Patrick Griffin

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

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.

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.

Randomized clinical trial: efficacy and safety of plecanatide in the treatment of chronic idiopathic constipation:

Background: Plecanatide, with the exception of a single amino acid replacement, is identical to human uroguanylin and is approved in the United States for adults with chronic idiopathic constipation (CIC). This double-blind, placebo-controlled, phase III study evaluated the efficacy and safety of plecanatide versus placebo in CIC. Methods: Adults meeting modified Rome III CIC criteria were randomized to plecanatide 3 mg (n = 443), 6 mg (n = 449), or placebo (n = 445). Patients recorded bowel movement (BM) characteristics [including spontaneous BMs (SBMs) and complete SBMs (CSBMs)] and rated CIC symptoms in daily electronic diaries. The primary endpoint was the percentage of durable overall CSBM responders (weekly responders for ⩾9 of 12 treatment weeks, including ⩾3 of the last 4 weeks). Weekly responders had ⩾3 CSBMs/week and an increase of ⩾1 CSBM from baseline for the same week. Results: A significantly greater percentage of durable overall CSBM responders resulted with each plecanatide dose compared with placebo (3 mg = 20.1%; 6 mg = 20.0%; placebo = 12.8%; p = 0.004 each dose). Over the 12 weeks, plecanatide significantly improved stool consistency and stool frequency. Significant increases in mean weekly SBMs and CSBMs began in week 1 and were maintained through week 12 in plecanatide-treated patients. Adverse events were mostly mild/moderate, with diarrhea being the most common (3 mg = 3.2%; 6 mg = 4.5%; placebo = 1.3%). Conclusions: Plecanatide resulted in a significantly greater percentage of durable overall CSBM responders and improved stool frequency and secondary endpoints. Plecanatide was well tolerated; the most common AE, diarrhea, occurred in a small number of patients. [ClinicalTrials.gov identifier: NCT02122471]

Efficacy and Safety of Plecanatide in Patients with Irritable Bowel Syndrome with Constipation: Results from 2 Randomized, Double-Blind, Placebo-Controlled Clinical Trials

Synergy will also present findings from the new BURDEN-CIC (Better Understanding and Recognition of the Disconnects, Experiences, and Needs of Patients with Chronic Idiopathic Constipation) study, which evaluated the experiences and perceptions of people living with CIC and healthcare providers who regularly treat this condition. In addition, the company will present four posters, which include two that have been recognized as Posters of Distinction.

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

Abstract 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.

Comment on Meta Analysis by Shah et al.

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Long-term treatment with plecanatide was safe and tolerable in patients with irritable bowel syndrome with constipation

Abstract Objective: This open-label, multi-center, fixed-dose study (NCT02706483) evaluated the long-term safety and tolerability of plecanatide for the treatment of adults with irritable bowel syndrome with constipation (IBS-C). Methods: Safety and tolerability of once-daily plecanatide 6 mg for up to 53 weeks was assessed in patients with IBS-C who either had been enrolled in one of the phase 3 studies or were study-naïve but met eligibility criteria of the double-blind studies. Safety was assessed by treatment-emergent adverse events (AEs). Patient-reported questionnaires assessed overall IBS symptoms, treatment satisfaction, and desire for treatment continuation. No dose adjustments or treatment interruptions were permitted during the study. Results: Of the 2272 patients enrolled, 1842 (81.1%) completed the study. AEs were experienced by 27.3%, and 4.3% discontinued due to an AE. Most AEs were mild or moderate (90.3%). The incidence of diarrhea, the most commonly reported AE, was low (6.7%), and declined in frequency over time. Diarrhea was the most common cause of AE-related withdrawals (2.7% of patients). At week 53 or end of treatment, 88.2% of patients reported “significant” or “moderate” relief, 72.4% were “very” or “quite” satisfied with treatment, and 76.6% were “very” or “quite” likely to continue treatment. Conclusions: Plecanatide 6 mg was safe and well tolerated in patients with IBS-C treated for up to 53 weeks, with an overall safety profile similar to the 12-week IBS-C studies. Patients reported high rates of relief and satisfaction with treatment, and interest in continuing therapy. Trial registration: ClinicalTrials.gov identifier: NCT02706483.

Effects of the CCK1-receptor antagonist dexloxiglumide on nippostrongylus brasiliensis-altered jejunal sensitivity in rats

Effects of the CCK 1 -receptor antagonist dexloxiglumide on nippostrongylus brasiliensis -altered jejunal sensitivity in rats

Effects of endogenous cholecystokinin on gastric emptying and tolerance to a liquid volume load in humans

Effects of endogenous cholecystokinin on gastric emptying and tolerance to a liquid volume load in humans