Randomized Trial of 2 Delayed-Release Formulations of Linaclotide in Patients With Irritable Bowel Syndrome With Constipation

Abstract

INTRODUCTION: Immediate-release (IR) formulation of linaclotide 290 μg improves abdominal pain and constipation (APC) in patients with irritable bowel syndrome (IBS) with constipation. Delayed-release (DR) formulations were developed on the premise that targeting the ileum (delayed-release formulation 1 [DR1]) or ileocecal junction and cecum (MD-7246, formerly DR2) would modulate linaclotide's secretory effects while preserving pain relief effects. METHODS: This phase 2b study randomized patients with IBS with constipation to placebo or 1 of 7 once-daily linaclotide doses (DR1 30, 100, or 300 μg; MD-7246 30, 100, or 300 μg; or IR 290 μg) for 12 weeks. Key efficacy endpoints were change from baseline in abdominal pain and complete spontaneous bowel movement frequency, and 6/12-week combined APC+1 responder rate. RESULTS: Overall, 532 patients were randomized; mean age was 45.1 years, and most were women (83.3%) and White (64.7%). All linaclotide DR1 and MD-7246 groups experienced greater improvements in abdominal pain from baseline and vs placebo throughout treatment. Linaclotide DR1 and IR led to numerically greater improvements from baseline in complete spontaneous bowel movement frequency and higher APC+1 responder rates compared with placebo; MD-7246 results were similar to placebo. Diarrhea was the most common adverse event with DR1 and IR; rates were similar between MD-7246 and placebo. DISCUSSION: Altering the site of drug delivery in the intestine might uncouple linaclotide's pain relief from secretory effects. Persistent, modest abdominal pain improvement with limited impact on bowel symptom parameters, as seen across MD-7246 doses, warrants further study of MD-7246 as a novel treatment for abdominal pain, regardless of IBS subtype.

British Society of Gastroenterology guidelines on the management of irritable bowel syndrome

“…The literature search identified 4111 citations, of which 46 appeared to be relevant, and 17 were eligible and were incorporated into this guideline. [164][165][166][167][168][169][170][171][172][173][174][175][176][177][178][179][180] Fourteen of these were used to update meta-analyses. [164][165][166][167][168][169][170][171][172][173][174][175][176][177] Agreement between reviewers for study eligibility was excellent (kappa statistic=0.81).…”

“…[164][165][166][167][168][169][170][171][172][173][174][175][176][177][178][179][180] Fourteen of these were used to update meta-analyses. [164][165][166][167][168][169][170][171][172][173][174][175][176][177] Agreement between reviewers for study eligibility was excellent (kappa statistic=0.81). Of these 14 studies, 2 compared linaclotide with placebo, 164 165 and were used to update a previous network meta-analysis, 155 8 compared various probiotics with placebo, [166][167][168][169][170][171][172][173] and were used to update an existing trial-based meta-analysis 158 and 4 were RCTs of a low FODMAP diet, [174][175][176][177] and again were used to update a prior trial-based meta-analysis.…”

“…292 An RCT of delayed-release linaclotide, with action confined to the ileo-caecal region of the gastrointestinal tract, demonstrated significant effects on abdominal pain, with lower rates of diarrhoea than conventionrelease linaclotide. 165 Other novel approaches include drugs that act on cannabinoid receptors, which are expressed in the gastrointestinal tract and may also modulate pain expression. The cannabinoid type-2 receptor agonist, olorinab, has been tested in patients with quiescent Crohn's disease, and led to reductions in abdominal pain and improved bowel movements 293 ; a trial in IBS is underway (NCT04043455).…”

Quantification of Fluid Volume and Distribution in the Paediatric Colon via Magnetic Resonance Imaging

“…Increasing the absorption window of a drug by targeting the colon offers advantages in terms of frequency of dosing, where controlled or extended release (XR) formulations can be used to enable once daily dosing (improving patient convenience [ 8 ], maintaining therapeutic concentrations [ 13 ] and reducing the risk of administration errors [ 14 ]). The low proteolytic activity and the potential of intact peptide absorption [ 15 ] (as demonstrated for insulin [ 16 ] or linaclotide [ 17 ]) enables the large intestine (with emphasis on the proximal colon) as an appropriate absorption site [ 5 , 18 ].…”

Guanylate cyclase-C agonists as peripherally acting treatments of chronic visceral pain

“…These data suggest that linaclotide may improve rectal hypersensitivity in IBS-C patients [54] and support the observations from preclinical studies that linaclotide inhibits nociceptors to reduce 'peripheral drive'. Along these lines, a recent report has documented that linaclotide delayed-release formulations, released in the terminal ileum (LIN-DR1) or colon (LIN-DR2: MD-7246), reduces abdominal pain in IBS-C patients compared with placebo, without altering bowel function or inducing diarrhea [55]. This may suggest the predominant analgesic site of action of linaclotide occurs within the colon, as indicated by rodent studies.…”