The Effect of Acid Suppression Therapy on the Safety and Efficacy of Plecanatide: Analysis of Randomized Phase III Trials.

PURPOSE: Plecanatide, an approved therapy for chronic idiopathic constipation (CIC) and irritable bowel syndrome with constipation, is an analogue of uroguanylin that replicates its pH-sensitive activity and binds to guanylate cyclase-C receptors expressed on intestinal epithelium, stimulating fluid secretion. This analysis explores concomitant acid suppression therapy's effect on the efficacy and safety of plecanatide in adults with CIC. METHODS: Data from 2 placebo-controlled, 12-week Phase III trials of plecanatide in CIC were pooled. Patients were randomized to receive placebo, plecanatide 3 mg, or plecanatide 6 mg. The primary endpoint was the durable, overall complete spontaneous bowel movement (CSBM) response rate (defined as ≥3 CSBMs in a given week and ≥1 CSBM increase from baseline within a week for ≥9 of 12 weeks, including ≥3 of the last 4 treatment weeks). Safety was also evaluated. Results were stratified by concomitant use or nonuse of acid suppression therapy. FINDINGS: Of the pooled intent-to-treat population, 338 of 2639 patients (12.8%) received concomitant acid suppression medication. Efficacy response rates in patients using acid suppressors were 23.6% with plecanatide 3 mg (P = 0.001 vs placebo), 22.1% with plecanatide 6 mg (P = 0.002), and 7.6% with placebo. Responses were similar in patients not using acid suppressors: 20.4% (plecanatide 3 mg, P < 0.001), 19.6% (plecanatide 6 mg, P < 0.001), and 12.1% (placebo). Serious adverse events were experienced by 3.3% of patients who used concomitant acid suppression and 1.0% of those who did not. IMPLICATIONS: Plecanatide treatment is safe and efficacious for patients with CIC when administered with concomitant acid suppression medication. CLINICALTRIALS: gov identifiers: NCT02122471 and NCT01982240.

Plecanatide Is Effective and Safe in the Treatment for Chronic Idiopathic Constipation: Results of a Phase II Trial.

BACKGROUND: 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. AIMS: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: Plecanatide is a well-tolerated treatment that relieved the symptoms of CIC with a relatively low incidence of diarrhea.

Plecanatide for the treatment of chronic idiopathic constipation in adult patients.

Introduction. Chronic idiopathic constipation (CIC) is a functional gastrointestinal disorder that is associated with an increased healthcare cost and an abnormally poor quality of life. Plecanatide is a natural analog to the peptide agonist of the guanylate cyclase-C (GC-C) receptor, uroguanylin. The conversion of guanosine 5-triphosphate to cyclic guanosine monophosphate results in an increased bowel fluid secretion. Plecanatide is a promising new agent for CIC unresponsive to current therapeutic regimes.Areas covered. A comprehensive online search of Medline and the Science Citation Index was made using the keywords 'plecanatide', 'guanylate cyclase-C agonists', and 'constipation', in various combinations. We reviewed the pharmacodynamics, pharmacokinetics, and metabolism of this agent, and the most significant studies regarding the clinical efficacy and safety of plecanatide in CIC therapy.Expert opinion. Experimental studies showed that plecanatide was significantly better than placebo in reducing CIC severity, straining, stool consistency, bowel movements and quality of life. Apart from limited cases of diarrhea, no serious adverse events were reported. However, few data are available on its long-term safety. Furthermore, patients' affordability of plecanatide can be limited by its costs. Finally, this new agent with a different way of action can be proposed in patients refractory to common therapy.

Benefit-Risk Assessment of Plecanatide in the Treatment of Chronic Idiopathic Constipation.

Plecanatide, a uroguanylin analog, activates the guanylate cyclase C receptors in the epithelial lining of the gastrointestinal tract in a pH-dependent fashion initiating (1) the conversion of intracellular guanosine triphosphate to cyclic guanosine monophosphate, which increases the activity of the cystic fibrosis transmembrane conductance regulator to increase chloride and bicarbonate secretion into the intestinal lumen and (2) a decrease in activity of the sodium-hydrogen ion exchanger. The resulting ionic shifts cause an increase in lumenal fluid to facilitate digestion. Plecanatide has been approved by the FDA for use in chronic idiopathic constipation (CIC) and irritable bowel syndrome with constipation. This manuscript is a critical assessment of the therapeutic efficacy and potential risks associated with the use of plecanatide in CIC. The discussion of CIC as a clinical and investigative disorder focuses on the importance of this problem as well and the difficulties involved in clinical management and scholarly investigation of a symptom arising from multiple pathophysiologic mechanisms. Clinical data from studies of recently approved drugs for CIC are utilized to construct a platform for thoughtful understanding of CIC and of how changes in investigation guidelines influence the interpretation of study data and guide symptom management. Plecanatide is a safe and effective medication for the management of adults with CIC.

Efficacy, safety, and tolerability of plecanatide in patients with irritable bowel syndrome with constipation: results of two phase 3 randomized clinical trials.

OBJECTIVES: 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). METHODS: 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). RESULTS: 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). CONCLUSIONS: Plecanatide significantly improved both abdominal pain and constipation symptoms of IBS-C with minimal associated side effects and high levels of tolerability.

Efficacy and Tolerability of Guanylate Cyclase-C Agonists for Irritable Bowel Syndrome with Constipation and Chronic Idiopathic Constipation: A Systematic Review and Meta-Analysis.

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 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. 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.

Efficacy and safety of plecanatide in treating constipation predominant irritable bowel syndrome.

INTRODUCTION: 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.

Safety and tolerability of plecanatide in patients with chronic idiopathic constipation: long-term evidence from an open-label study.

OBJECTIVE: 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). METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

A Human Study to Evaluate Safety, Tolerability, and Cyclic GMP Activating Properties of Cenderitide in Subjects With Stable Chronic Heart Failure.

Cenderitide is a novel designer natriuretic peptide (NP) composed of C-type natriuretic peptide (CNP) fused to the C-terminus of Dendroaspis natriuretic peptide (DNP). Cenderitide was engineered to coactivate the two NP receptors, particulate guanylyl cyclase (pGC)-A and -B. The rationale for its design was to achieve the renal-enhancing and antifibrotic properties of dual receptor activation, but without clinically significant hypotension. Here we report the first clinical trial on the safety, tolerability, and cyclic guanosine monophosphate (cGMP) activating properties of Cenderitide in subjects with stable heart failure (HF). Four-hour infusion of Cenderitide was safe, well-tolerated, and significantly increased plasma cGMP levels and urinary cGMP excretion without adverse effects with no change in blood pressure. Thus, Cenderitide has a favorable safety profile and expected pharmacological effects in stable human HF. Our results support further investigations of Cenderitide in HF as a potential future cGMP-enhancing therapeutic strategy.

New pharmacological treatment options for chronic constipation.

INTRODUCTION: A number of new medications were recently demonstrated to be more effective than placebo in treating chronic constipation, including the intestinal chloride channel activator lubiprostone, the prokinetic selective 5-HT4 receptor agonist prucalopride and the guanylate cyclase-C agonist linaclotide. Recent publications have also revisited traditional laxatives like PEG. Moreover, a number of pharmacological treatments are in development and these include another guanylate cyclase-C agonist, plecanatide and an ileal bile acid transporter inhibitor, elobixibat. AREAS COVERED: This review focuses on the pharmacology, efficacy and safety profile of prucalopride, linaclotide, plecanatide and elobixibat. EXPERT OPINION: The possible present or future clinical application of prucalopride, linaclotide, plecanatide and elobixibat in both chronic constipation and irritable bowel syndrome with constipation is reported, and some considerations on the possible role of PEG taking into account recent literature are advanced.

Plecanatide, an oral guanylate cyclase C agonist acting locally in the gastrointestinal tract, is safe and well-tolerated in single doses.

PURPOSE: Plecanatide, an analogue of uroguanylin, activates the guanylate cyclase C (GC-C) receptor found on the GI mucosal epithelial cells, leading to secretion of fluid, facilitating bowel movements. Plecanatide is being investigated as a potential treatment for constipating GI disorders. The aim of this investigation was to assess the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of single doses of plecanatide in healthy volunteers. METHODS: A total of 72 healthy volunteers at a single site were randomized in 9 cohorts to receive oral plecanatide or placebo from 0.1 to 48.6 mg. Plasma PK samples were collected pre-dose and post-dose. PD assessments included time to first stool, stool frequency, and stool consistency using the Bristol Stool Form Scale. All adverse events were documented. RESULTS: Plecanatide was safe and well-tolerated at all dose levels. A total of 17 of 71 subjects (23.9%) reported 25 treatment-emergent adverse events (TEAEs) during the study. The number of TEAEs reported by subjects who received plecanatide or placebo was comparable (24.5 vs. 22.2%, respectively). There were no dose-related increases in TEAEs or any SAEs reported. No measurable systemic absorption of oral plecanatide was observed at any of the oral doses studied, utilizing an assay sensitive down to 1 ng/mL. CONCLUSIONS: Plecanatide, an oral GC-C agonist, acting locally within the GI tract without measurable systemic exposure, was safe and well-tolerated in single doses up to 48.6 mg. The study was not powered for statistical analyses, but trends in PD parameters supported continued clinical development.

CNGA3: a target of spinal nitric oxide/cGMP signaling and modulator of inflammatory pain hypersensitivity.

A large body of evidence indicates that nitric oxide (NO) and cGMP contribute to central sensitization of pain pathways during inflammatory pain. Here, we investigated the distribution of cyclic nucleotide-gated (CNG) channels in the spinal cord, and identified the CNG channel subunit CNGA3 as a putative cGMP target in nociceptive processing. In situ hybridization revealed that CNGA3 is localized to inhibitory neurons of the dorsal horn of the spinal cord, whereas its distribution in dorsal root ganglia is restricted to non-neuronal cells. CNGA3 expression is upregulated in the superficial dorsal horn of the mouse spinal cord and in dorsal root ganglia following hindpaw inflammation evoked by zymosan. Mice lacking CNGA3 (CNGA3(-/-) mice) exhibited an increased nociceptive behavior in models of inflammatory pain, whereas their behavior in models of acute or neuropathic pain was normal. Moreover, CNGA3(-/-) mice developed an exaggerated pain hypersensitivity induced by intrathecal administration of cGMP analogs or NO donors. Our results provide evidence that CNGA3 contributes in an inhibitory manner to the central sensitization of pain pathways during inflammatory pain as a target of NO/cGMP signaling.

Novel therapeutic targets for the treatment of heart failure.

Despite considerable therapeutic advances, heart failure remains a medical and socioeconomic problem. Thus, there is a compelling need for new drugs that could improve clinical outcomes. In recent years, new potential therapeutic targets that are involved in the pathogenesis of heart failure have been identified, and new drugs are currently under investigation. A repeated finding is that the positive results that have been observed in preclinical studies and Phase II trials are not always confirmed in Phase III studies. This Review analyses the new therapeutic targets (for example, ventricular remodelling, renin-angiotensin-aldosterone system activation, defects in Ca(2+) cycling, and so on), the mechanism of action, efficacy and future perspectives of new drugs that are currently under development for the treatment of heart failure, and the possible explanations for the discrepancy between Phase II and Phase III trials.

The role of natriuretic peptide administration in cardiovascular surgery-associated renal dysfunction: a systematic review and meta-analysis of randomized controlled trials.

OBJECTIVE: Randomized controlled trials involving natriuretic peptide administration in the perioperative cardiovascular setting have shown inconsistent effects for renal and other clinical endpoints. The authors aimed to systematically review these trials to ascertain the role of natriuretic peptide administration in the management of cardiovascular surgery-associated renal dysfunction. DESIGN: A systematic review and meta-analysis. SETTING: A hospital. PARTICIPANTS: A total of 934 adult patients from 13 randomized controlled trials. INTERVENTIONS: Natriuretic peptides. MEASUREMENTS AND MAIN RESULTS: MEDLINE, EMBASE, Cochrane Renal Health Library, and Google scholar were searched independently by 2 reviewers for randomized controlled studies comparing natriuretic peptides with placebo in patients undergoing cardiovascular surgeries. Studies reporting data on renal outcomes were included. Two reviewers independently assessed the studies for eligibility and extracted the relevant data. The pooled estimate showed that natriuretic peptide administration was associated with a reduction in acute renal failure requiring dialysis (odds ratio = 0.32 [0.15-0.66]) and a statistically nonsignificant trend toward a reduction in 30-day or in-hospital mortality (odds ratio = 0.59 [0.31-1.12]). Other benefits were a reduction in postsurgery peak serum creatinine levels, an increase in postsurgery urine output, a reduction in postsurgery serum aldosterone levels, and reductions in mechanical ventilation duration and intensive care unit stay length. Most of the included studies addressing this topic were small and lacked adequate power to reach statistical significance on their own. CONCLUSIONS: Current literature analyzing studies evaluating the administration of natriuretic peptides in cardiovascular surgery may be associated with significant improvements in clinical outcomes. Given the limitations of meta-analysis, these observations need to be confirmed in a larger, adequately powered, prospective multicenter study.

Effect of nesiritide infusion duration on renal function in acutely decompensated heart failure patients.

BACKGROUND: Nesiritide, a synthetic B-type natriuretic peptide, is used for the treatment of patients with acutely decompensated heart failure. Although nesiritide has been reported to worsen renal function, as reflected by significant elevations in serum creatinine (SCr), the impact of infusion duration on renal function has not been evaluated. OBJECTIVE: To investigate the effect of nesiritide infusion duration (< 24 h vs > or = 24 h) on worsening renal function in patients with acutely decompensated heart failure. METHODS: Medical records of hospitalized patients receiving nesiritide were retrospectively reviewed, and 84 consecutive charts of patients with acute decompensated heart failure and available renal function tests were identified for the study. SCr and blood urea nitrogen (BUN) were documented at baseline and during infusion. Worsening renal function was defined as an increase in SCr of 0.5 mg/dL or more or BUN 10 mg/dL or more from baseline. RESULTS: Univariate analysis showed a significant association between nesiritide infusion duration of 24 hours or more (26.1% vs 2.6%; p = 0.003), high diuretic doses (61.5% vs 32.4%; p = 0.045), and baseline SCr (2.0 +/- 0.8 vs 1.5 +/- 0.7 mg/dL; p = 0.04) with increases in SCr of 0.5 mg/dL or more. However, only infusion duration of 24 hours or more was statistically significant on multivariate analysis, after adjusting for baseline SCr (OR 10.46; 95% CI 1.26 to 86.72; p = 0.03). Longer duration of infusion was also a consistent variable in both univariate and multivariate analysis when elevated BUN was evaluated (34.8 vs 2.6%; p < 0.001 and OR 19.73; 95% CI 2.47 to 157.46; p = 0.005, respectively). CONCLUSIONS: Nesiritide infusion of 24 hours or more appears to be significantly associated with elevated markers of worsening renal function in patients with acutely decompensated heart failure compared with infusion of less than 24 hours; however, prospective studies are needed to corroborate this finding.