Profile of plecanatide in the treatment of chronic idiopathic constipation: design, development, and place in therapy

Clinical and Experimental Gastroenterology Dovepress open access to scientific and medical research Review Clinical and Experimental Gastroenterology downloaded from https://www.dovepress.com/ by 88.198.20.149 on 17-Aug-2019 For personal use only. Open Access Full Text Article Profile of plecanatide in the treatment of chronic idiopathic constipation: design, development, and place in therapy This article was published in the following Dove Press journal: Clinical and Experimental Gastroenterology Amol Sharma Anam Asif Herekar Jigar Bhagatwala Satish SC Rao Division of Gastroenterology and Hepatology, Department of Medicine, Medical College of Georgia, Augusta University, Augusta, GA, USA Introduction Correspondence: Amol Sharma Division of Gastroenterology and Hepatology, Digestive Health Center, Medical College of Georgia, Augusta University, 1120 15th Street, AD-2226, Augusta, GA 30912, USA Email Constipation is a major health problem both domestically and globally. The average US and global prevalence is ~14%–15%.1 Two and a half million outpatient doctor visits are attributed to constipation each year.2 In US alone, constipation results in a significant economic burden with an estimated $821 million spent annually on laxatives.3 Constipation severely impairs quality of life and causes significant psychological distress.4 Constipation affects females more than males, older individuals, and more people of lower socioeconomic status.1 Constipation is associated with <3 complete spontaneous bowel movements (CSBMs) a week.5 However, if the definition is restricted to number of bowel movements (BMs), constipation is grossly underdiagnosed, and the prevalence is underestimated. Other key historical clues associated with constipation include hard or lumpy stool character, lengthy and ineffective attempted defecation or straining, sense of incomplete evacuation of stool, bloating, and use of digital maneuvers. After the exclusion of secondary causes, constipation can be further subclassified into dyssynergic defecation, irritable bowel syndrome, constipation-predominant (IBS-C), and chronic idiopathic constipation (CIC). According to a meta-analysis of 41 studies, CIC has a pooled prevalence of 14% (CI 12%–17%).6 CIC is a chronic, multisymptom disorder that is associated with negative impact on workplace and school productivity. An estimated 23% annual loss of productivity is attributed to absenteeism of a quarter of employees suffering from CIC.7 Approximately 60% of the patients with CIC were not satisfied by their current prescribed chronic treatment, 31 submit your manuscript | www.dovepress.com Clinical and Experimental Gastroenterology 2019:12 31–36 Dovepress © 2019 Sharma et al. This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms. php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php). http://dx.doi.org/10.2147/CEG.S145668 Powered by TCPDF (www.tcpdf.org) Abstract: Constipation is a multifactorial disorder that can cause significant psychological distress to patients and economic burden on the health care system. Many patients are not satisfied with their current established treatment, highlighting the need for new and improved therapeutic options. Guanylate cyclase-C (GC-C)/cyclic guanosine monophosphate agonists have emerged as a safe and efficacious class of drugs for the treatment of chronic idiopathic constipation (CIC). Plecanatide, a second-in-class, US FDA-approved, synthetic GC-C agonist, has recently been approved in the US for the treatment of irritable bowel syndrome with constipation at doses of 3 and 6 mg and CIC at the 3 mg dosage. In this study, we summarize the design of this novel 16-amino acid uroguanylin analog, drug development through Phase I, II, and III clinical studies, and its role in the treatment of CIC. Keywords: plecanatide, uroguanylin, constipation Dovepress Clinical and Experimental Gastroenterology downloaded from https://www.dovepress.com/ by 88.198.20.149 on 17-Aug-2019 For personal use only. Sharma et al highlighting the need for new and improved therapeutic options.7 Guanylate cyclase-C (GC-C)/cyclic guanosine monophosphate (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.8–10 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 heatstable 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. GC-C receptors play a critical role in a multitude of routine gastrointestinal (GI) tract functions. GC-C receptor activation maintains intestinal electrolyte and fluid homeostasis, supports the mucosal barrier, attenuates visceral pain, and inhibits inflammation.8–12 In addition, GC-C receptor modulation may have a role in the treatment of colorectal cancer.13 GC-C receptors are located on the mucosal epithelial cells throughout the entire length of the GI tract. Endogenous paracrine peptide hormones, uroguanylin and guanylin, act on these receptors in a pH-dependent manner. Uroguanylin, a 16-amino acid peptide, acts proximally in the acidic environments (pH 5–7) of duodenum and proximal jejunum through its N-terminal pH-sensing aspartate and glutamate residues. In contrast, guanylin, a 15-amino acid peptide, is most potent in the neutral to slightly basic environment of the colorectum.14,15 Activation of the GC-C receptor results in a cascade of events, starting with the conversion of GTP into cGMP. cGMP activates a series of mediators that stimulate cystic fibrosis transmembrane conductance regulator channels, resulting in the release of Cl− and HCO3– ions that osmotically draw the water into the intestinal lumen. It also blocks the Na+/H+ exchanger-3, allowing Na+ to remain in the lumen, as shown in Figure 1. Increased luminal water content helps facilitate BMs by softening the stool. Plecanatide (Synergy Pharmaceuticals, New York, NY, USA) shares the same structural features of uroguanylin, differing only in the substitution of aspartate with glutamate at the third posit (...truncated)