Velusetrag

Gastroparesis significantly affects quality of life and healthcare expenditure. Effective treatment options are limited, and the utility of current prokinetic agents is inhibited by serious adverse effects. There exists an unmet need for prokinetic agents demonstrating both efficacy and an acceptable adverse effect profile. Highly selective 5-Hydroxytryptamine receptor 4 (5-HT4) agonists have exhibited clinical efficacy and safety in randomized controlled trials (RCTs). Consequently, we conducted a meta-analysis to comprehensively assess the safety and efficacy of these highly selective agents. Multiple databases, including PubMed, Scopus, and Embase, were systematically screened from inception until September 2023. Only RCTs evaluating the efficacy and safety of highly selective 5-HT4 agonists for gastroparesis were included. Key outcomes of interest included the pooled rates of Gastroparesis Cardinal Symptom Index (GCSI) scores, gastric emptying time (GET), and adverse event rates in each group. We adhered to standard meta-analysis methodology utilizing the random-effects model, with heterogeneity assessed by I² statistics. Our analysis identified six RCTs, comprising 570 patients with diabetic (48%) or idiopathic (51%) gastroparesis, with mean ages of 46 and 45.9 years in the intervention and placebo groups, respectively. In the meta-analysis, highly selective 5-HT4 agonists demonstrated significantly superior pooled GCSI scores compared to placebo (mean difference: 4.283, (1.380, 7.186), p<0.05). Pooled GET was also significantly improved with 5-HT4 agonists compared to placebo (mean difference: 2.534, (1.695, 3.373), p<0.05). Although pooled rates of total adverse events were higher with 5-HT4 agonists (mean difference: 6.975, (1.042, 46.684), p<0.05), rates of specific adverse events such as diarrhea, abdominal pain, and headaches were comparable. In conclusion, this meta-analysis underscores a statistically significant improvement in GET and GCSI scores among patients receiving highly selective 5-HT4 agonists (Velusetrag, Felcisetrag, Prucalopride) for both diabetic and idiopathic gastroparesis. While the overall adverse effect profile is deemed acceptable, larger studies with extended follow-up periods are needed to investigate rare and/or serious adverse events. Moreover, future high-quality RCTs comparing the efficacy and safety of these novel agents with currently available agents are essential to further validate these findings.

This study assessed the efficacy and safety of velusetrag—a 5‐HT4 agonist with pan‐gastrointestinal prokinetic activity—for gastroparesis symptom management and gastric emptying (GE).

In this multicenter, double‐blind, randomized, placebo‐controlled study, subjects with diabetic or idiopathic gastroparesis received velusetrag 5, 15, or 30 mg or placebo for 12 weeks. The primary efficacy outcome was a 7‐day mean Gastroparesis Cardinal Symptom Index 24‐h composite score (GCSI‐24H) change from baseline at week 4; GE was evaluated using scintigraphy (GES) and breath tests, and safety from adverse events (AEs).

232 subjects (183 females; 113 idiopathic gastroparesis) received treatment from February 2015 through June 2017. Least‐squares mean improvement from baseline GCSI‐24H (primary endpoint) at week 4 was −1.5 following velusetrag 5 mg vs −1.1 following placebo (treatment difference, −0.4; 95% confidence interval, −0.75 to −0.03; nominal p = 0.0327; Hochberg‐adjusted p = 0.0980 [not significant]). Symptom improvement from baseline was achieved only with velusetrag 5 mg, which resulted in greater improvement from baseline vs placebo in all gastroparesis core symptoms, especially in subjects with idiopathic gastroparesis. Improvement from baseline GE by GES was greater in subjects receiving velusetrag (all doses) vs placebo; >70% of subjects receiving velusetrag 30 mg had GE normalization at 4 h. Treatment‐emergent AEs were generally mild.

Velusetrag treatment was generally well‐tolerated and associated with improved GE vs placebo in subjects with diabetic or idiopathic gastroparesis; however, only the lowest dose, velusetrag 5 mg, was associated with short‐term improvement in gastroparesis symptoms.

NCT02267525.