Guanylate cyclase-C Receptor Research Articles

Linaclotide: a novel agent for chronic constipation and irritable bowel syndrome.

The pharmacology, pharmaco-kinetics, and clinical efficacy and safety of linaclotide in the management of chronic constipation (CC) and constipation-predominant irritable bowel syndrome (IBS-C) are reviewed. Linaclotide (Linzess, Forest Pharmaceuticals) is a 14-amino acid peptide indicated for the treatment of adults with CC and IBS-C. Linaclotide acts on guanylate cyclase-C receptors on the luminal membrane to increase chloride and bicarbonate secretions into the intestine and inhibit the absorption of sodium ions, thus increasing the secretion of water into the lumen and improving defecation; the drug is minimally absorbed into the systemic circulation. Linaclotide is approved by the Food and Drug Administration (FDA) for oral once-daily administration at doses of 145 μg for CC and 290 μg for IBS-C. In placebo-controlled Phase III clinical trials, linaclotide significantly increased weekly spontaneous bowel movements and complete spontaneous bowel movements (CSBMs) while reducing abdominal pain in patients with CC. In patients with IBS-C, linaclotide was demonstrated to be effective in meeting FDA-recommended endpoints such as reductions of at least 30% from baseline in abdominal pain scores and CSBM frequency. The most common adverse effect of linaclotide is diarrhea, which was reported in 16-20% of clinical trial participants. Linaclotide is an important advance in the treatment of CC and IBS-C, with a novel mechanism of action resulting in accelerated intestinal transit. In clinical trials, linaclotide demonstrated efficacy relative to placebo for treatment of both CC and IBS-C. Linaclotide's adverse effects are generally mild and confined to the gastrointestinal tract.

Emerging Pharmacologic Therapies for Constipation-predominant Irritable Bowel Syndrome and Chronic Constipation.

Irritable bowel syndrome with constipation and chronic functional constipation are common digestive disorders that negatively impact quality of life and account for billions of dollars in health care costs. Related to the heterogeneity of pathogenesis that underlie these disorders and the failure of symptoms to reliably predict underlying pathophysiology, traditional therapies provide relief to only a subset of affected individuals. The evidence surrounding new and emerging pharmacologic treatments, which include both luminally and systemically acting drugs, is discussed here. These include agents such as lubiprostone, bile acid modulations, guanylate cyclase-C receptor agonists, serotonin receptor modulators and herbal therapies.

▼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...

Linaclotide-a Novel Secretagogue in the Treatment of Irritable Bowel Syndrome with Constipation and Chronic Idiopathic Constipation

Irritable bowel syndrome with constipation (IBS-C) and chronic idiopathic constipation (CIC) are highly prevalent gastrointestinal disorders. Traditional symptoms based therapies had somewhat limited success and efficacy in addressing the disorders. Recently, linaclotide emerged as novel peptide capable of improving abdominal symptoms in patients suffering from IBS-C and CIC. Guanylate cyclase C (GC-C) receptor a multi domain protein, found to be molecular target for linaclotide which acts by activating GC-C receptor on the apical surface of intestinal epithelial cells. Binding of linaclotide to GC-C receptor triggers the elevation of second messenger cGMP that elicits fluid secretion into intestinal cells which play a critical role in maintaining homeostasis through cystic fibrosis transmembrane conductance regulator (CFTR). Data from Phase II and III clinical trials demonstrated that linaclotide seems to produce a statistically significant increase in stool frequency, improved straining, decreased abdominal pain and discomfort.

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...

925g Plecanatide, a Novel Guanylate Cyclase-C (GC-C) Receptor Agonist, is Efficacious and Safe in Patients with Chronic Idiopathic Constipation (CIC): Results from a 951 Patient, 12 Week, Multi-Center Trial

while changes in the CLP were subtle. Enhancer of zeste homolog2 (EZH2) protein increased significantly in the crypt at days–6 and 12 and coincided with expression of EZH2 target protein H3K27me3 that marks the repressive chromatin signature. Knockdown of EZH2 decreased TOP-Flash reporter activity due to loss of β-catenin concomitant with increases in Wnt-inhibitory factor–1 (WIF–1) protein expression. Intriguingly, simultaneous increases in both H3K4me3 and H3K27me3 in the crypt at days–6 and 12 coincided with dramatic increases in β-catenin, Jagged–1, and SMYD3 while expression of E-cadherin decreased significantly due to upregulation of Slug and Snail, respectively. In the CLP, an almost complete loss of H3K27me3 at days–6 and 12 compared to uninfected control correlated with trans-differentiation of cultured crypt epithelial cells into messenchymal cells that stained positive for vimentin and αSMA indicating an EMT-like behavior. Chromatin immunoprecipitation assay in the crypt showed accumulation of EZH2 around E-cadherin promoter while that of H3K4m3 around β-catenin, Jagged–1, SMYD3 and Snail promoter respectively further supporting EMT-like phenomenon. Conclusion: Epigenetic mechanism seems to play an important role in the regulation of crypt cell hyperplasia and may be EMT.

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.

Uroguanylin Regulates Net Fluid Secretion via the NHE2 Isoform of the Na+/H+ Exchanger in an Intestinal Cellular Model

Uroguanylin (UGN) has been proposed as a key regulator of salt and water intestinal transport. Uroguanylin activates cell-surface guanylate cyclase C receptor (GC-C) and modulates cellular function via cyclic GMP (cGMP), thus increasing electrolyte and net water secretion. It has been suggested that the action of UGN could involve the Na⁺/H⁺ exchanger, but the actual contribution of this transporter still remains unclear. The objective of our study was to investigate the putative effects of UGN on some members of the Na⁺/H⁺ exchanger family (NHEs), as well as to clarify its consequences on transepithelial fluid flow in T84 cells. In order to do so, transepithelial fluid flow (J_v) was studied by optic techniques and intracellular pH (pH_i) was measured with a fluorescence method. Results showed that NHE2 is found at the apical membrane and has a major role in Na⁺ absorption; NHE1 and NHE4 are localized at the basolateral membrane with a house-keeping role in steady state pH_i. In the assayed conditions, cell exposure to apical UGN increases net secretory J_v, without changing short-circuit currents nor transepithelial resistance, and reduces NHE2 activity. Therefore, at physiological pH, the effect on net J_v was produced mainly by a reduction in normal Na⁺ absorption through NHE2, rather than by the stimulation of electrolyte secretion. Our study shows that the effect of UGN on pH_i is GC-C/cGMP-mediated and enhanced by sildenafil, thus involving PDE5 enzyme. Additionally, cell exposure to apical UGN results in intracellular alkalinization, probably due to indirect effects on basolateral NHE1 and NHE4, which have a major role in pH_i regulation.

Treatment of irritable bowel syndrome: beyond fiber and antispasmodic agents.

Irritable bowel syndrome (IBS) is a chronic functional disorder of the gastrointestinal tract of unknown etiology. The diagnosis of IBS is made clinically, using symptom-based criteria such as the Manning or Rome criteria. Medical therapy for this condition has traditionally been directed towards symptom relief, using fiber or antispasmodic agents. In recent years, emerging data have confirmed the efficacy of antidepressants, psychological therapies, 5-HT(3) antagonists, 5-HT(4) agonists, and probiotics in the short-term treatment of IBS, although whether these therapies influence the long-term course of the disease is unknown. Increasing knowledge regarding the pathophysiological mechanisms underlying IBS has resulted in a number of novel molecular treatments, which show promise. These include therapies targeting gastrointestinal mucosal chloride channels and guanylate cyclase-C receptors, as well as highly selective agents influencing serotonergic transmission that, at the time of writing, do not appear to have any severe deleterious effects. In this article we provide a summary of current and emerging therapies in this field.

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.

Linaclotide - a secretagogue and antihyperalgesic agent - what next?

Ongoing clinical trials suggest that linaclotide, a first-in-class, 14-amino acid peptide guanylate cyclase-C (GC-C) receptor agonist and intestinal secretagogue is an effective treatment for chronic constipation. A study in this issue of the Journal suggests that linaclotide also has antihyperalgesic effects in three common rat models of inflammation- and stress-induced hypersensitivity (i.e., acute trinitrobenzene sulfonic acid colitis, water avoidance stress [WAS], and restraint-induced stress) but not in naïve animals. In mice, linaclotide at least partly reduces hyperalgesia via GC-C receptors. Dose-effect relationships of linaclotide were complicated and non-linear. This viewpoint discusses human clinical trials with linaclotide and the results of this study. Potential mechanisms and clinical significance of these findings are explored. Collectively, these data suggest that GC-C receptors exert other, as yet poorly understood, effects on gastrointestinal sensitivity in conditions associated with inflammation and/or stress-induced increased intestinal permeability. However, the data need to be confirmed in humans and in long-term animal models. Further studies are also necessary to elucidate the mechanisms as these effects cannot be explained by linaclotide's known effects on epithelial GC-C receptors.

This Month in Gastroenterology

This Month in Gastroenterology

Efficacy of Linaclotide for Patients With Chronic Constipation

Linaclotide is a minimally absorbed peptide agonist of the guanylate cyclase-C receptor that stimulates intestinal fluid secretion and transit and reduces pain in animal models. We assessed the safety and efficacy of a range of linaclotide doses in patients with chronic constipation. We performed a multicenter, double-blind, placebo-controlled, parallel-group study of 310 patients with chronic constipation. Patients were randomly assigned to groups given 75, 150, 300, or 600 microg oral linaclotide or placebo once daily for 4 weeks. Symptom assessments included spontaneous bowel movements (SBMs), complete SBMs, stool consistency, straining, abdominal discomfort, and bloating. Severity of constipation, adequate relief of constipation, global relief of constipation, treatment satisfaction, quality of life, adverse events, clinical laboratory data, and electrocardiogram results were assessed. All doses of linaclotide improved the weekly rate of SBM (primary end point) compared with placebo; the increases in overall weekly number of SBMs from baseline were 2.6, 3.3, 3.6, and 4.3 for linaclotide doses of 75, 150, 300, and 600 microg, respectively, compared with 1.5 for placebo (P < or = .05 for each pair-wise comparison of a linaclotide dose to placebo). Likewise, linaclotide significantly improved the weekly rate of complete SBM, stool consistency, straining, abdominal discomfort, bloating, global assessments, and quality of life. The most common and only dose-related adverse event was diarrhea (only 6 patients discontinued treatment because of diarrhea). Linaclotide therapy was associated with few adverse events and produced rapid and sustained improvement of bowel habits, abdominal symptoms, global relief, and quality of life in patients with chronic constipation.

Guanylate cyclase C-mediated antinociceptive effects of linaclotide in rodent models of visceral pain

BACKGROUND Linaclotide is a novel, orally administered investigational drug currently in clinical development for the treatment of constipation-predominant irritable bowel syndrome (IBS-C) and chronic idiopathic constipation. Visceral hyperalgesia is a major pathophysiological mechanism in IBS-C. Therefore, we investigated the anti-nociceptive properties of linaclotide in rodent models of inflammatory and non-inflammatory visceral pain and determined whether these pharmacological effects are linked to the activation of guanylate cyclase C (GC-C). METHODS Orally administered linaclotide was evaluated in non-inflammatory acute partial restraint stress (PRS) and acute water avoidance stress (WAS) models in Wistar rats, and in a trinitrobenzene sulfonic acid (TNBS)-induced inflammatory model in Wistar rats and GC-C null mice. KEY RESULTS In TNBS-induced colonic allodynia, linaclotide significantly decreased the number of abdominal contractions in response to colorectal distension without affecting the colonic wall elasticity change in response to distending pressures after TNBS. However, linaclotide had no effect on visceral sensitivity under basal conditions. In addition, linaclotide significantly decreased colonic hypersensitivity in the PRS and WAS models. In wild type (wt) and GC-C null mice, the instillation of TNBS induced similar hyperalgesia and allodynia. However, in post-inflammatory conditions linaclotide significantly reduced hypersensitivity only in wt mice, but not in GC-C null mice. CONCLUSIONS & INFERENCES These findings indicate that linaclotide has potent anti-nociceptive effects in several mechanistically different rodent models of visceral hypersensitivity and that these pharmacological properties of linaclotide are exerted through the activation of the GC-C receptor. Therefore, linaclotide may be capable of decreasing abdominal pain in patients suffering from IBS-C.