Editorial: felcisetrag—forward movement as a novel prokinetic for gastroparesis

Abstract

5hydroxytryptamine type 4 (5HT4) receptor agonists promote intestinal peristalsis, increase gastric emptying and improve oesophageal motility. Accordingly, 5HT4 agonists hold strong potential to improve hypomotility symptoms via their prokinetic properties. However, 5HT4 drug development has presented numerous challenges, and even controversy, over the past three decades. Cisapride, a nonselective 5HT4 agonist, showed early promise in improving foregut symptoms, but was withdrawn from the market worldwide in 20001 over concerns of arrhythmogenic potential resulting from effects on potassium ion channels.2 Tegaserod, a more selective 5HT4 agonist, emerged as a treatment option for constipation disorders, but never gained approval for use in Europe, and was withdrawn from the US market in 2009 due to possible cardiovascular adverse events. It was later reapproved for more restricted use in 2019. These early 5HT4 agonist experiences tarnished the initial lustre shown by this medication class, limiting the available 5HT4 prokinetic options to prucalopride (a highly selective 5HT4 agonist for use in constipation), metoclopramide (a moderate 5HT4 agonist with antagonist effects on dopamine D2 receptors, the latter potentially leading to extrapyramidal effects) and domperidone. As a disorder of delayed gastric emptying, gastroparesis management intuitively depends on successful implementation of prokinetic agents. However, at present, metoclopramide is the only such agent indicated for use in the United States, and for safety reasons its use is restricted to ≤12 weeks, and to ≤5 days in Europe. This background underscores the desperate need for additional prokinetic options for gastroparesis sufferers, and demonstrates the importance of the recent report by Chedid et al on their phase IIa trial evaluating the effects of intravenous felcisetrag (0.1, 0.3 or 1.0 mg daily for 3 days) on gastric emptying and whole gut motility in gastroparesis patients (idiopathic or diabetic).3 The study revealed significant gastric emptying acceleration with all three felcisetrag doses, independent of gastroparesis aetiology. Although such improvements in gastric motility with felcisetrag represent an exciting advance to the gastroenterology community, patients remain more concerned with symptom improvement than gastric emptying times. While a clearer understanding of felcisetrag s potential impact on gastroparesis symptoms requires further study, the observed robust effects on gastric emptying are cause for optimism. Indeed, 18/25 (72%) of felcisetragtreated (vs 1/9, 11% placebotreated) patients experienced a ≥10% (~20 minutes) reduction in gastric emptying halftime, a threshold previously established to correspond with meaningful symptom improvement. As a chronic condition, prokinetics for gastroparesis ideally would include an oral formulation, facilitating maintenance use. Although this trial only examined shortterm, intravenous dosing, earlier felcisetrag (formerly TD8954) studies revealed a favourable oral pharmacokinetic profile,4,5 and minimal offtarget receptor affinities compatible with the lower risk of adverse events observed in the current investigation. Larger, multicentre studies of felcisetrag should be conducted to address remaining questions regarding optimal use and clinical efficacy, confirm adequate safety and exclude potential tachyphylaxis with longterm use. In the meantime, these initial results cast a new shine on 5HT4 agonists, and provide hope for an expanded gastroparesis treatment armamentarium in the future.