Phase I double-blind, placebo-controlled trial of dolcanatide (SP-333) 27 mg to explore colorectal bioactivity in healthy volunteers

Abstract

Guanylyl cyclase C (GUCY2C) is a tumor-suppressing receptor silenced by loss of expression of the luminocrine hormones guanylin and uroguanylin early in colorectal carcinogenesis. This observation suggests oral replacement with a GUCY2C agonist may be an effective targeted chemoprevention agent. Previous studies revealed that linaclotide, an oral GUCY2C agonist formulated for gastric release, did not persist to activate guanylyl cyclase signaling in the distal rectum. Dolcanatide is an investigational oral uroguanylin analog, substituted with select D amino acids, for enhanced stability and extended persistence to activate GUCY2C in small and large intestine. However, the ability of oral dolcanatide to induce a pharmacodynamic (PD) response by activating GUCY2C in epithelial cells of the colorectum in humans remains undefined. Here, we demonstrate that administration of oral dolcanatide 27 mg daily for 7 d to healthy volunteers did not activate GUCY2C, quantified as accumulation of its product cyclic GMP, in epithelial cells of the distal rectum. These data reveal that the enhanced stability of dolcanatide, with persistence along the rostral-caudal axis of the small and large intestine, is inadequate to regulate GUCY2C across the colorectum to prevent tumorigenesis. These results highlight the importance of developing a GUCY2C agonist for cancer prevention formulated for release and activity targeted to the colorectum.

Keywords: Colorectum; colorectal cancer chemoprevention; cyclic GMP; dolcanatide; guanylyl cyclase C.

Figure 1.

CONSORT flow diagram of subject progress through the clinical trial

Figure 2.

Differences in mean rectal cGMP following seven days of treatment. Cyclic GMP was quantified, and differences calculated, as described in Methods

Figure 3.

Pharmacodynamic (PD) Response Rate for 24 subjects evaluable for the primary endpoint. Cyclic GMP was quantified, and PD responses calculated, as described in Methods. A threshold rate of 1.645 (horizontal blue line) was taken as a positive response to dolcanatide

Figure 4.

GUCY2C Expression Before and After Treatment. GUCY2C mRNA was quantified by RT-PCR as outlined in Materials and Methods and normalized to glyceraldehyde 3-phosphate dehydrogenase (GAPDH) mRNA expression