Randomised Clinical Trial

Effects of MD-7246 on Irritable Bowel Syndrome With Diarrhoea

Anthony Lembo; Braden Kuo; Ramesh Boinpally; Ella Li; Madhuja Mallick; Wieslaw Bochenek; Wilmin Bartolini

Disclosures

Aliment Pharmacol Ther. 2023;57(2):192-204. 

In This Article

Abstract and Introduction

Abstract

Background: MD-7246, a delayed-release formulation of linaclotide, is designed to target the ileocaecal junction and caecum with the aim of relieving abdominal pain independently of bowel function.

Aims: To evaluate the efficacy, safety and dose–response of MD-7246 in patients with irritable bowel syndrome with diarrhoea (IBS-D).

Methods: A randomised, double-blind, phase 2 clinical trial enrolled adult patients with IBS-D (Rome IV criteria). Patients were randomised to placebo or once-daily oral MD-7246 300, 600 or 1200 μg for 12 weeks. Abdominal and bowel symptoms were assessed daily. Key efficacy endpoints were change from baseline in abdominal pain and responder rates for a 30% reduction in abdominal pain in 6/12 weeks. Additional abdominal pain responder and exploratory bowel function endpoints were also assessed.

Results: Among the 388 randomised patients, there was no significant difference in mean change from baseline in abdominal pain between the MD-7246 300 μg, 600 μg and 1200 μg groups and placebo (−1.93, −1.58, −1.95 and − 2.01, respectively; p > 0.05 for each group vs placebo). The abdominal pain responder rates in the MD-7246 groups were similar to or lower than those in the placebo group. All doses of MD-7246 had a minimal effect on bowel function and were generally well tolerated.

Conclusions: MD-7246 at the doses studied did not improve abdominal pain relative to placebo in an IBS-D patient population. Similarly, most additional efficacy endpoints showed no improvement with MD-7246 relative to placebo.

Introduction

Irritable bowel syndrome (IBS) is a chronic disorder of brain–gut interaction and is characterised by recurrent abdominal pain associated with changes in bowel habits and bloating.[1,2] There are four defined IBS subtypes (predominant diarrhoea [IBS-D], predominant constipation [IBS-C], mixed bowel habits and unclassified)[3] that affect approximately 4.1% of the global population based on Rome IV criteria,[4] with IBS-D accounting for approximately one-third of all IBS cases.[5] Symptoms of IBS-D impair patients' health-related quality of life,[6,7] with faecal incontinence and abdominal pain considered the most burdensome.[7] The management of IBS-D includes loperamide, tricyclic antidepressants, 5-HT3 agonists, rifaximin and mixed opioid agonists/antagonists (e.g. eluxadoline).[8] However, no current IBS treatments have only visceral analgesic effects, exclusively benefiting abdominal pain without impacting bowel habits.[9]

The currently available linaclotide formulation is an oral, immediate-release, 14-amino-acid, synthetic peptide agonist of guanylate cyclase-C approved for treating IBS-C and chronic idiopathic constipation in adults.[10–13] By binding to guanylate cyclase-C expressed on intestinal epithelial cells, linaclotide increases fluid secretion and accelerates gastrointestinal transit.[14] Linaclotide has been shown to reduce abdominal pain and discomfort in patients with IBS-C in phase 3 trials,[15,16] potentially due to a reduction in visceral hypersensitivity of colonic nerves, as observed in animal models.[15] The drug undergoes rapid proteolysis in the duodenum and jejunum[14] and is minimally absorbed. Delayed-release formulations of linaclotide have been developed to target more distal regions of the gastrointestinal tract, with the aim of causing differential effects on abdominal pain and bowel function: DR1 (delayed-release formulation 1) was designed to target the ileum and DR2 (delayed-release formulation 2; MD-7246) was designed to be released more distally in the ileocaecal junction and caecum.[9] In a 12-week, phase 2b, randomised, dose-ranging trial in patients with IBS-C, MD-7246 at once-daily doses of 30, 100 and 300 μg resulted in numerical improvement in abdominal pain without increasing bowel movement frequency or altering stool consistency compared to placebo.[9]

Based on these results, MD-7246 was further evaluated as an option for treating IBS-associated abdominal pain in patients with IBS-D. This study aimed to evaluate MD-7246's safety and tolerability, treatment effect on abdominal pain, and dose–response in patients with IBS-D, with an exploratory objective to assess any changes in bowel function.

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