Early investigational therapeutics for gastrointestinal motility disorders: from animal studies to Phase II trials

Abstract

Introduction The most common gastrointestinal disorders which include evidence of dysmotility include: gastroparesis, the lower functional gastrointestinal disorders associated with altered bowel function [such as chronic (functional) diarrhea, chronic idiopathic constipation (CIC)], and opioid induced constipation (OIC). These conditions, which are grouped as gastrointestinal motility and functional disorders, are characterized by abnormal motor, sensory, or secretory functions that alter bowel function and result in a significant disease burden, since currently available treatments do not completely alleviate symptoms. New drugs are being developed for these disorders, targeting mechanisms involved in the pathophysiology of these diseases, specifically, motor function, intestinal secretion and bile acid modulation. Areas Covered The article provides a brief overview of motility disorders and the drugs approved and currently available for these indications. It also provides an evaluation of the efficacy, safety and possible mechanisms of the drugs currently under investigation for the treatment of gastroparesis, chronic diarrhea, CIC and OIC, based on animal to phase II studies. Medications with complete phase III trials are excluded from this discussion. Expert opinion Treatment of gastrointestinal motility disorders requires the understanding of the pathophysiological mechanisms, biomarkers to identify subgroups of these disorders, and robust pharmacological studies from animal to phase II studies. These are prerequisites for the development of efficacious medications and individualizing therapy in order to enhance the treatment of these patients.

A single‐center, prospective, double‐blind, sham‐controlled, randomized study of the effect of a vibrating capsule on colonic transit in patients with chronic constipation

“…There are several treatments for functional constipation already approved and these include stimulants, osmotic laxatives, secretagogues and surface active agents. However, there is still unmet need and a number of novel pharmacological approaches are in development including YKP10811 (5‐HT 4 receptor agonist), plecanatide (guanylate cyclase C receptor agonist), and relamorelin (ghrelin receptor agonist) …”

“…However, there is still unmet need and a number of novel pharmacological approaches are in development including YKP10811 (5-HT 4 receptor agonist), plecanatide (guanylate cyclase C receptor agonist), and relamorelin (ghrelin receptor agonist). 5,6 Recently, a vibrating (VIBRANT) capsule (parameters described below) has been shown in an open-label study to significantly increase the mean number of bowel movements per week (88.5% of patients being responders) in 26 patients with constipation-predominant irritable bowel syndrome and chronic constipation. 7 The effects of this novel device on regional colonic transit in patients with functional constipation are unclear.…”

A comparative pharmacokinetic study of three flavonoids and three anthraquinones in normal and gastrointestinal motility disorders rat plasma after the oral administration of Wei‐Chang‐Shu tablet using high‐performance liquid chromatography–tandem mass spectrometry

“…Gastrointestinal motility disorders (GMD) are a group of diseases that include gastrointestinal dysfunction, screw weakening and delayed gastric emptying and intestinal propulsion (Valentin, Acosta, & Camilleri, ; Yin & Chen, ). At present, the most commonly used drugs for the treatment of GMD are cisapride and domperidone.…”

An expert consensus definition of failure of a treatment to provide adequate relief (F‐PAR) for chronic constipation – an international Delphi survey

“…Although diagnostic criteria have existed for some time for functional gastrointestinal disorders, establishing the correct diagnosis and identifying aetio‐pathogenesis of CC are key first steps required to optimise the clinical outcome for the patient. As new research has provided a better understanding of the range of primary and secondary causes of CC, so it has also identified new targets for physical and pharmacological treatment of the disease . With new behavioural, pharmacological and surgical treatments becoming available it is essential to recognise when a treatment is failing to work adequately and thus should be switched.…”