Plecanatide for Chronic Idiopathic Constipation

Chronic idiopathic constipation (CIC) is a complex, functional gastrointestinal (GI) disorder characterized by infrequent bowel movements that are incomplete or hard to pass. In addition, the physical symptoms of CIC such as abdominal bloating and discomfort negatively affect quality of life.1 CIC poses substantial health burdens worldwide; an estimated 14 percent of the global population has CIC, including approximately 33 million Americans.2

Previous trial results demonstrated the efficacy and safety of the novel therapeutic peptide, plecanatide, as a once-daily treatment in 946 adults with CIC.3 Plecanatide is a structural analog of uroguanylin engineered with a single pH-sensitive residue replacement for enhanced therapeutic potency. Uroguanylin is an endogenous human GI peptide that agonizes guanylate cyclase-C (GC-C) receptors in the epithelial lining of the small intestine in a pH-sensitive manner. Plecanatide-mediated GC-C receptor signaling alters transport mechanisms and ionic absorption across the intestinal epithelium. As a result, plecanatide facilitates fluid secretion into the gut lumen to hydrate and promote more frequent bowel movements in patients with CIC.1

As part of a phase 3 trial designed to further evaluate plecanatide for CIC treatment, a total of 1394 patients with CIC were randomized to receive once-daily oral plecanatide (3 mg or 6 mg) or placebo for 12 weeks. Plecanatide treatment efficacy was defined via spontaneous bowel movements (CSBMs); patients who achieved at least 3 complete CSBMs each week with an increase of at least 1 CSBM each week compared with baseline were considered weekly responders. The primary efficacy end point was defined as patients who were weekly responders for a minimum of 9 weeks during the 12-week trial, including in at least 3 of the last 4 weeks of the treatment period. Additional end points included frequency of CSBMs and patient-evaluated improvements in CIC symptoms.1

Within the first week of the study, plecanatide treatment led to a significantly (P <.001) greater number of responders; 35.8% (3 mg) and 29.3% (6 mg) of plecanatide-treated patients achieved at least 3 CSBMs compared with 16.6% of placebo-treated patients. The rates of durable overall CSBM response after 12 weeks (primary efficacy outcome) were significantly (P <.001) higher in the plecanatide groups at 21.0% (3 mg) and 19.5% (6 mg) compared with a rate of 10.2% in the placebo group.1

Patients who received plecanatide treatment also demonstrated improvements in secondary efficacy outcomes, and plecanatide showed rapid onset of activity. Within 24 hours after the first dose of study treatment, significantly (P <.001) more patients treated with 3 mg (28.7%) and 6 mg (25.2%) plecanatide experienced CSBMs compared with placebo-treated patients (13.3%). Plecanatide-treated patients maintained an increase in weekly CSBMs from baseline (by at least 1 movement) throughout the 12-week treatment period. Additionally, plecanatide treatment significantly (P <.001) increased the frequency of CSBMs compared with placebo during the 12 weeks; mean increases of 2.5 (3 mg) and 2.2 (6 mg) CSBMs per week from baseline were observed with plecanatide treatment compared with a mean increase of 1.2 CSBMs per week from baseline with placebo treatment.1

The secondary end point data of this trial also confirmed the efficacy of plecanatide at either dose in the management of CIC (Table1). Based on an analysis of patient entries in daily symptom diaries during the 12-week treatment period, with plecanatide treatment, patient-recorded straining, abdominal bloating, and discomfort scores were improved compared with baseline scores. Analysis of patient-recorded bowel movement diary entries indicated stool consistency improvements with plecanatide were significantly (P <.001) greater than those with placebo treatment. CIC symptom improvements were also associated with reductions in constipation severity; greater percentages of patients in the plecanatide treatment groups reported improvements compared with the placebo group: 71.5% (3 mg plecanatide) and 68.7% (6 mg plecanatide) compared with 56.9% (placebo).1

Plecanatide was well tolerated; the majority of adverse events (AEs) were mild to moderate in severity. Diarrhea, the most common adverse reaction to plecanatide treatment, occurred at rates of 5.9% (3 mg) and 5.7% (6 mg) in the plecanatide treatment groups compared with 1.3% in the placebo treatment group. Discontinuation rates due to AEs were low among patients in both treatment groups at 5.1% (3 mg) and 5.3% (6 mg) of patients in the plecanatide groups, respectively, and 1.3% in the placebo arm. In the plecanatide groups, 2.7% (3 mg) and 2.6% (6 mg) discontinued study treatment due to treatment-related diarrhea compared with 0.4% of placebo-treated patients.1

Across 2 studies in more than 2600 patients, treatment with plecanatide has successfully demonstrated durable efficacy compared with placebo in promoting bowel movements and improving physical symptoms in patients with CIC.1-3 Based on these results, once-daily 3-mg plecanatide received approval from the FDA for the treatment for adults with CIC.2

References

1. Miner PB Jr, Koltun WD, Wiener GJ, et al. A randomized phase III clinical trial of plecanatide, a uroguanylin analog, in patients with chronic idiopathic constipation [published online February 7, 2017]. Am J Gastroenterol. 2017. doi: 10.1038/ajg.2016.611.

2. Synergy Pharmaceuticals’ Trulance (plecanatide) receives US FDA approval for the treatment of adults with chronic idiopathic constipation [news release]. New York, NY: Synergy Pharmaceuticals, Inc; January 19, 2017. http://ir.synergypharma.com/press-releases/detail/1831/synergy-pharmaceuticals-trulance-plecanatide. Accessed February 14, 2017.

3. Miner PB, Surowitz R, Fogel R, et al. Plecanatide, a novel guanylate-cyclase C (GC-C) receptor agonist, is efficacious and safe in patients with chronic idiopathic constipation (CIC): results from a 951 patient, 12 week, multi-center trial [abstract 925g]. Gastroenterology. 2013;144(5 suppl 1):S163. doi: 10.1016/S0016-5085(13)60585-5.