Phase II Clinical Evaluation of SP-304, a Guanylate Cyclase-C Agonist, for Treatment of Chronic Constipation: 1322

Purpose: Uroguanylin (UG) and guanylin (GN) are physiological agonists of guanylate cyclase-C (GC-C) receptors. Activation of GC-C receptor promotes intracellular synthesis of cGMP and subsequent activation of the cystic fibrosis transmembrane conductance regulator (CFTR), resulting in fluid and bicarbonate secretion into the intestinal lumen. Optimum volume of fluid secretion in the proximal intestine is critical for normal bowel movement and for complete defecation. Thus, oral treatment with a GC-C agonist is expected to promote spontaneous bowel movement (SBM) and to reduce abdominal pain and bloating. SP-304 is a superior analog of UG that appears to mimic physiological functions of UG in the GI tract. In T84 cell assays, SP-304 exhibits an 8-fold higher binding affinity to GC-C receptors than UG. The present trial is designed to evaluate efficacy and safety in chronic constipation (CC) patients. Methods: This phase II clinical study (double-blind, placebo-controlled, randomized with cohorts of 0.3, 1, 3 and 9 mg repeated daily dose for 14-days) in CC patients has completed enrollment and dosing of the first 2 of 4 cohorts. CC patients are being evaluated primarily for safety and efficacy of SP-304. Bowel habits (stool frequency, consistency, straining, time to first BM and completeness of evacuation) and degree of abdominal discomfort were monitored daily using patient diary. Patient reported outcomes of severity of constipation and overall relief were evaluated weekly. Results: A total of 14 sites open in the U.S. are presently evaluating SP-304 in CC patients. Total enrollment for the study is 80 patients. At present, 40 patients have been dosed, and the 1.0 mg and 3.0 mg dosage arms have been completed. Patients are currently being dosed at 9 mg. We recently added a fourth dosage arm of 0.3 mg to the study. To date, no unexpected safety issues have been reported and based on the blinded review some patients in each cohort are experiencing improvements in bowel function. Phase II clinical data will be discussed to highlight pharmacodynamic and safety profile of SP-304 in CC patients. Conclusion: GC-C agonists are rapidly emerging as a new class of drug candidates to treat GI disorders. UG and Escherichia coli heat-stable (ST) toxins bind to a common GC-C receptor to stimulate fluid secretion in the gut. The present study demonstrates that SP-304 possesses a similar clinical profile as other GC-C agonists, based on the early clinical observations. Complete phase II clinical data on safety & efficacy in CC patients will be discussed. Disclosure: Dr Shailubhai-Employee Dr Talluto-Employee Dr Steve Comiskey-Employee Dr John Foss-Employee Dr Alan Joslyn-consultant Dr Gary Jacob-Employee.