Guanylate cyclase-C Receptor Agonist Research Articles

Linaclotide (Linzess) for functional constipation.

The guanylate cyclase-C receptor agonist linaclotide (Linzess – Abbvie/Ironwood) was first approved by the FDA in 2012 for treatment of chronic idiopathic constipation and irritable bowel syndrome with constipation in adults.

ID: 3519286 COMPARISON OF 1-L PEG PLUS ASCORBIC ACID WITH LINACLOTIDE VERSUS SENNOSIDE FOR COLON CLEANING IN CONSTIPATED PATIENTS

Background and Aim: The 2-L polyethylene glycol plus ascorbic acid (PEG-Asc) is an effective alternative to standard 4-L PEG for bowel preparation before colonoscopy. Several studies have reported the adjunctive laxative agents can effectively reduce the volume of PEG-Asc solution required and increase patient tolerability. We recently reported the efficacy of 1-L PEG-Asc plus sennoside for bowel preparation, but this regimen was insufficient for patients with chronic constipation (2020 GIE vol 91 S6). Linaclotide is a guanylate cyclase-C receptor agonist currently approved and available for the treatment of adults with chronic constipation in many countries. We hypothesized that addition of linaclotide to 1-L PEG-Asc would yield to better results than that of sennoside regimen in patients with chronic constipation.

Optimizing the Use of Linaclotide in Patients with Constipation-Predominant Irritable Bowel Syndrome: An Expert Consensus Report.

IntroductionIrritable bowel syndrome (IBS) is a functional bowel disorder characterized by chronic or recurrent abdominal pain in association with defecation or a change in bowel habits. A predominant disorder of bowel habits, IBS is classified into three main subtypes: constipation-predominant IBS (IBS-C), diarrhea-predominant IBS (IBS-D) and IBS alternating between constipation and diarrhea (IBS-M). Linaclotide is a first-in-class, oral, once-daily guanylate cyclase-C receptor agonist (GC-CA) that is licensed for the symptomatic treatment of moderate-to-severe IBS-C in adults. This review aims to facilitate and optimize clinical practices, establishing common guidelines to monitor patients with IBS-C that are treated with linaclotide.MethodsA group of experts in functional digestive disorders was convened to review the efficacy and safety of linaclotide and to develop an updated consensus report for the treatment of patients with IBS-C. A search was performed for English, French and Spanish language articles in PubMed. On the basis of the articles identified, an initial document was drafted addressing different issues frequently raised by general practitioners and GI specialists that are related to the prescription, efficacy and safety of linaclotide. This document was then reviewed and modified by the expert panel until a final text was agreed upon and validated.ResultsBased on the evidence, the panel addressed the following recommendations: (1) Linaclotide is indicated for the treatment of moderate to severe IBS-C in adults; (2) it is recommended that patients take linaclotide continuously and not sporadically; (3) patients should be warned about the risk of diarrhea and given choices concerning how to deal with this possible side effect; (4) the absence of tachyphylaxis or potential risks implies that linaclotide treatment can be maintained for long periods of time.ConclusionsThis document seeks to lay down a set of recommendations and to identify key issues that may be useful for the clinical management of IBS-C patients treated with linaclotide.

▼Linaclotide for constipation-predominant IBS

Irritable bowel syndrome is a chronic relapsing disorder characterised by abdominal pain or discomfort associated with defaecation, abdominal bloating and a change in bowel habit.1,2 IBS may be classified by...

PTU-135 Mechanism of Action for Linaclotide-Induced Abdominal Pain Relief

IntroductionCyclic GMP (cGMP) is a 2nd messenger produced in intestinal epithelial cells in response to guanylate cyclase C receptor (GCC) activation. Linaclotide (LIN), an investigational GCC agonist (GCCA), improved constipation...

OC-082 26-Week efficacy and safety of once-daily oral linaclotide in patients with irritable bowel syndrome with constipation (IBS-C): a European perspective

IntroductionLinaclotide, a minimally absorbed guanylate cyclase-C receptor agonist, is an investigational drug treatment for IBS-C. As part of the European Medicines Authority submission we evaluated the efficacy and safety of...

PWE-127 Two randomised, double-blind, placebo-controlled phase 3 trials of linaclotide in adults with irritable bowel syndrome: effects on quality of life

IntroductionLinaclotide, a minimally absorbed guanylate cyclase-C receptor agonist, is an investigational drug for the treatment of irritable bowel syndrome with constipation (IBS-C) that has shown statistically significant improvements in abdominal...

Mo1849 Mechanism of Action for Linaclotide Induced Abdominal Pain Relief

Introduction Cyclic GMP (cGMP) is a 2nd messenger produced in intestinal epithelial cells in response to guanylate cyclase C receptor (GCC) activation. Linaclotide (LIN), an investigational GCC agonist (GCCA), improved constipation and reduced abdominal pain in patients with irritable bowel syndrome with constipation (IBS-C) in clinical trials. We have shown that exogenous extracellular cGMP has contrasting effects on colorectal (CR) afferent mechanosensitivity. 1 Here we assessed the effects of GCCAs on CR afferent mechanosensitivity in healthy and chronic visceral hypersensitivity (CVH) mouse models Methods We investigated CVH in healthy mice and CVH 28 days post-TNBS administration, when inflammation had resolved and nociceptors were mechanically hypersensitive. Mechanosensory responses of CR splanchnic nociceptors and pelvic mucosal afferents were compared in vitro ± GCCAs STc (1, 50, 250, 1000nM) and LIN (1, 30, 100, 300, 1000nM), which were applied individually to the CR mucosal surface. GCC expression in the CR mucosa was determined via qRT-PCR Results In healthy mice, STc dose-dependently (50, 250, 1000nM) reduced nociceptor mechanosensitivity (max. effect at 1000nM [n = 10], –38%; p 0.05). qRT-PCR analysis revealed abundant GCC expression in CR mucosa of both healthy and CVH mice Conclusion STc and LIN significantly reduced colonic nociceptor mechanosensitivity, with greatest effect in CVH. Although these overall effects mirror those of exogenously applied cGMP, GCCAs are more potent at inhibiting nociceptors. Overall, LIN induced the greatest inhibitory effects on nociceptors, particularly in CVH. Reducing colonic nociceptive input would help to reduce pain, which supports LIN clinical data showing a significant reduction in abdominal pain in humans with IBS-C. Increased mucosal afferent sensitivity may help coordinate defecation. Disclosure of Interest S. Brierley Grant/Research Support from: Ironwood Pharmaceuticals, J. Castro: None Declared, A. Harrington: None Declared, P. Hughes: None Declared, C. Martin: None Declared, A. Silos-Santiago Employee of: Ironwood Pharmaceuticals, C. Kurtz Employee of: Ironwood Pharmaceuticals, A. Blackshaw Grant/Research Support from: Ironwood Pharmaceuticals. Reference Gastro. 2011. Supported by Ironwood Pharmaceuticals Inc and by Forest Laboratories Inc. Medical writing assistance was provided by Complete Medical Communications, funded by Almirall.

Tu1068 Effects of Linaclotide Treatment on Patient-Reported Ratings of Change for Symptoms of Irritable Bowel Syndrome With Constipation (IBS-C): Pooled 12-Week Findings From Two Phase 3 Trials

Introduction: Linaclotide, an investigational drug, is a minimally-absorbed guanylate cyclaseC receptor agonist that has demonstrated symptom improvement in IBS-C patients in two large Phase 3 trials. Patient-reported ratings of change for individual and overall IBS-C symptoms provide interpretation of clinical relevance for patient-reported outcome measures of abdominal and bowel symptoms. Aim: To examine the effects of linaclotide on patientreported ratings of change and the extent of improvement in individual IBS-C symptoms within these patient-reported ratings of change categories. Methods: In two Phase 3 IBS-C trials of linaclotide, patients reported daily ratings for abdominal symptoms (pain, bloating, fullness, cramping, discomfort) and bowel symptoms (spontaneous bowel movement [SBM] and complete SBM [CSBM] frequency, straining, stool consistency, unsuccessful BM attempts) via an interactive voice response system diary (pooled data). Patient-reported ratings of change included relief or improvement for each specific abdominal and bowel symptom, respectively, for the prior 7 days, at study visits during weeks 2, 4, 8, and 12 of the Treatment Period, compared to before the trial began, using a 7-point balanced ordinal scale (1= completely improved/relieved, 4=unchanged, 7=as bad as I can imagine). Overall Degree of Relief of IBS symptoms was also assessed weekly using the same 7-point balanced scale. P-values were obtained from the Cochran-Mantel-Haenszel (CMH) row-mean score tests comparing linaclotide to placebo. Results: For all of the patient-reported rating-of-change parameters, significantly more linaclotide vs placebo patients were completely/considerably relieved (Table 1); additionally, more placebo than linaclotide patients reported their symptoms as unchanged, somewhat worse or considerably worse/as bad as I can imagine. Although patients on linaclotide, in general, reported greater improvement in symptoms across all categories of relief/improvement, patients who had greater relief/improvement ratings tended to report greater changes in symptom score for the corresponding symptom, regardless of treatment group assignment (Table 2). Within the category of completely/considerably relieved, patients on linaclotide tended to report greater benefit than those patients on placebo. Conclusions: In clinical studies, linaclotide was approximately twice as likely as placebo to provide complete or considerable relief for overall and individual abdominal and bowel symptoms in IBS-C patients. Nearly half of IBS-C patients randomized to linaclotide reported complete/considerable relief of their IBS symptoms. This analysis provides perspective on themagnitude of change in patients' individual symptoms that corresponds to reporting of complete/considerable relief of their individual and overall IBS-C symptoms. Table 1. Patient-Reported Rating of Change (Week 12), Percentage of Patients in Each Category by Treatment Group

Tu1069 Do Baseline Factors Contribute to Treatment Satisfaction in Patients With Chronic Constipation Treated With Linaclotide vs Placebo?

Introduction: Linaclotide, an investigational drug, is a minimally-absorbed guanylate cyclaseC receptor agonist that has demonstrated symptom improvement in IBS-C patients in two large Phase 3 trials. Patient-reported ratings of change for individual and overall IBS-C symptoms provide interpretation of clinical relevance for patient-reported outcome measures of abdominal and bowel symptoms. Aim: To examine the effects of linaclotide on patientreported ratings of change and the extent of improvement in individual IBS-C symptoms within these patient-reported ratings of change categories. Methods: In two Phase 3 IBS-C trials of linaclotide, patients reported daily ratings for abdominal symptoms (pain, bloating, fullness, cramping, discomfort) and bowel symptoms (spontaneous bowel movement [SBM] and complete SBM [CSBM] frequency, straining, stool consistency, unsuccessful BM attempts) via an interactive voice response system diary (pooled data). Patient-reported ratings of change included relief or improvement for each specific abdominal and bowel symptom, respectively, for the prior 7 days, at study visits during weeks 2, 4, 8, and 12 of the Treatment Period, compared to before the trial began, using a 7-point balanced ordinal scale (1= completely improved/relieved, 4=unchanged, 7=as bad as I can imagine). Overall Degree of Relief of IBS symptoms was also assessed weekly using the same 7-point balanced scale. P-values were obtained from the Cochran-Mantel-Haenszel (CMH) row-mean score tests comparing linaclotide to placebo. Results: For all of the patient-reported rating-of-change parameters, significantly more linaclotide vs placebo patients were completely/considerably relieved (Table 1); additionally, more placebo than linaclotide patients reported their symptoms as unchanged, somewhat worse or considerably worse/as bad as I can imagine. Although patients on linaclotide, in general, reported greater improvement in symptoms across all categories of relief/improvement, patients who had greater relief/improvement ratings tended to report greater changes in symptom score for the corresponding symptom, regardless of treatment group assignment (Table 2). Within the category of completely/considerably relieved, patients on linaclotide tended to report greater benefit than those patients on placebo. Conclusions: In clinical studies, linaclotide was approximately twice as likely as placebo to provide complete or considerable relief for overall and individual abdominal and bowel symptoms in IBS-C patients. Nearly half of IBS-C patients randomized to linaclotide reported complete/considerable relief of their IBS symptoms. This analysis provides perspective on themagnitude of change in patients' individual symptoms that corresponds to reporting of complete/considerable relief of their individual and overall IBS-C symptoms. Table 1. Patient-Reported Rating of Change (Week 12), Percentage of Patients in Each Category by Treatment Group

Tu1402 Impact of Linaclotide Treatment on Work Productivity and Activity Impairment in Adults With Irritable Bowel Syndrome With Constipation

Background: Irritable bowel syndrome with constipation (IBS-C) is a chronic functional gastrointestinal disorder characterized by abdominal pain or discomfort with bowel symptoms of constipation. IBS-C has been shown to decrease work productivity and increase activity impairment, resulting in a substantial economic burden for patients and employers. Linaclotide is an investigational minimally absorbed guanylate cyclase-C receptor agonist shown to significantly improve abdominal and bowel symptoms in 2 Phase 3 IBS-C trials. Aim: To evaluate the impact of linaclotide treatment on work productivity and activity impairment in IBS-C patients. Methods: Adult patients meeting modified Rome II criteria for IBS-C were randomized to oral once-daily 290-μg linaclotide or placebo for 12 weeks in 2 Phase 3 trials. The Work Productivity and Activity Impairment questionnaire for IBS-C (WPAI:IBSC), a self-administered questionnaire consisting of 6 items, was used to measure absenteeism (work hours missed due to IBS-C), presenteeism (degree IBS-C symptoms affected productivity while at work), overall work productivity loss (absenteeism + presenteeism due to IBSC), and daily activity impairment (degree IBS-C symptoms affected regular daily activities, including housework, shopping, childcare, exercising, studying) over the previous 7 days. Based on pooled Phase 3 trial data, changes from baseline to weeks 4, 8, and 12 for all 4 WPAI scores were assessed using an analysis of covariance (ANCOVA) model. Scores are represented as percentages, with higher percentages indicating greater work productivity loss and activity impairment. Results: A total of 1602 patients were randomized in the 2 Phase 3 trials. Patients included in this analysis had both baseline and at least 1 postbaseline WPAI:IBS-C assessment. Daily activity impairment was computed for all patients. Summary measures for absenteeism, presenteeism, and overall work productivity included employed patients only. Compared to placebo, linaclotide significantly reduced presenteeism, overall work productivity loss, and daily activity impairment at weeks 4, 8, and 12. A greater decrease in absenteesim was also observed for linaclotide compared to placebo at weeks 4, 8, and 12. Differences versus placebo in change from baseline to week 12 were 5.6% (p<0.0001) for presenteeism, 4.6% (p<0.0001) for overall work productivity, and 4.7% (p<0.001) for daily activity impairment (Table). Assuming a 40-hour work week, linaclotide reduced overall work productivity loss by 1.8 hours/week. Conclusions: Compared to placebo, once-daily linaclotide significantly reduced overall work productivity loss and daily activity impairment among IBS-C patients, with significant improvements seen at Week 4 and maintained through Week 12. Table. Mean WPAI Scores and Change from Baseline to Week 12

Current and future therapies for chronic constipation

In this article, traditional and novel therapies for chronic constipation are reviewed. Traditional laxatives are effective at inducing bowel movements, but efficacy in long-term management and efficacy on constipation-associated abdominal symptoms are less well established, with the exception of polyethylene glycol, for which long-term studies confirm sustained efficacy. Recently approved drugs include the colonic secretagogue lubiprostone and the 5-HT4 agonist prucalopride. In controlled trials in chronic constipation, these drugs were shown to significantly improve constipation and its associated symptoms, with a favourable safety record. Methylnaltrexone, a subcutaneously administered peripherally acting mu opioid receptor antagonist, has recently been approved for opioid-induced constipation in terminally ill patients. New agents under evaluation include the 5-HT4 agonists velusetrag and naronapride, the guanylate cyclase-C receptor agonist linaclotide and the peripherally acting mu opioid receptor antagonist alvimopan.

Correlation of Global Assessments with Symptom Endpoints in Phase 3 Clinical Trials of Linaclotide in Chronic Constipation

Purpose: Linaclotide is a first-in-class, minimally-absorbed guanylate cyclase-C receptor agonist that statistically significantly improved bowel and abdominal symptoms, and patient global assessments in two recent Phase 3 chronic constipation (CC) trials. Both trials featured patient-reported global assessments - multidimensional endpoints that have been shown to integrate individual bowel and abdominal symptom endpoints and are useful overall measures of treatment efficacy in CC clinical trials. Here, we evaluate the correlation of 3 patient-reported global endpoints with the primary and secondary symptom-based endpoints. Methods: Two placebo-controlled Phase 3 trials evaluated the effects of 133 and 266 μg linaclotide administered orally once daily for 12 weeks to 1272 adults meeting modified Rome II CC criteria. Bowel symptoms (stool consistency, straining, completeness of evacuation for each spontaneous bowel movement [SBM]), abdominal symptoms (daily abdominal discomfort, bloating), weekly constipation severity, and global relief of constipation symptoms were assessed using an interactive voice response system. Treatment satisfaction was collected at multiple timepoints during the treatment period. A post-hoc analysis of the correlation of key efficacy endpoints with the global assessments was performed. Results: Both linaclotide doses demonstrated a statistically significant treatment effect for all endpoints, including bowel and abdominal symptoms, global relief, and treatment satisfaction. Weekly global relief and constipation severity correlated well with improvement in bowel habits (r-values 0.51-0.60) and abdominal symptoms (0.46-0.59). Treatment satisfaction also showed good correlation with bowel (0.44-0.59) and abdominal (0.43-0.48) symptom improvement.[1304] Table. Spearman correlations of global parameters with Key CC symptoms*Conclusion: In both Phase 3 clinical trials, linaclotide 133 and 266 μg demonstrated statistically significant treatment effects on CC bowel and abdominal symptoms and global assessments. All 3 global assessments were correlated with bowel and abdominal symptoms, with strongest correlations occurring for weekly assessments. Disclosure: A. Lembo - Paid Consultant: Ironwood Pharmaceuticals. H. Schneier, S. Shiff, and D. Jia - Employees: Forest Research Institute and owner of stock/stock options in Forest Labs. B. Lavins, J. MacDougall, C. Kurtz, M. Currie, and J. Johnston - Employees of and owners of stock/stock options in Ironwood Pharmaceuticals. Disclosure: Funded by Ironwood Pharmaceuticals and Forest Laboratories.

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