ORLANDO, Florida — For some patients with chronic idiopathic constipation, the number of complete spontaneous bowel movements improved after treatment with plecanatide (Synergy Pharmaceuticals), a 12-week multicenter placebo-controlled study has shown.
Plecanatide belongs to a new class of oral agents, known as guanylate cyclase-C receptor agonists. These mimic the effects of the natriuretic peptide uroguanylin and induce intestinal fluid secretion into the lumen of the gastrointestinal tract.
"Plecanatide has oral once-daily dosing, is essentially nonsystemic, and models normal physiology," explained Philip Miner, MD, from the Oklahoma Foundation for Digestive Research in Oklahoma City.
Dr. Miner presented the study results during a late-breaking session here at Digestive Disease Week 2013.
"All 3 doses of plecanatide examined demonstrated a statistically significant improvement in the number of complete spontaneous bowel movements experienced by study participants who responded to the treatment," he said. "In addition to an increased frequency of complete spontaneous bowel movements, the participants reported improvements in other symptoms of chronic constipation, including decreased stool hardness and straining."
Dr. Miner said the drug was well tolerated, and the safety data are consistent with previous phase 1 and 2a trials of plecanatide.
Patients meeting modified Rome III diagnostic criteria for constipation with fewer than 3 complete spontaneous bowel movements per week at baseline were randomized to receive plecanatide 0.3, 1.0, or 3.0 mg or placebo daily for 12 weeks. Researchers used a daily interactive voice response system to collect bowel-associated symptom data.
The primary outcome measure was the number of complete spontaneous bowel movements per week.
All of the 946 patients had undergone at least 1 postdose efficacy assessment, and three quarters completed the 12-week treatment.
Approximately 5% of the patients withdrew because of an adverse event, 5% withdrew because of lack of efficacy, and 10% withdrew because of administrative issues.
The researchers found that the effectiveness of plecanatide increased as the dose increased. On multiple parameters, the greatest improvement in complete spontaneous bowel movements was with the 3 mg dose, Dr. Miner reported.
Table. Outcomes at 12 Weeks With Placebo and the Highest Dose of Plecanatide
|End Point||Placebo (n = 234)||Plecanatide 3 mg (n = 237)||P Value|
|Response for ≥9 weeks||11.5%||21.5%||<.01|
|Response in 3 of the last 4 weeks||10.7%||19%||<.01|
|Increase of ≥1 bowel movement per week from baseline||36.8%||52.3%||<.001|
|Time to first spontaneous bowel movement||27.3 hours||12.5 hours||<.001|
|First bowel movement within 24 h||41.5%||67.5%||<.001|
|Complete bowel movement within 24 h||11.5%||31.2%||<.001|
There was a statistically significant difference between the 3 mg dose and placebo for the secondary end points of frequency of spontaneous bowel movements, complete bowel movements, stool consistency, straining, chronic idiopathic constipation severity, treatment satisfaction, and Patient Assessment of Constipation Symptoms and Quality of Life.
"You can see the significance of the 3 mg dose for all the criteria we have for patient satisfaction," Dr. Miner noted.
At baseline, patients in the 3 mg group took rescue medication for a mean of 3 days a month; this dropped to less than 1 day a month by the third month.
The most common adverse event was diarrhea, which was reported as "bothersome" by more patients in the 3 mg group than in the placebo group (9.7% vs 1.3%). Five patients receiving plecanatide (1 in the 3 mg group) rated diarrhea as severe, "but study withdrawal related to diarrhea was infrequent," Dr. Miner reported.
No serious adverse events were considered to be related to treatment, and there were no signals in serum chemistries, hematologic parameters, urinalysis, electrocardiography, or vital signs.
Dr. Miner explained that "it is commonly thought that if you use any drug, including an over-the-counter laxative, the improvement in constipation will be accompanied by diarrhea. This observation needs to be clarified. I would like to think that we could have medications that would impact constipation without creating diarrhea, particularly for patients such as those with spinal cord injury."
Plecanatide "appears to be efficacious," said Lauren Gerson, MD, from Stanford University in Palo Alto, California, who was asked by Medscape Medical News to comment on the findings. However, "whether it is just another drug that could be effective or is superior to agents we have now — lubiprostone, lactulose, polyethylene glycol — I can't tell."
Dr. Gerson asked Dr. Miner to what degree these patients had been treated with other agents for constipation. Dr. Miner explained that a full analysis of the data has not been completed, so he could not provide that information. "At my site, most patients had been on regular prescription medications and other things we do as gastroenterologists, and were considered failures," he said.
Dr. Gerson said she would like to learn how refractory these patients are, and looks forward to seeing a full profile of patients' medications at baseline.
This study was funded by Synergy Pharmaceuticals. Dr. Miner reports a financial relationship with Synergy Pharmaceuticals. Dr. Gerson has disclosed no relevant financial relationships.
Digestive Disease Week (DDW) 2013. Abstract 925g. Presented May 21, 2013.
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Cite this: Plecanatide Eases Chronic Constipation - Medscape - May 24, 2013.