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Plecanatide, an Oral Guanylate Cyclase C Agonist Acting Locally in the Gastrointestinal Tract, Is Safe and Well-Tolerated in Single Doses

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Abstract

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.

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Acknowledgments

Authors are grateful to ClinPharm Consulting, LLC (Research Triangle Park, NC, USA) for their assistance in preparation of this manuscript. This study was funded by Synergy Pharmaceuticals.

Conflict of interest

All authors are employees of Synergy Pharmaceuticals, Inc.

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Authors and Affiliations

  1. Synergy Pharmaceuticals, Inc., 3805 Old Easton Road, Doylestown, PA, 18902, USA

    Kunwar Shailubhai, Stephen Comiskey, John A. Foss, Rong Feng & Gail M. Comer

  2. Synergy Pharmaceuticals, Inc., 420 Lexington Avenue, Suite 1609, New York, NY, 10170, USA

    Laura Barrow & Gary S. Jacob

  3. 3805 Old Easton Road, Doylestown, PA, 18903, USA

    Kunwar Shailubhai

Authors
  1. Kunwar Shailubhai
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  2. Stephen Comiskey
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  3. John A. Foss
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  4. Rong Feng
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  5. Laura Barrow
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  6. Gail M. Comer
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  7. Gary S. Jacob
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Corresponding author

Correspondence to Kunwar Shailubhai.

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Shailubhai, K., Comiskey, S., Foss, J.A. et al. Plecanatide, an Oral Guanylate Cyclase C Agonist Acting Locally in the Gastrointestinal Tract, Is Safe and Well-Tolerated in Single Doses. Dig Dis Sci 58, 2580–2586 (2013). https://doi.org/10.1007/s10620-013-2684-z

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  • DOI: https://doi.org/10.1007/s10620-013-2684-z

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