Gastroparesis - Emerging treatments

5-HT4 agonists

Prucalopride, felcisetrag, and velusetrag are 5-HT4 agonists that are currently being developed for the treatment of gastroparesis (prucalopride is already commercially available and approved for the treatment of chronic idiopathic constipation).[1] In one phase 2 trial, velusetrag was associated with a significant decrease in gastric emptying time in people with idiopathic and diabetic gastroparesis compared with placebo.[107] A single-center, placebo-controlled study of 36 participants receiving placebo or intravenous felcisetrag found that it significantly accelerated gastric, small-bowel, and colonic transit in patients with gastroparesis.[108] One randomized placebo-controlled crossover trial of 15 patients reported that prucalopride accelerated gastric emptying and bowel movement frequency but did not appear to ameliorate gastroparesis or meal-related symptoms.[109] Another randomized placebo-controlled crossover study of 34 patients, however, found that 4 weeks of prucalopride treatment significantly improved symptoms and quality of life and enhanced gastric emptying compared with placebo.[110]

Ghrelin agonists

Synthetic selective ghrelin receptor agonists, including ulimorelin, relamorelin, and TZP-102 have been evaluated in clinical trials for patients with gastroparesis.[111][112][113][114][115][116][117] One systematic review and meta-analysis of six randomized controlled trials (RCTs) found that ghrelin agonists significantly improved symptoms of gastroparesis compared to placebo. No significant treatment-related safety issues emerged. Conclusions could not be drawn regarding their long-term efficacy in managing diabetic gastroparesis, however, as the maximum study period among included trials was only 12 weeks.[118] Notably, in one of the included RCTs, a phase 2B randomized placebo-controlled trial of 393 patients with moderate to severe diabetic gastroparesis, relamorelin significantly reduced symptoms of gastroparesis and accelerated gastric emptying compared with placebo, and was generally safe and well tolerated.[117] Further evidence is required and large-scale clinical studies are needed to evaluate the long-term efficacy and safety profile of ghrelin agonists in the treatment of gastroparesis.[118] American College of Gastroenterology guidelines do not currently support the use of ghrelin agonists due to lack of evidence.[1]

Sepiapterin

Diabetic gastroparesis may be associated with impaired nitric oxide metabolism and reduced tetrahydrobiopterin (BH4) synthesis. One phase 2 RCT targeted this pathway in women with diabetic gastroparesis using oral sepiapterin (CNSA-001). Sepiapterin is a small-molecule natural precursor of the intracellular enzymatic cofactor BH4. The authors found that in patients treated with sepiapterin, gastric accommodation (the reduction in gastric tone and increase in compliance that follows ingestion of a meal) increased significantly during ingestion of a liquid test meal compared with placebo treatment. However, there were no significant group differences in upper gastrointestinal symptom scores or in gastric emptying breath test parameters. Larger controlled studies are needed.[119]

Trazpiroben

Trazpiroben is a dopamine D2/D3 receptor antagonist with minimal brain penetration. It has been designed to avoid the adverse effects associated with metoclopramide and domperidone. It appears to be well tolerated with a favorable safety profile and may represent a viable new treatment option for patients with gastroparesis.[120][121][122]