plecanatide and Irritable-Bowel-Syndrome

Topics: Chronic Disease; Constipation; Gastrointestinal Agents; Guanylyl Cyclase C Agonists; Humans; Irritable Bowel Syndrome; Isoquinolines; Lubiprostone; Natriuretic Peptides; Peptides; Randomized Controlled Trials as Topic; Sulfonamides

Chronic idiopathic constipation and irritable bowel syndrome with constipation are commonly encountered in ambulatory patients, but limited options exist for patients with persistent or severe symptoms following treatment with nonprescription products. Plecanatide (Trulance, Synergy Pharmaceuticals, New York, NY) is a 16-amino acid peptide analog of uroguanylin that stimulates guanylate cyclase-C receptors to increase chloride and bicarbonate secretion into the intestine and prevents the absorption of sodium ions, thereby increasing the secretion of water into the lumen. The influx of additional fluid accelerates intestinal transit, softens the stool, and facilitates easier defecation. Plecanatide is the second guanylate cyclase-C receptor agonist to be approved by the US Food and Drug Administration for chronic idiopathic constipation and irritable bowel syndrome, but plecanatide is unique because its effects are limited to the proximal small bowel.

Topics: Constipation; Gastrointestinal Agents; Humans; Irritable Bowel Syndrome; Natriuretic Peptides; Receptors, Guanylate Cyclase-Coupled; Treatment Outcome

Uroguanylin interacting with intestinal Guanylate Cyclase C (GC-C) receptors plays an important role in gastrointestinal fluid and electrolyte homeostasis. Plecanatide is the first uroguanylin analog that stimulates GC-C receptors on gastrointestinal mucosa with pH-sensitive receptor binding. Binding to the GC-C receptor activates intracellular conversion of GTP to cGMP resulting in the stimulation of intestinal fluid secretion. Areas covered: Herein, all published research regarding the development of and clinical experience with plecanatide is reviewed. Clinical study results in patients with Chronic Idiopathic Constipation (CIC) and Irritable Bowel Syndrome with Constipation (IBS-C) are also reviewed. Success in the treatment of CIC and IBS-C is supported by beneficial effects on stool viscosity, Complete Spontaneous Bowel Movements and visceral sensation. Finally, the discussion within focuses on the importance of plecanatide in understanding the physiology of uroguanylin, the pathophysiology of IBS-C and the potential for development of uroguanylin and guanylin analogs. Expert opinion: Given this broad spectrum of potential activity for GC-C agonists, it would not be surprising to see that the use of agents such as plecanatide in new areas grow to a level even greater than the use for the present CIC and IBS-C indications.

Topics: Chronic Disease; Clinical Trials as Topic; Constipation; Diarrhea; Gastrointestinal Agents; Humans; Irritable Bowel Syndrome; Natriuretic Peptides; Product Surveillance, Postmarketing; Receptors, Enterotoxin

Linaclotide and plecanatide are guanylate cyclase-C (GCC) agonists for the treatment of chronic idiopathic constipation (CIC) and irritable bowel syndrome with constipation (IBS-C). Our objective is to evaluate the efficacy and tolerability of GCC agonists based on data from multiple randomized controlled trials (RCTs).. We searched PubMED, EMBASE, Cochrane databases, clinicaltrials.gov, major conference abstracts, Food and Drug Administration (FDA) websites, and United States Securities and Exchange Commission filings of drug sponsors to identify RCTs of CIC or IBS-C patients. We assessed efficacy based on FDA-approved composite responder endpoints, diarrhea as an adverse event, and study withdrawal owing to diarrhea for each therapy. Trial results were pooled using DerSimonian and Laird random effects model of meta-analysis and exact logistic regression when appropriate with 95% confidence intervals. Meta-regression was performed to compare outcomes between therapies adjusting for placebo event rate.. Eight linaclotide trials (five CIC; three IBS-C) and seven plecanatide trials (four CIC; three IBS-C) evaluating 10,369 patients met inclusion criteria. FDA publications documented that different definitions for diarrhea were used in linaclotide vs. plecanatide trials. Both drugs were efficacious in treating CIC (linaclotide 72 μg (Odds ratio (OR)=3.11, 95% CI 1.81-5.34); linaclotide 145 μg (OR=3.25, 2.15-4.91); plecanatide 3 mg (OR=1.99, 1.57-2.51)) and IBS-C (linaclotide 290 μg (OR=2.43, 1.48-3.98); plecanatide 3 mg (OR=1.87, 1.47-2.38); plecanatide 6 mg (OR=1.92, 1.48-2.48)). Diarrhea occurred in excess of placebo in treating CIC (linaclotide 72 μg (OR=3.07, 1.97-4.77); linaclotide 145 μg (OR=3.70, 2.69-5.10); plecanatide 3 mg (OR=3.86, 1.83-8.12)) and IBS-C (linaclotide 290 μg (OR=8.02, 5.20-12.37); plecanatide 3 mg (OR=5.55, 1.62-19.00); plecanatide 6 mg (OR=4.13, 1.57-10.83)). Based on meta-regression, there were no statistically significant differences between therapies in odds ratios for efficacy, diarrhea, or diarrhea-related study withdrawals.. Both linaclotide and plecanatide demonstrate similar efficacy and tolerability in treating IBS-C and CIC. No differences in odds of diarrhea were seen between linaclotide and plecanatide.

Topics: Chronic Disease; Constipation; Diarrhea; Guanylyl Cyclase C Agonists; Humans; Irritable Bowel Syndrome; Natriuretic Peptides; Peptides; Randomized Controlled Trials as Topic

Several secretagogues have been approved for the treatment of irritable bowel syndrome with constipation (IBS-C). However, their relative efficacy is unclear because there have been no head-to-head randomized controlled trials. We conducted a network meta-analysis to compare their efficacies in patients with IBS-C.. We searched MEDLINE, EMBASE, EMBASE Classic, and the Cochrane Central Register of Controlled Trials through June 2018 to identify randomized controlled trials assessing the efficacy of secretagogues in adults with IBS-C. Trials included in the analysis reported a dichotomous assessment of overall response to therapy, and data were pooled using a random-effects model. Efficacy and safety of secretagogues were reported as a pooled relative risk with 95% confidence interval to summarize the effect of each comparison tested, and treatments were ranked according to their P score.. We identified 15 eligible randomized controlled trials of secretagogues that included 8462 patients. Linaclotide, lubiprostone, plecanatide, and tenapanor were superior to placebo for the treatment of IBS-C. Linaclotide (290 μg once daily) was ranked first in efficacy based on the end point recommended by the Food and Drug Administration for trials in IBS-C, the primary end point used in each trial, abdominal pain, and complete spontaneous bowel movements. Tenapanor (50 mg twice daily) was ranked first for decreasing bloating. Total numbers of adverse events were significantly larger with linaclotide (290 and 500 μg once daily) and plecanatide (3 mg once daily) compared with placebo. However, plecanatide 6 mg once daily ranked first for safety. Diarrhea was significantly more common with all drugs, except lubiprostone (8 μg twice daily). Nausea was significantly more common in patients who received lubiprostone.. In a network analysis of randomized controlled trials of secretagogues for IBS-C, we found all drugs to be superior to placebo. Efficacy was similar among individual drugs and dosages for most end points. However, data were extracted at the 12-week time point, so the long-term relative efficacy of these drugs is unknown.

Topics: Adult; Constipation; Female; Gastrointestinal Agents; Humans; Irritable Bowel Syndrome; Isoquinolines; Lubiprostone; Male; Middle Aged; Natriuretic Peptides; Network Meta-Analysis; Peptides; Randomized Controlled Trials as Topic; Secretagogues; Sulfonamides; Treatment Outcome

A number of new medications were recently demonstrated to be more effective than placebo in treating chronic constipation, including the intestinal chloride channel activator lubiprostone, the prokinetic selective 5-HT4 receptor agonist prucalopride and the guanylate cyclase-C agonist linaclotide. Recent publications have also revisited traditional laxatives like PEG. Moreover, a number of pharmacological treatments are in development and these include another guanylate cyclase-C agonist, plecanatide and an ileal bile acid transporter inhibitor, elobixibat.. This review focuses on the pharmacology, efficacy and safety profile of prucalopride, linaclotide, plecanatide and elobixibat.. The possible present or future clinical application of prucalopride, linaclotide, plecanatide and elobixibat in both chronic constipation and irritable bowel syndrome with constipation is reported, and some considerations on the possible role of PEG taking into account recent literature are advanced.

Topics: Benzofurans; Chronic Disease; Constipation; Dipeptides; Humans; Irritable Bowel Syndrome; Laxatives; Natriuretic Peptides; Peptides; Thiazepines

Patients with chronic idiopathic constipation (CIC) and irritable bowel syndrome with constipation (IBS-C) often experience severe symptoms. The current aim was to evaluate plecanatide in adults with CIC or IBS-C with severe constipation.. Data were analyzed post hoc from randomized, placebo-controlled trials (CIC [n = 2], IBS-C [n = 2]) of plecanatide 3 mg, 6 mg, or placebo administered for 12 weeks. Severe constipation was defined as no complete spontaneous bowel movements (CSBMs) and an average straining score ≥3.0 (CIC; 5-point scale) or ≥8.0 (IBS-C; 11-point scale) during a 2-week screening. Primary efficacy endpoints were durable overall CSBM responders (CIC: ≥3 CSBMs/week, plus increase from baseline of ≥1 CSBM/week, for ≥9 of 12 weeks, including ≥3 of the last 4 weeks) and overall responders (IBS-C: ≥30% reduction from baseline in abdominal pain and ≥1 CSBM/week increase for ≥6 of 12 weeks).. Severe constipation was observed in 24.5% (646/2639) and 24.2% (527/2176) of CIC and IBS-C populations, respectively. The CIC durable overall CSBM response rate (plecanatide 3 mg, 20.9%; plecanatide 6 mg, 20.2%; placebo, 11.3%) and IBS-C overall response rate (plecanatide 3 mg, 33.0%; plecanatide 6 mg, 31.0%; placebo, 19.0%) were significantly greater with plecanatide versus placebo (p ≤ 0.01 for all). Median time to first CSBM in CIC and IBS-C populations were significantly shorter with plecanatide 3 mg versus placebo (p = 0.01 for both).. Plecanatide was effective in the treatment of severe constipation in adults with CIC or IBS-C.

Topics: Adult; Constipation; Double-Blind Method; Humans; Irritable Bowel Syndrome; Natriuretic Peptides; Peptides; Treatment Outcome

Plecanatide, an approved therapy for chronic idiopathic constipation (CIC) and irritable bowel syndrome with constipation, is an analogue of uroguanylin that replicates its pH-sensitive activity and binds to guanylate cyclase-C receptors expressed on intestinal epithelium, stimulating fluid secretion. This analysis explores concomitant acid suppression therapy's effect on the efficacy and safety of plecanatide in adults with CIC.. Data from 2 placebo-controlled, 12-week Phase III trials of plecanatide in CIC were pooled. Patients were randomized to receive placebo, plecanatide 3 mg, or plecanatide 6 mg. The primary endpoint was the durable, overall complete spontaneous bowel movement (CSBM) response rate (defined as ≥3 CSBMs in a given week and ≥1 CSBM increase from baseline within a week for ≥9 of 12 weeks, including ≥3 of the last 4 treatment weeks). Safety was also evaluated. Results were stratified by concomitant use or nonuse of acid suppression therapy.. Of the pooled intent-to-treat population, 338 of 2639 patients (12.8%) received concomitant acid suppression medication. Efficacy response rates in patients using acid suppressors were 23.6% with plecanatide 3 mg (P = 0.001 vs placebo), 22.1% with plecanatide 6 mg (P = 0.002), and 7.6% with placebo. Responses were similar in patients not using acid suppressors: 20.4% (plecanatide 3 mg, P < 0.001), 19.6% (plecanatide 6 mg, P < 0.001), and 12.1% (placebo). Serious adverse events were experienced by 3.3% of patients who used concomitant acid suppression and 1.0% of those who did not.. Plecanatide treatment is safe and efficacious for patients with CIC when administered with concomitant acid suppression medication.. gov identifiers: NCT02122471 and NCT01982240.

Topics: Adult; Chronic Disease; Constipation; Defecation; Double-Blind Method; Gastrointestinal Agents; Humans; Irritable Bowel Syndrome; Natriuretic Peptides; Treatment Outcome

Chronic idiopathic constipation (CIC) and irritable bowel syndrome with constipation (IBS-C) are common functional gastrointestinal disorders. The prevalence of constipation-related issues tends to increase with age. This analysis pooled data from Phase III trials in CIC and IBS-C to assess the safety and efficacy of plecanatide in patients aged ≥65 years.. Patients randomized to receive plecanatide (3 or 6 mg) or placebo from two CIC and two IBS-C trials were pooled. Efficacy end points common to all trials included changes in stool consistency (Bristol Stool Form Scale), changes in weekly frequency of complete spontaneous bowel movements (CSBMs) and spontaneous bowel movements (SBMs), and time to first CSBM and SBM. Efficacy and safety profile results are reported per age group (≥65 and <65 years of age).. The pooled intention-to-treat population comprised 451 patients aged ≥65 years (mean age, 70 years) and 4364 patients aged <65 years (mean age, 41.9 years), of whom 287 and 2914, respectively, were randomized to receive plecanatide. Compared with placebo, plecanatide produced statistically significant improvements in stool consistency from baseline at week 12 (both age groups), CSBM and SBM frequency from baseline at week 12 (plecanatide 3 mg group aged ≥65 years and both plecanatide groups aged <65 years), and time from start of therapy to first CSBM (both age groups) and SBM (plecanatide 6 mg group aged ≥65 years and both plecanatide groups aged <65 years). No new safety issues were observed.. Plecanatide is a well-tolerated and effective treatment option for patients aged ≥65 years with CIC or IBS-C. CLINICALTRIALS.. NCT01982240, NCT02122471, NCT02387359, and NCT02493452.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Constipation; Defecation; Double-Blind Method; Female; Gastrointestinal Agents; Humans; Irritable Bowel Syndrome; Male; Middle Aged; Natriuretic Peptides; Treatment Outcome; Young Adult

Two identical, phase 3, randomized, double-blind, placebo-controlled trials evaluated the efficacy and safety of plecanatide in patients with irritable bowel syndrome with constipation (IBS-C).. Adults meeting Rome III criteria for IBS-C were randomized (1:1:1) to placebo or plecanatide (3 or 6 mg) for 12 weeks. The primary efficacy end point was the percentage of overall responders (patients reporting ≥30% reduction from baseline in worst abdominal pain plus an increase of ≥1 complete spontaneous bowel movement (CSBM)/week from baseline in the same week for ≥6 of 12 treatment weeks). Safety was assessed by adverse events (AEs).. Overall, 2189 individuals were randomized across the two studies and 1879 completed the studies. Demographic and baseline characteristics were similar across treatment groups and between studies. The percentage of overall responders in Study 1 was 30.2% and 29.5% for plecanatide 3 and 6 mg, respectively, vs. 17.8% placebo (P < 0.001 for each dose vs. placebo), and in Study 2 was 21.5% (P = 0.009) and 24.0% (P < 0.001) for plecanatide 3 and 6 mg, respectively, compared to 14.2% for placebo. The percentage of sustained efficacy responders (overall responders plus weekly responders for ≥2 of last 4 weeks of the 12-week treatment period) was significantly greater for both doses of plecanatide vs. placebo across both studies. All secondary end points (stool frequency/consistency, straining, abdominal symptoms) showed statistically significant improvements compared with placebo. The most common AE was diarrhea (3 mg, 4.3%; 6 mg, 4.0%; placebo, 1.0%). Discontinuation due to diarrhea was infrequent (3 mg, 1.2%; 6 mg, 1.4%; placebo, 0).. Plecanatide significantly improved both abdominal pain and constipation symptoms of IBS-C with minimal associated side effects and high levels of tolerability.

Topics: Abdominal Pain; Adult; Aged; Aged, 80 and over; Constipation; Defecation; Diarrhea; Dose-Response Relationship, Drug; Double-Blind Method; Female; Gastrointestinal Agents; Humans; Irritable Bowel Syndrome; Male; Middle Aged; Natriuretic Peptides; Placebos; Treatment Outcome; Young Adult

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Constipation; Diarrhea; Female; Humans; Irritable Bowel Syndrome; Male; Middle Aged; Natriuretic Peptides; Surveys and Questionnaires; Treatment Outcome; Young Adult

Prouroguanylin (ProUGN) in the intestine is cleaved to form uroguanylin (UGN), which stimulates guanylate cyclase C (GUCY2C), inducing cyclic guanosine monophosphate signaling. Paracrine release regulates fluid secretion, contributing to bowel function, whereas endocrine secretion evoked by eating forms a gut-brain axis, controlling appetite. Whereas hormone insufficiency contributes to hyperphagia in obesity, its contribution to the pathophysiology of constipation syndromes remains unexplored. Here, we compared circulating ProUGN and UGN in healthy subjects and in patients with chronic idiopathic constipation (CIC) and patients with irritable bowel syndrome with constipation (IBS-C).. Circulating ProUGN and UGN levels were measured in 60 healthy subjects, 53 patients with CIC, and 54 patients with IBS-C. After an overnight fast, the participants ingested a standardized meal; blood samples were drawn at fasting and at 30, 60, and 90 minutes thereafter, and hormone levels were quantified by enzyme-linked immunosorbent assay.. Fasting ProUGN levels were >30% lower in patients with CIC and those with IBS-C compared with healthy subjects regardless of age, sex, or disease state. After eating, ProUGN levels increased compared with fasting levels, although the rate of change was slower and maximum levels were lower in patients with CIC and those with IBS-C. Similarly, fasting UGN levels were lower in patients with CIC and those with IBS-C compared with healthy subjects. However, unlike ProUGN levels, UGN levels did not increase after eating.. These observations support a novel pathophysiologic model in which CIC and IBS-C reflect a contribution of ProUGN insufficiency dysregulating intestinal fluid and electrolyte secretion.. This study suggests that CIC and IBS-C can be treated by oral GUCY2C hormone replacement. Indeed, these observations provide a mechanistic framework for the clinical utility of oral GUCY2C ligands like plecanatide (Trulance) and linaclotide (Linzess) to treat CIC and IBS-C.

Topics: Adult; Case-Control Studies; Constipation; Enzyme-Linked Immunosorbent Assay; Fasting; Female; Guanylyl Cyclase C Agonists; Humans; Irritable Bowel Syndrome; Male; Middle Aged; Natriuretic Peptides; Nucleotides, Cyclic; Peptides; Protein Precursors; Receptors, Atrial Natriuretic Factor

To investigate the effects of plecanatide and dolcanatide on maintenance of paracellular permeability, integrity of tight junctions and on suppression of visceral hypersensitivity.. Transport of fluorescein isothiocyanate (FITC)-dextran was measured to assess permeability across cell monolayers and rat colon tissues. Effects of plecanatide and dolcanatide on the integrity of tight junctions in Caco-2 and T84 monolayers and on the expression and localization of occludin and zonula occludens-1 (ZO-1) were examined by immunofluorescence microscopy. Anti-nociceptive activity of these agonists was evaluated in trinitrobenzene sulfonic acid (TNBS)-induced inflammatory as well as in non-inflammatory partial restraint stress (PRS) rat models. Statistical significance between the treatment groups in the permeability studies were evaluated using unpaired. Treatment of T84 and Caco-2 monolayers with lipopolysaccharide (LPS) rapidly increased permeability, which was effectively suppressed when monolayers were also treated with plecanatide or dolcanatide. Similarly, when T84 and Caco-2 monolayers were treated with LPS, cell surface localization of tight junction proteins occludin and ZO-1 was severely disrupted. When cell monolayers were treated with LPS in the presence of plecanatide or dolcanatide, occludin and ZO-1 were localized at the cell surface of adjoining cells, similar to that observed for vehicle treated cells. Treatment of cell monolayers with plecanatide or dolcanatide without LPS did not alter permeability, integrity of tight junctions and cell surface localization of either of the tight junction proteins. In rat visceral hypersensitivity models, both agonists suppressed the TNBS-induced increase in abdominal contractions in response to colorectal distension without affecting the colonic wall elasticity, and both agonists also reduced colonic hypersensitivity in the PRS model.. Our results suggest that activation of GC-C signaling might be involved in maintenance of barrier function, possibly through regulating normal localization of tight junction proteins. Consistent with these findings, plecanatide and dolcanatide showed potent anti-nociceptive activity in rat visceral hypersensitivity models. These results imply that activation of GC-C signaling may be an attractive therapeutic approach to treat functional constipation disorders and inflammatory gastrointestinal conditions.

Topics: Administration, Oral; Animals; Caco-2 Cells; Colon; Constipation; Dextrans; Female; Fluorescein-5-isothiocyanate; Guanylyl Cyclase C Agonists; Humans; Intestinal Mucosa; Irritable Bowel Syndrome; Lipopolysaccharides; Male; Natriuretic Peptides; Nociception; Peptides; Permeability; Rats; Rats, Sprague-Dawley; Receptors, Enterotoxin; Signal Transduction; Tight Junctions; Trinitrobenzenesulfonic Acid; Visceral Pain

Topics: Abdominal Pain; Constipation; Humans; Irritable Bowel Syndrome; Natriuretic Peptides; Randomized Controlled Trials as Topic

Topics: Animals; Benzimidazoles; Benzofurans; Bile Acids and Salts; Carbolines; Colesevelam Hydrochloride; Colestipol; Disease Models, Animal; Enteric Nervous System; Female; Humans; Imidazoles; Indoles; Irritable Bowel Syndrome; Loperamide; Lubiprostone; Male; Mice; Natriuretic Peptides; Peptides; Phenylalanine; Receptors, Serotonin, 5-HT3; Receptors, Serotonin, 5-HT4; Rifamycins; Rifaximin; Serotonin; Serotonin Antagonists; Serotonin Receptor Agonists; Visceral Pain

Topics: Apoptosis; Chlorides; Colon; Constipation; Gastrointestinal Agents; Humans; Intestinal Mucosa; Irritable Bowel Syndrome; Natriuretic Peptides; Peptides; Receptors, Atrial Natriuretic Factor