Plecanatide, an Oral Guanylate Cyclase C Agonist Acting Locally in the Gastrointestinal Tract, Is Safe and Well-Tolerated in Single Doses
- Kunwar ShailubhaiAffiliated withSynergy Pharmaceuticals, Inc. Email author
- , Stephen ComiskeyAffiliated withSynergy Pharmaceuticals, Inc.
- , John A. FossAffiliated withSynergy Pharmaceuticals, Inc.
- , Rong FengAffiliated withSynergy Pharmaceuticals, Inc.
- , Laura BarrowAffiliated withSynergy Pharmaceuticals, Inc.
- , Gail M. ComerAffiliated withSynergy Pharmaceuticals, Inc.
- , Gary S. JacobAffiliated withSynergy Pharmaceuticals, Inc.
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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.
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.
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.
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.
KeywordsGuanylate cyclase C (GC-C) Cystic fibrosis transmembrane conductance regulator (CFTR) Gastrointestinal (GI) Uroguanylin (UG) Cyclic GMP (cGMP) Chronic functional constipation (CC) Irritable bowel syndrome-constipation predominant (IBS-C)
- Plecanatide, an Oral Guanylate Cyclase C Agonist Acting Locally in the Gastrointestinal Tract, Is Safe and Well-Tolerated in Single Doses
Digestive Diseases and Sciences
Volume 58, Issue 9 , pp 2580-2586
- Cover Date
- Print ISSN
- Online ISSN
- Springer US
- Additional Links
- Guanylate cyclase C (GC-C)
- Cystic fibrosis transmembrane conductance regulator (CFTR)
- Gastrointestinal (GI)
- Uroguanylin (UG)
- Cyclic GMP (cGMP)
- Chronic functional constipation (CC)
- Irritable bowel syndrome-constipation predominant (IBS-C)
- Industry Sectors
- Author Affiliations
- 1. Synergy Pharmaceuticals, Inc., 3805 Old Easton Road, Doylestown, PA, 18902, USA
- 3. 3805 Old Easton Road, Doylestown, PA, 18903, USA
- 2. Synergy Pharmaceuticals, Inc., 420 Lexington Avenue, Suite 1609, New York, NY, 10170, USA