-HT4 agonist that has demonstrated prokinetic effects in the lower gastrointestinal tract in subjects with chronic idiopathic constipation. The current study evaluated VEL prokinetic effects in the upper gastrointestinal tract by assessing GE time in both diabetic and idiopathic gastroparesis subjects. Methods: Subjects with gastroparesis were screened for increased GE time (t1/2 > 160 mins), symptoms consistent with gastroparesis for ≥3 months, Gastroparesis Cardinal Symptom Index score between 2-4 inclusive, and HbA1c < 10% (diabetics). Subjects were randomized in an incomplete block, 3-period, cross-over design to 3 of 4 treatments, VEL 5-, 15and 30-mg and placebo stratified for diabetic or idiopathic gastroparesis. In all 3 treatment periods, subjects performed a 6-hr 13C-octanoate breath test of GE time on Day -1 (baseline) and after the 7th dose. Efficacy was assessed by the change from baseline in GE t1/2. All efficacy endpoints were evaluated using mixed-effect models with a covariate for baseline GE. Results: 34 subjects were randomized; n=26 (placebo), 26 (VEL 5-mg), 25 (VEL 15-mg), and 25 (VEL 30-mg). The study populationwas 68% female, 82%Caucasian, and 53% diabetic, with mean (SD) age of 46 (10.3) yrs and baseline GE t1/2 mean (SD) [range]: 206 min (91.1) [107-640]. The proportion of subjects with at least a 20% reduction in GE t1/2 was 5% for placebo and 26%, 20%, 52% for VEL 5-, 15-, and 30-mg respectively. Statistical significance was observed in the 30-mg dose group (p=0.002). The mean (SD) change from baseline of GE t1/2 was -13 (14.9) mins for placebo and -35 (14.6), -34 (15.5), and -52 (15.2) mins for VEL 5-, 15-, and 30-mg, respectively. Similar treatment effects were observed with VEL in both diabetic and idiopathic subjects. A pre-specified analysis of subjects with delayed GE time at baseline (GE between 180-350 mins excluding relatively normal and extremely abnormal GE times) revealed a placebo-adjusted mean (SD) reduction [% improvement] from baseline in VEL-treated subjects of -76 (41.9) [-33%], -73 (50.4) [28%] and -85 (40.9) [-37%] mins for VEL 5-, 15and 30-mg, respectively. All doses of VEL were generally well tolerated. The most common adverse events were diarrhea (n=16) and headache (n=6). No on-treatment serious adverse events were observed. Conclusions: Velusetrag treatment was generally well tolerated and resulted in a statistically significant improvement in GE time at the 30 mg dose in subjects with diabetic or idiopathic gastroparesis. Future studies will assess the translation of these pharmacodynamics effects into symptomatic improvement.