Plecanatide is used to treat chronic idiopathic constipation (CIC) and irritable bowel syndrome with constipation (IBS-C). It works by increasing the fluid secretion of the bowels, which helps ease the passage of stools and relieve the symptoms of constipation.

Efficacy and Safety of Plecanatide in Treatment of Irritable Bowel Syndrome

Plecanatide is approved by the US Food and Drug Administration (FDA) for the treatment of adults with CIC or IBS-C. Ahmed and colleagues reported on the results of a systemic review and meta-analysis that focused on the efficacy and safety of plecanatide in the treatment of these 2 conditions. This analysis included 7 studies consisting of 6316 individuals, of which 4349 received plecanatide and 1967 received placebo. Across the studies, plecanatide was evaluated at different doses, ranging from 0.3 mg once daily up to 9 mg once daily.Different outcomes were assessed for IBS-C and CIC. A pooled effect size was reported for all outcomes to convey the weighted average of the effect sizes across all studies reporting that outcome. These pooled effect sizes were evaluated for each dose of plecanatide with data for that outcome. Also reported were 2 statistics to evaluate the quality of the metaanalysis. The first of these was the I value, indicating the fraction of variance that is owing to heterogeneity across the publications (with lower percentages indicative of more homogeneity and therefore a suggestion that the treatment will have a similar effect when applied to new patients). [1]

Once again, plecanatide is shown to be safe and efficacious in improving abdominal pain and bowel frequency despite its side effect of diarrhea. Interpretation of the risk of urinary tract infections with use of plecanatide should be done with caution given the higher known risk of these infections in patients with constipation in general and because baseline urinary symptom data, history of fecal or urinary incontinence, and known objective measures are not reported. Two adverse effects were significantly associated with plecanatide: diarrhea (relative risk, 4.11; 95% CI, 2.50-6.77; P<.01) and urinary tract infection (relative risk, 1.70; 95% CI, 0.99-2.91; P=.05). Other adverse effects reported that were not significantly associated with plecanatide were headache, nausea, nasopharyngitis, and upper respiratory tract infection.The study authors concluded that the results of this systemic review and meta-analysis supported the efficacy of plecanatide for the treatment of IBS-C and CIC. However, they noted that this benefit should be weighed against the increased risk of diarrhea and urinary tract infection associated with its use.

Profile of plecanatide in the treatment of chronic idiopathic constipation

Guanylate cyclase-C (GC-C)/cyclic guanosine mono-phosphate (cGMP) agonists have emerged as a safe and efficacious class of drugs for the treatment of CIC. GC-C agonists not only improve stool consistency and number of BMs in subjects with CIC but also provide visceral analgesia. Plecanatide is the second-in-class GC-C agonist following linaclotide and was approved by the US FDA for the treatment of CIC (3 mg) and IBS-C (3 and 6 mg) in patients aged >18 years. Plecanatide is a 16-amino acid peptide analog to endogenous uroguanylin, whereas linaclotide is a 14-amino acid peptide derived from Escherichia coli heat-stable enterotoxin. This study aims to review the steps taken in the design and development of plecanatide and its current use in the treatment of CIC. In the first in-human placebo-controlled trial conducted on a cohort of healthy volunteers, 71 subjects were administered oral doses of plecanatide up to 48.6 mg to assess its safety and tolerability.[2]

With the exception of 5.1 mg cohort, all doses resulted in first BM within 24 hours. Blood samples collected up to 48 hours demonstrated no detectable plasma concentration of drug. Mean BSFS scores plateau between doses of 5.4 and 8.1 mg. Plecanatide doses between 0.3 and 9 mg were selected for the Phase IIa study. Eighty CIC subjects were enrolled in a dose-ranging Phase IIa study evaluating plecanatide doses of 0.3, 1, 3, and 9 mg vs placebo to assess the pharmacokinetic and pharmacodynamic profiles. Reported adverse event rate with the study drug was 17.2% compared to 10% in placebo. None of the subjects in the study drug arm reported bothersome diarrhea. A decrease in time-to-first BM was noted with all doses of plecanatide compared to placebo. Subjects also showed improvement in abdominal discomfort, straining, stool consistency, and frequency. Two separate large plecanatide Phase III studies in over 1,300 CIC subjects each (CIC3 and National CIC3) compared treatment arms of 3 and 6 mg once daily to placebo over a 12-week period of treatment. Both followed similar clinical trial design with the same FDA-approved composite primary end point. Inclusion criteria consisted of male or female patients from 18 to 80 years with a body mass index of 18–40 kg/m2 with CIC meeting the modified Rome III criteria.

Plecanatide, an endogenous uroguanylin analog and GC-C agonist, is an effective treatment option for patients suffering from CIC. Its lack of systemic absorption helps to avoid systemic adverse effects and drug–drug interactions, providing plecanatide with an excellent safety profile. Despite its pH-dependent action predominantly in the proximal small bowel, plecanatide has similar rates of its predominant adverse event of diarrhea to linaclotide, the first-to-market GC-C agonist. Therefore, plecanatide or linaclotide may be considered first-line agents for the treatment of laxative-refractory CIC in the absence of or adequately addressed medically refractory conditions. Future therapeutic options for CIC patients include serotonergic or 5-HT promotility agents and IBATs.

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

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).[3]

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. The percentage of weekly CSBM responders in both plecanatide groups was greater than with placebo within the first week of treatment (plecanatide 3 mg, 35.8%; plecanatide 6 mg, 29.3%; placebo, 16.6%; p < 0.001 for each drug dose versus placebo), and this difference persisted for the duration of the 12-week treatment period. During the follow-up period after the completion of plecanatide, the proportions of CSBM weekly responders in both plecanatide dose groups decreased and were comparable with placebo.

References

[1]Efficacy and Safety of Plecanatide in Treatment of Irritable Bowel Syndrome With Constipation and Chronic Idiopathic Constipation. Gastroenterol Hepatol (N Y). 2024 Dec;20(12 Suppl 9):7-9.

[2]Sharma A, Herekar AA, Bhagatwala J, Rao SS. Profile of plecanatide in the treatment of chronic idiopathic constipation: design, development, and place in therapy. Clin Exp Gastroenterol. 2019 Jan 22;12:31-36.

[3]Rao SSC. Plecanatide: a new guanylate cyclase agonist for the treatment of chronic idiopathic constipation. Therap Adv Gastroenterol. 2018 Jun 8;11:1756284818777945.