Synergy Pharmaceuticals Inc., a developer of new drugs to treat gastrointestinal disorders, has initiated oral dosing of healthy adult volunteers in a phase I clinical trial of SP-333, a guanylate cyclase C (GC-C) agonist designed to treat ulcerative colitis (UC).  SP-333 has exhibited potent anti-inflammatory activity in animal studies of colitis, displaying a novel mechanism-of-action that the company believes can provide a new way to treat UC patients with mild to moderate disease.

The present trial is designed as a placebo-controlled, dose-escalating, single-dose study in healthy adult volunteers that is primarily focused on exploring the safety profile of SP-333. A multi-dose, dose-escalation trial is planned for early 2013.

"Disruption of intestinal barrier function resulting in mucosal inflammation and immune activation is one of the primary causes of the pathogenesis of inflammatory bowel diseases such as ulcerative colitis," said Dr. Kunwar Shailubhai, chief scientific officer of Synergy Pharmaceuticals.  "Oral treatment with SP-333 to augment intestinal GC-C activation represents a novel approach for restoring mucosal barrier function and suppressing inflammation. In experimental models of colitis in mice, we have found that treatment with SP-333 ameliorates GI inflammation, likely through inhibition of NF-kappa B signaling to suppress production of pro-inflammatory cytokines."

SP-333 is a synthetic analog of uroguanylin, a natriuretic peptide hormone which is normally produced in the lumen of the intestinal tract. Deficiency of uroguanylin is likely to be one of the primary reasons associated with formation of polyps as well as debilitating and difficult-to-treat GI inflammatory disorders such as ulcerative colitis and Crohn's disease. Orally-administered SP-333 binds to and activates the GC-C receptor expressed on epithelial cells lining the GI mucosa, resulting in stimulation of cyclic GMP in target tissues. SP-333 has been found to be highly stable against proteolysis in simulated intestinal fluid for up to 24 hours. Its enhanced stability makes this peptide an extremely potent GC-C agonist in animal studies in mice and monkeys, promoting bowel movement in monkeys, and ameliorating GI inflammation in mice, respectively.

More than 500,000 Americans are afflicted with ulcerative colitis (UC), a type of Inflammatory Bowel Disease (IBD) that causes chronic inflammation of the colon. Along with Crohn's disease, the other major form of IBD, ulcerative colitis is painful and debilitating. Patients with UC are at increased risk for colon cancer and may ultimately require surgical removal of the colon. There is currently no medical cure for ulcerative colitis.   Long-term remission with current treatments is limited.   Therefore, there is a need for new treatment approaches to treat patients with ulcerative colitis.