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Plecanatide improves CIC, appears safe long-term
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LAS VEGAS — Two doses of plecanatide were more effective than placebo for treating chronic idiopathic constipation, and long-term use was associated with low rates of adverse events and drug discontinuation, according to research presented at ACG 2016.
Plecanatide (Synergy Pharmaceuticals) is an orally administered investigational compound designed to replicate the function of the human GI peptide uroguanylin to stimulate fluid secretion and promote stool consistency, according to a press release from the manufacturer. It is currently under review by the FDA for the treatment of chronic idiopathic constipation (CIC), and the Prescription Drug User Fee Act (PDUFA) target action date for the CIC indication is January 29, 2017. Synergy also plans to report phase 3 clinical trial data in constipation-predominant irritable bowel syndrome (IBS-C) later this year.
“Although we have a few drugs, there is a very large unmet need — I still have over 50% of my patients dissatisfied with the current treatments available,” Satish S.C. Rao, MD, PhD, professor of medicine and chief of gastroenterology and hepatology at Augusta University, and director of the Digestive Health Center at the Medical College of Georgia, told Healio Gastroenterology at ACG. “This is one of the new classes of secretable drugs designed to mimic the production of uroguanylin, which is one of the intrinsic hormones that induces secretion within the gut.”
Describing the drug’s known mechanism of action, Rao said it binds to the guanylate cyclase-C [GC-C] receptor and releases cyclic guanosine monophosphate (cGMP), “which leads to secretion of chloride, sodium and water into the lumen of the gut,” thus distending the gut and promoting peristalsis and laxation.
Rao and colleagues performed a pooled analysis of safety and efficacy data from two 12-week phase 3 randomized, double blind, placebo-controlled trials evaluating two oral daily doses of plecanatide (3 mg and 6 mg) in patients with CIC. The pooled efficacy population included 2,683 patients and the pooled safety population included 2,791 patients.
The trials included “the strictest definition [of efficacy] ever for any constipation trial so far,” Rao said.
To meet the composite primary efficacy endpoint of durable overall complete spontaneous bowel movements (CSBMs), patients had to have at least three CSBMs) per week and an increase from baseline of at least one CSBM for that week, for at least 9 of the 12 treatment weeks and in at least 3 of the last 4 weeks of treatment.
Overall, 20.5% of the 3 mg group, 19.8% of the 6 mg group and 11.5% of the placebo group were durable overall CSBM responders (P < .001 for both doses vs. placebo). Significant improvements were seen as early as the first week of treatment and were maintained throughout the treatment period compared with placebo.
At 12 weeks, stool consistency, straining and bloating were also significantly improved in both dose groups compared with placebo. Adverse event rates were comparable across all groups, ranging from 28.7% in the placebo group to 31.1% in the 6 mg group, the most common of which was diarrhea, occurring in 4.6% of the 3 mg group, 5.1% in the 6 mg group and 1.3% in the placebo group. Discontinuation rates were also low across all groups, with 4.1% in the 3 mg group, 4.5% in the 6 mg group and 2.2% in the placebo group.
“Both 3 mg and 6 mg seem to be effective for improving constipation symptoms, and [the drug] was generally very well tolerated,” Rao said. “I really think that this will fill the niche of the large unmet need for managing chronic constipation.”
Researchers also presented long-term safety data from an open-label multicenter study of plecanatide at ACG, which showed low rates of adverse events and drug discontinuation at both doses for up to 72 weeks.
Among 2,370 patients with CIC, the most common adverse events in the treatment groups were diarrhea (7.1%) and urinary tract infection (2.2%), and discontinuation due to an adverse event occurred in 5.3% of the treatment group (3.1% due to diarrhea). In addition, the median score for treatment satisfaction indicated patients were “quite satisfied” and the median score for continuation of treatment indicated patients were “quite likely” to continue. – by Adam Leitenberger
References:
Rao SSC, et al. Abstract P1041A. Presented at: American College of Gastroenterology Annual Scientific Meeting; Oct. 17-19, 2016; Las Vegas, NV.
De La Portilla M, et al. P1120. Presented at: American College of Gastroenterology Annual Scientific Meeting; Oct. 17-19, 2016; Las Vegas, NV.
Disclosures: Rao reports he serves on the advisory committee/board and consults for Forest Laboratories. A number of other researchers report financial relationships with Synergy Pharmaceuticals.