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Efficacy and Safety of Plecanatide in Patients with Irritable Bowel Syndrome with Constipation: Results from 2 Randomized, Double-Blind, Placebo-Controlled Clinical Trials
Ronald Fogel1, Spencer D. Dorn2, Richard Krause3, Paul Eng4, Robert KIrshoff5, Anhthu Nguyen5, Patrick Griffin5
1Clinical Research Institute of Michigan, Chesterfield, MI; 2Division of Gastoenterology and Hepatology, University of North Carolina, Chapel Hill, NC; 3WR-ClinSearch, Chattanooga, TN; 4Synergy Pharmaceuticals Inc. (Former Employee), New York, NY; 5Synergy Pharmaceuticals Inc., New York, NY.
Background: Irritable bowel syndrome (IBS) is a chronic gastrointestinal disorder characterized by recurrent abdominal pain and changes in stool frequency or consistency. Many patients suffer from the subtype of IBS with constipation (IBS-C), with hard / lumpy stools ≥25% of the time. Plecanatide is an orally-active peptide. It replicates the function of uroguanylin, a guanylate cyclase-C agonist that stimulates fluid secretion and promotes stool consistency necessary for normal bowel function. The current 2 trials evaluate the efficacy and safety of once-daily plecanatide in IBS-C patients.
Methods: Two phase 3 double-blind, placebo (PBO)-controlled clinical trials were conducted in the US to evaluate plecanatide 3mg and 6mg in IBS-C patients. Both studies were identical in design, with a 2-week pre-treatment period, 12-week treatment period, and 2-week post-treatment follow-up period. Plecanatide was taken once daily, with or without food, no restrictions. Patients were selected using Rome III criteria for IBS-C—defined as a history of constipation and abdominal pain for ≥6 months, including hard/lumpy stools for ≥25% of defecations, loose/watery stools for ≥25% of defecations, and abdominal pain/discomfort for ≥3 days/month in the last 3 months. The primary efficacy endpoint in both trials was the percentage of Overall Responders during the 12-week treatment period—defined as patients with ≥30% reduction in worst abdominal pain and an increase of ≥1 complete spontaneous bowel movement (CSBM) from baseline, in the same week, for ≥50% of the 12 treatment weeks. Adverse events (AEs) were evaluated for safety and tolerability.
Results: Study One randomized 1055 patients (76.4% female) to plecanatide 3mg (n=351), 6mg (n=350) or PBO (n=354). Study Two randomized 1135 patients (71.8% female) to plecanatide 3mg (n=377), 6mg (n=379) or PBO (n=379).
Plecanatide 3mg and 6mg met the primary endpoint in both studies, with a significant difference vs PBO in Overall Responders across the 12-week treatment period (Study One: 3mg, 30.2%, P<0.001; 6mg, 29.5%, P<0.001; PBO,
17.8% | Study Two: 3mg, 21.5%, P=0.009; 6mg, 24.0%, P<0.001; PBO, 14.2%). The most common AE was diarrhea (Study One: 3mg, 5.4%; 6mg, 4.3%; PBO, 0.6% | Study Two: 3mg, 3.2%; 6mg, 3.7%; PBO, 1.3%). Overall, 11 patients (1.0%) in Study One and 6 patients (0.5%) in Study Two experienced a serious treatment-emergent AE (sTEAE), with little difference across treatment groups – sTEAEs were not GI-related, with no incidence of dehydration. Withdrawal rates due to AEs were low (Study One: 3mg, 3.1%; 6mg, 2.3%; PBO, 0.8% | Study Two: 3mg, 1.9%; 6mg, 2.1%; PBO, 0%). Discontinuations due to diarrhea were infrequent (Study One: 3mg, 1.7%; 6mg, 1.2%; PBO, 0% | Study Two: 3mg, 0.8%; 6mg, 1.6%; PBO, 0%).
Conclusions: These clinical studies indicate plecanatide may offer a promising new treatment for patients with IBS-C.
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