Plecanatide safe, effective in patients with chronic idiopathic constipation
Use of plecanatide in the treatment of chronic idiopathic constipation (CIC) appears to induce notable improvements in bowel movement frequency, stool consistency, and straining and abdominal symptoms, with a low incidence of adverse events, according to the results of a phase III trial.
Over a 12-week treatment period, the primary endpoint of percentage of patients with durable overall complete spontaneous bowel movement (CSBM) response was significantly greater in the plecanatide 3 and 6 mg arms than in the placebo arm (21 and 19.5 percent, respectively, vs 10.2 percent; p<0.001 for both comparisons). [Am J Gastroenterol 2017;112:613–621]
CSBM is defined as a spontaneous bowel movement (occurring within 24 hours in the absence of laxative use) with the sense of complete evacuation. A patient with a CSBM response for at least 9 of the 12 treatment weeks was identified as an overall CSBM responder, while a patient showing a response in at least 3 of the last 4 weeks was a durable overall CSBM responder.
Compared with placebo, both 3 and 6 mg doses of plecanatide produced a significant increase from baseline in mean weekly CSBM frequency (2.5 and 2.2/week, respectively, vs 1.2/week; p<0.001 for both) and mean weekly spontaneous bowel movement frequency (3.2 and 3.1/week, respectively, vs 1.3/week; p<0.001 for both).
Other improvements observed with the study drug included stool consistency (p<0.001 for each dose vs placebo), straining (p<0.001 for each dose vs placebo), abdominal bloating (p=0.002 for 3 mg and p=0.045 for 6 mg vs placebo) and abdominal discomfort (p<0.001 for 3 mg and p=0.014 for 6 mg vs placebo).
“Patients treated with plecanatide expressed satisfaction with their treatment and an intention to continue treatment,” the investigators said. “Plecanatide treatment was associated with a low frequency of AEs. The incidence of [the most commonly reported AE], diarrhoea, was no more than 5.9 percent and no other clinically meaningful safety findings were observed.”
The efficacy analysis included 1,346 CIC patients who received plecanatide at a dose of 3 mg (n=453; mean age 45 years; 81.2 percent female) or 6 mg (n=441; mean age 45.1 years; 82.1 percent female) or placebo (n=452; mean age 46.4 years; 79 percent female), whereas the safety population comprised 1,389 patients who received at least one dose of the study drug.
All patients had Rome III functional criteria for at least 3 months prior to the screening visit and had been experiencing symptoms (eg, <3 BMs per week and no use of manual manoeuvres to facilitate defecations; and straining during, lumpy or hard stool, sensation of incomplete evacuation, and/or sensation of anorectal blockage/obstruction for at least 25 percent of defecations) for at least 6 months before the diagnosis.
“Plecanatide is the first uroguanylin analogue to be approved for the treatment of CIC or other functional GI disorders. It is also the first treatment for CIC to be evaluated in a clinical study using the stringent criteria of a durable overall CSBM responder rate,” the investigators said.
“[The CSBM] endpoint requires a clinical response in at least 3 of the 4 last weeks of treatment in addition to the previously required 9 out of 12 weeks overall to evaluate the durability of efficacy. In meeting this revised regulatory endpoint, plecanatide has successfully demonstrated significant durable efficacy,” they added.
Dr Kok-Ann Gwee, a gastroenterologist at Gleneagles Hospital Singapore and an adjunct associate professor of medicine at the National University of Singapore, told MIMS that the demonstration of a durable response with the drug was a particularly interesting finding from the present trial.
Stressing the importance of durable overall CSBM response, Dr Gwee said, “[I]t is a common complaint among CIC patients that while they may experience good early response to a given treatment, they seem to lose the effect with extended use.”
“We should pay more attention to the possibility of constipation in patients who complain of bloating,” he said, citing a recently published study of real-world treatment experiences reporting that CIC and straining at defecation were the conditions that received the most dissatisfaction among of patients with various functional bowel disorders. [J Gastroenterol Hepatol 2017;doi:10.1111/jgh.13730]
“In many of such patients, the constipation may be mild as the frequency of bowel movement could be normal. However, if we ask our patients carefully many will report a sense of incomplete evacuation of their bowels,” he continued.
He also emphasized that asking patients with chronic constipation to drink more water and eat more dietary fibre would not help, but rather make the patients feel worse because such practices could aggravate the associated bloating.
“I find that for CIC patients, it is often helpful for them to receive laxative treatment on a daily basis rather than intermittently. The belief that frequent use of laxatives encourages habituation has not been supported by carefully conducted research,” Dr Gwee said.