plecanatide and Diarrhea

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

Many patients with chronic idiopathic constipation (CIC) remain unsatisfied with their treatment options. Plecanatide is a pH-sensitive uroguanylin analog that increases fluid and ion movement into the gastrointestinal lumen, softening stools and encouraging motility, while limiting the risk of diarrhea.. The objective of this phase 2 study is to evaluate the safety and efficacy of once-daily oral plecanatide in patients with CIC and identify the most effective dose.. A 12-week, multicenter, randomized, double-blind, placebo-controlled, dose-ranging study was conducted in patients aged 18-75 years and diagnosed with CIC based on modified Rome III criteria (< 3 complete spontaneous bowel movements [CSBMs] per week and infrequent loose stools without the use of laxatives). Participants were randomized to placebo or plecanatide 0.3, 1.0, or 3.0 mg. The primary efficacy endpoint was the proportion of overall CSBM responders. Key secondary endpoints included time to first CSBM, change in CSBM and spontaneous bowel movement (SBM) frequency rates, patient-reported outcomes, safety, and tolerability.. Of 951 randomized participants, 946 were included in the modified intent-to-treat population. Plecanatide 0.3 and 3.0 mg significantly increased overall CSBM responder rates compared with placebo (0.3 mg, P = 0.016; 3.0 mg, P = 0.009). Plecanatide was associated with decreased time to first CSBM, significant increases in CSBM and SBM frequency, and decreased patient-reported constipation severity compared with placebo. Diarrhea was the most frequently reported treatment-emergent adverse event.. Plecanatide is a well-tolerated treatment that relieved the symptoms of CIC with a relatively low incidence of diarrhea.

Topics: Adolescent; Adult; Aged; Chronic Disease; Constipation; Diarrhea; Dose-Response Relationship, Drug; Double-Blind Method; Female; Gastrointestinal Agents; Humans; Male; Middle Aged; Natriuretic Peptides; Treatment Outcome; Young Adult

This multi-center, fixed-dose, open-label study evaluated the long-term safety and tolerability of once-daily oral plecanatide for the treatment of adults with chronic idiopathic constipation (CIC).. Eligible patients completed a phase 2b or phase 3 double-blind study of plecanatide, or had not previously been treated with plecanatide. Enrolled patients received plecanatide (3 or 6 mg) for up to 72 weeks. Safety and tolerability were assessed by the incidence, nature, and severity of spontaneously reported treatment-emergent adverse events (TEAEs). Patients also completed Patient Global Assessment questionnaires, which included measures of treatment satisfaction and the desire to continue treatment.. There were 2370 patient exposures in this study, with the vast majority (90.5%) receiving treatment with plecanatide 6 mg. At the time of study closure, 1932 (81.5%) had completed or were still receiving study drug. TEAEs were qualitatively and quantitatively similar to those observed in prior double-blind studies. The most common TEAEs were diarrhea (7.1%) and urinary tract infection (2.2%). TEAEs leading to discontinuation occurred in 5.3% of patients, with diarrhea leading to discontinuation in 3.1%. Most TEAEs were mild/moderate in severity and were generally considered not related to plecanatide treatment. At the end of treatment, the median score for treatment satisfaction was 4.0 (quite satisfied), and the median score for treatment continuation was 4.0 (quite likely).. Long-term treatment of adults with CIC demonstrated that plecanatide was safe and well tolerated, with low TEAE and discontinuation rates. Patients indicated satisfaction and a desire to continue with plecanatide treatment.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Constipation; Diarrhea; Female; Humans; Male; Middle Aged; Natriuretic Peptides; Time Factors; 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

This study assessed the efficacy and safety of plecanatide, a guanylate cyclase-C (GC-C) agonist and the first uroguanylin analog approved for the treatment of chronic idiopathic constipation (CIC).. This phase III, multicenter, double-blind, placebo-controlled study randomized 1,394 patients with CIC. Patients received either plecanatide (3 or 6 mg) or placebo, orally, once daily, for 12 weeks. The primary efficacy endpoint was the percentage of patients who were durable overall complete spontaneous bowel movement (CSBM) responders over the 12-week treatment period. Patients were instructed to record their daily bowel movements, stool consistency scores, and abdominal symptoms in an electronic diary. Treatment-emergent adverse events (AEs) were collected.. Each dose of plecanatide resulted in a significantly greater percentage of durable overall CSBM responders (21.0%, 3 mg; 19.5%, 6 mg) as compared with placebo (10.2%; P<0.001 for both). Plecanatide (3 and 6 mg) also significantly increased mean weekly CSBM frequency from baseline (increase of 2.5 and 2.2/week, respectively) vs. placebo (1.2/week; P<0.001 for both) and mean weekly spontaneous bowel movement frequency (increase of 3.2 and 3.1/week, respectively) vs. placebo (1.3/week; P<0.001, for both) over the 12-week treatment period. Both plecanatide doses significantly improved all secondary and additional efficacy endpoints. The most common AE, diarrhea, occurred in 1.3% (placebo), 5.9% (3 mg) and 5.7% (6 mg) of patients.. Plecanatide significantly improved constipation and its related symptoms with a low rate of adverse events. These results suggest that plecanatide will be a useful treatment option in the management of CIC. ClinicalTrials.gov: NCT01982240.

Topics: Adolescent; Adult; Aged; Chronic Disease; Constipation; Defecation; Diarrhea; Double-Blind Method; Female; Gastrointestinal Agents; Humans; Male; Middle Aged; Natriuretic Peptides; 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