A Randomized Phase III Clinical Trial of Plecanatide, a Uroguanylin Analog, in Patients With Chronic Idiopathic Constipation

Abstract

Objectives: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).Methods: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.Results: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.Conclusions: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.

Abnormal Uroguanylin Immunoreactive Cells Density in the Duodenum of Patients with Diarrhea-Predominant Irritable Bowel Syndrome Changes following Fecal Microbiota Transplantation

“…This explains the correlations between uroguanylin immunoreactive cells density and diarrhea in PI-IBS patients at baseline before FMT. Correlations between uroguanylin and other IBS symptoms such as bloating and abdominal pain are most probably due to the same mechanism of the GC-C and cGMP pathway activation leading to reduced visceral hypersensitivity [58,59], thus linking it to the gut-brain axis. Plecanatide®, a medication structurally related to uroguanylin, has newly been introduced to the market for the treatment of abdominal pain and constipation in patients with constipation-predominant IBS [60].…”

Chronic idiopathic constipation in adults: epidemiology, pathophysiology, diagnosis and clinical management

“…In RCTs of plecanatide for treating CIC, 76 , 77 the drug improved constipation‐related symptoms, when compared with placebo, over 12 weeks, but diarrhoea was again the predominant side effect. Patients taking plecanatide had significantly more spontaneous bowel movements per week, as well as significant improvements in stool consistency.…”

Diabetes Mellitus and the Colon

“…All of these agents require a prescription. This includes the peripheral acting guanylate cyclase-C agonists, linaclotide, and plecanatide [27, 28]. Both agents have been shown to stimulate intestinal fluid secretion and transit.…”