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Plecanatide: a new guanylate cyclase agonist for the treatment of chronic idiopathic constipation.

ABSTRACT: Chronic constipation affects millions of Americans, consumes significant healthcare resources, and significantly affects quality of life (QOL). Recently, several new treatment options have become available for the treatment of constipation, including intestinal secretagogues such as lubiprotone, and linaclotide, prokinetics such as prucalopride, and bile acid transporter antagonists. Plecanatide is the newest of the secretagogue class of compounds that has been approved by the US Food and Drug Administration for the treatment of adults with chronic idiopathic constipation (CIC) in the USA. It is a guanylate cyclase agonist, and a 16 amino acid synthetic peptide that is a structural analog of human uroguanylin. Two large randomized, double-blind, placebo-controlled studies assessed the efficacy and safety of plecanatide in CIC patients (Rome III). Both doses of plecanatide, 3 mg and 6 mg resulted in a significantly greater percentage of patients who were durable overall complete spontaneous bowel movement (CSBM) responders (primary endpoint) compared with those who received placebo (plecanatide 3 mg, 21.0%; plecanatide 6 mg, 19.5%; placebo, 10.2%; p < 0.001 for each drug dose versus placebo). Plecanatide treatment also significantly reduced the severity of other CIC symptoms (straining effort, stool consistency, bloating). Also, plecanatide-treated patients reported high levels of satisfaction and improved QOL and desire to continue treatment. The rate of treatment-emergent adverse events with plecanatide was low, including rates of diarrhea (5%). Plecanatide is a luminally acting secretagogue that is efficacious and safe for the treatment of CIC. This article provides an overview of plecanatide in the management of adults with CIC.

SUBMITTER: Rao SSC

PROVIDER: S-EPMC6009086 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Plecanatide: a new guanylate cyclase agonist for the treatment of chronic idiopathic constipation.

Rao Satish S C SSC

Therapeutic advances in gastroenterology 20180608

Chronic constipation affects millions of Americans, consumes significant healthcare resources, and significantly affects quality of life (QOL). Recently, several new treatment options have become available for the treatment of constipation, including intestinal secretagogues such as lubiprotone, and linaclotide, prokinetics such as prucalopride, and bile acid transporter antagonists. Plecanatide is the newest of the secretagogue class of compounds that has been approved by the US Food and Drug A ...[more]

PMID: 29942351

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Project description:OBJECTIVES: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). METHODS: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. RESULTS: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??g (Odds ratio (OR)=3.11, 95% CI 1.81-5.34); linaclotide 145??g (OR=3.25, 2.15-4.91); plecanatide 3?mg (OR=1.99, 1.57-2.51)) and IBS-C (linaclotide 290??g (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??g (OR=3.07, 1.97-4.77); linaclotide 145??g (OR=3.70, 2.69-5.10); plecanatide 3?mg (OR=3.86, 1.83-8.12)) and IBS-C (linaclotide 290??g (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. CONCLUSIONS: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.

Project description:The use of doxorubicin, a potent chemotherapeutic agent, is limited by cardiotoxicity. We tested the hypothesis that decreased soluble guanylate cyclase (sGC) enzyme activity contributes to the development of doxorubicin-induced cardiotoxicity.Doxorubicin administration (20?mg/kg, intraperitoneally [IP]) reduced cardiac sGC activity in wild-type (WT) mice. To investigate whether decreased sGC activity contributes to doxorubicin-induced cardiotoxicity, we studied mice with cardiomyocyte-specific deficiency of the sGC ?1-subunit (mice with cardiomyocyte-specific deletion of exon 6 of the sGC?1 allele [sGC?1-/-CM]). After 12 weeks of doxorubicin administration (2?mg/kg/week IP), left ventricular (LV) systolic dysfunction was greater in sGC?1-/-CM than WT mice. To further assess whether reduced sGC activity plays a pathogenic role in doxorubicin-induced cardiotoxicity, we studied a mouse model in which decreased cardiac sGC activity was induced by cardiomyocyte-specific expression of a dominant negative sGC?1 mutant (DNsGC?1) upon doxycycline removal (Tet-off). After 8 weeks of doxorubicin administration, DNsGC?1tg/+, but not WT, mice displayed LV systolic dysfunction and dilatation. The difference in cardiac function and remodeling between DNsGC?1tg/+ and WT mice was even more pronounced after 12 weeks of treatment. Further impairment of cardiac function was attenuated when DNsGC?1 gene expression was inhibited (beginning at 8 weeks of doxorubicin treatment) by administering doxycycline. Furthermore, doxorubicin-associated reactive oxygen species generation was higher in sGC?1-deficient than WT hearts. Innovation and Conclusion: These data demonstrate that a reduction in cardiac sGC activity worsens doxorubicin-induced cardiotoxicity in mice and identify sGC as a potential therapeutic target. Various pharmacological sGC agonists are in clinical development or use and may represent a promising approach to limit doxorubicin-associated cardiotoxicity. Antioxid. Redox Signal. 26, 153-164.

Dataset Information

Plecanatide: a new guanylate cyclase agonist for the treatment of chronic idiopathic constipation.

Publications

Plecanatide: a new guanylate cyclase agonist for the treatment of chronic idiopathic constipation.

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