Synergy Pharmaceuticals Inc., a developer of new drugs to treat gastrointestinal (GI) disorders and diseases, has successfully completed phase I single-ascending-dose clinical trial of SP-333, a guanylate cyclase C (GC-C) agonist designed to treat ulcerative colitis (UC) and other GI diseases. 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.

This study is designed as a placebo-controlled, dose-escalating, single-dose trial in healthy adult volunteers, primarily focused on exploring the safety profile of SP-333. Eight cohorts were dosed, ranging from 0.1 to 60 mg of SP-333. There were no serious or unexpected adverse events in this study. Importantly, SP-333 exhibited gastrointestinal pharmacodynamic characteristics that were anticipated based on its GC-C receptor agonist activity. A multi-dose, dose-escalation trial in volunteers is planned to start in January.

"We specifically designed SP-333 to have superior stability against proteolytic degradation which normally occurs in intestinal fluid designed to break down proteins and peptides as part of the normal digestive process," said Dr Kunwar Shailubhai, chief scientific officer of Synergy Pharmaceuticals. "SP-333, to our knowledge, represents the most proteolytically stable analog of uroguanylin - the physiological agonist of GC-C - ever developed, and is designed to remain biologically active in the gut, a factor we consider ideal for its potential use in treating UC."

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.

When 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.

SP-333 has been found to exhibit potent anti-inflammatory activity in several animal models of experimental colitis, through a mechanism-of-action involving inhibition of NF-kB to suppress production of pro-inflammatory cytokines.

Ulcerative Colitis (UC) is 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.