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

Philip B Miner Jr, William D Koltun, Gregory J Wiener, Marianela De La Portilla, Blas Prieto, Kunwar Shailubhai, Mary Beth Layton, Laura Barrow, Leslie Magnus, Patrick H Griffin, Philip B Miner Jr, William D Koltun, Gregory J Wiener, Marianela De La Portilla, Blas Prieto, Kunwar Shailubhai, Mary Beth Layton, Laura Barrow, Leslie Magnus, Patrick H Griffin

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.

Conflict of interest statement

Guarantor of the article: Leslie Magnus, MD.

Specific author contributions: Study concept: Drs Miner and Shailubhai; study design: Drs Miner, Barrow, and Griffin; data acquisition: Drs Miner, Koltun, Wiener, De La Portilla, and Prieto; data analysis: Drs Miner, Barrow, and Griffin and Ms Layton; data interpretation, drafting of the manuscript, critical revision of the manuscript for important intellectual content, and final approval of the manuscript: all authors.

Financial support: Funding for this trial and manuscript support were provided by Synergy Pharmaceuticals Inc. Synergy Pharmaceuticals Inc. also provided the plecanatide and placebo used for the study.

Potential competing interests: Drs Shailubhai, Barrow, Magnus, and Griffin and Ms Layton are employees and stockholders of Synergy Pharmaceuticals Inc. Drs Miner, Koltun, Wiener, De La Portilla, and Prieto were study investigators paid for their participation in this clinical trial. Dr Koltun has received funding for either advisory boards or speaking from the following institutions: Synergy Pharmaceuticals, Symiomix Theraputics, Ferring Pharmaceuticals, Enteris Pharmaceuticals, and Shionogi Inc. Dr Miner has received funding for advisory board meetings. Transcript Profiling: does not apply.

Figures

Figure 1
Figure 1
Disposition of the study population.
Figure 2
Figure 2
(a) Percentage of patients in each treatment group assessed as a durable overall complete spontaneous bowel movement (CSBM) responder in the intention-to-treat (ITT) population, the primary efficacy endpoint. Durable overall CSBM responders were defined as patients who fulfilled both ≥3 CSBMs per week and an increase of ≥1 CSBM from baseline, in the same week, for ≥9 of the 12 treatment weeks, including ≥3 of the last 4 weeks of treatment. Error bars represent 95% confidence intervals. (b) Weekly evolution of the percentage of CSBM responders in the ITT population. Values are LS means; bars represent 95% confidence intervals. *P=0.001, **P=0.003, †P=0.005, ‡P=0.011 vs. placebo.
Figure 3
Figure 3
(a) Changes from baseline in weekly complete spontaneous bowel movement (CSBM) frequency. Values are least squares (LS) mean; bars represent s.e. *P<0.001 vs. placebo. (b) Changes from baseline in mean weekly spontaneous bowel movement (SBM) frequency. Values are LS mean; bars represent s.e. *P<0.001 vs. placebo. (c) Percentage of patients experiencing a CSBM or SBM within 24 h after the first dose of study medication. *P<0.001 vs. placebo.
Figure 4
Figure 4
(a) Changes from baseline in weekly stool consistency. Stool consistency was measured by the Bristol Stool Form Scale (BSFS). Values are least squares (LS) mean; bars represent s.e. *P<0.001 vs. placebo. (b) Weekly BSFS scores during the study. Values are LS mean.

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