Synergy Pharmaceuticals, Inc., a biopharmaceutical company focused on the development of new drugs to treat gastrointestinal disorders and diseases, has reported that its investigational oral drug, plecanatide for the treatment of chronic idiopathic constipation (CIC), was well tolerated and met the primary and key secondary endpoints of a phase IIb/III clinical study. Full study results will be presented at a major scientific meeting this year.
The randomized, double-blind, placebo-controlled, repeat-dose, dose-ranging study was designed to determine whether plecanatide could increase the number of complete spontaneous bowel movements (CSBM's) and impact other parameters such as stool consistency, straining and time to first bowel movement in patients with CIC. The 12-week study, which included 951 CIC patients at 113 clinical sites in the United States, evaluated 3 doses of plecanatide (0.3, 1.0, 3.0 mg) plus a placebo arm.
Evidence of increasing efficacy was seen at increasing dose levels. Notably, the 3 mg dose in the current trial demonstrated a 19% (p=0.009) overall responder rate (vs. placebo of 10.7%), as well as demonstrating a mean increase in CSBMs over the 12-week treatment period of 2.13 (p<0.001). In addition, statistically significant improvements were seen in key secondary endpoints. The incidence of diarrhea at 3 mg was observed to be 9.7% (vs. placebo incidence of 1.3%).
Plecanatide is a member of a new class of essentially non-systemic drugs, referred to as guanylate cyclase C (GC-C) agonists, which are currently in development to treat CIC and IBS-C. Plecanatide is a synthetic analog of uroguanylin, a natriuretic hormone that regulates ion and fluid transport in the GI tract. Orally-administered plecanatide binds to and activates GC-C receptors expressed on epithelial cells lining the GI mucosa, resulting in activation of the cystic fibrosis transmembrane conductance regulator (CFTR), and leading to augmented flow of chloride and water into the lumen of the gut. Activation of the GC-C receptor pathway is believed to facilitate bowel movement as well as producing other beneficial physiological responses including improvement in abdominal pain and inflammation. In animal models, oral administration of plecanatide promotes intestinal secretion and also ameliorates GI inflammation.
"We look forward to presenting the full results of this clinical study, which confirmed the efficacy and safety of plecanatide," said Dr. Gary S. Jacob, president and CEO of Synergy Pharmaceuticals. "This trial also represents a major milestone for Synergy. We pioneered the study of analogs of the human hormone uroguanylin to treat gastrointestinal disorders in an effort to identify an agent that would normalize bowel movements with minimal diarrhoea."
"Based on the results of this trial, we are convinced that plecanatide has the potential to be a safe, effective and much-needed new treatment for millions of patients who are living with chronic constipation," Dr. Jacob added.
The study, which concluded late, last month, was part of an ongoing CIC development program for plecanatide. Synergy is also conducting a Phase IIb study to assess plecanatide in the treatment of irritable bowel syndrome with constipation (IBS-C). In addition, a Phase I study was recently completed with Synergy's second GC-C agonist, known as SP-333, for the treatment of inflammatory bowel diseases.
Chronic constipation is the most common digestive complaint in the United States and the world. About 15%, or 45 million people, suffer from chronic constipation in the US, with a similar prevalence in other developed countries. Although chronic constipation affects both men and women of every age, it disproportionately impacts women as well as the elderly, a large and growing population.
Current treatments provide temporary relief, but because they fail to address the underlying causes of chronic constipation, they do not normalize patients' bowel function. Such treatments are also associated with unpleasant side effects, the most common of which is diarrhea, causing patients to see-saw between extremes. As a result, most doctors and their patients are dissatisfied with current treatments for chronic constipation.