Plecanatide

Mechanism (as reported)

Plecanatide is described as a guanylate cyclase-C agonist (uroguanylin analogue) that is associated with increased bowel fluid secretion via conversion of guanosine 5-triphosphate to cyclic guanosine monophosphate; one source also describes effects as limited to the proximal small bowel and as involving increased chloride/bicarbonate secretion and reduced sodium absorption in the intestine. PMID 29942351, 31575291, 30550753.

Key findings (each cites a source)

• A study/review reported plecanatide (Trulance) is an oral guanylate cyclase-C agonist being developed for gastrointestinal disorders such as CIC and IBS-C, and that it received first global approval in the USA in January 2017 for adult CIC. [PMID 28255961]
• A review reported plecanatide is a 16-amino-acid synthetic peptide/analogue of human uroguanylin and acts as a guanylate cyclase agonist for CIC; it also described plecanatide as a secretagogue class member approved by the US FDA for adults with CIC. [PMID 29942351, 31575291]
• Clinical trial literature reviewed/included reported that in randomized, double-blind, placebo-controlled CIC studies (Rome III), durable overall complete spontaneous bowel movement (CSBM) response was higher with plecanatide than placebo (reported examples: 3 mg 21.0%, 6 mg 19.5% vs placebo 10.2%). [PMID 29942351]
• A review reported that plecanatide is associated with increased bowel fluid secretion through GC-C signaling (via conversion of guanosine 5-triphosphate to cyclic guanosine monophosphate). [PMID 31575291]
• A review reported plecanatide stimulates guanylate cyclase-C receptors and is described as increasing chloride and bicarbonate secretion, preventing sodium absorption, increasing water secretion into the intestinal lumen, and being associated with accelerated transit and stool softening/facilitation of defecation; it also stated plecanatide effects are limited to the proximal small bowel. [PMID 30550753]
• A phase III, randomized, double-blind, placebo-controlled trial in Chinese patients with functional constipation reported durable overall CSBM response rates of 23.5% with plecanatide vs 10.2% with placebo at 12 weeks (p<0.001) and reported statistically significant improvements in other secondary efficacy endpoints. [PMID 40571893]
• The phase III Chinese functional constipation trial reported diarrhea as the most common treatment-related emergent adverse event (4.3% with plecanatide vs 0.6% with placebo; p=0.002). [PMID 40571893]
• The phase III Chinese functional constipation trial reported that plasma concentrations of plecanatide and its metabolite SP-338 remained below the lower limit of quantification (0.500 ng/ml) at assessed time points. [PMID 40571893]
• A review/expert opinion source stated that in CIC trials, plecanatide reduced severity of other symptoms (e.g., straining effort, stool consistency, bloating) and that satisfaction and quality of life/improved desire to continue treatment were reported; it also summarized low treatment-emergent adverse event rates including diarrhea (reported 5%). [PMID 29942351]
• A pooled phase 3 analysis reported plecanatide significantly reduced bloating severity and abdominal pain and increased CSBM frequency versus placebo in the moderate-to-severe bloating subgroup, and reported improvements in abdominal pain and CSBM frequency (without significant bloating change) in the mild bloating subgroup. [PMID 38594429]
• A pooled analysis reported that in IBS-C patients aged 18–40 with baseline bloating, plecanatide had higher proportions of responders for a composite trisymptom endpoint (abdominal pain, bloating, and CSBM/ week) than placebo across several thresholds (e.g., 30% pain/bloating improvement plus ≥1 CSBM/week: 23.3% vs 13.4%; and ≥2 CSBM/week: 19.5% vs 8.9%). [PMID 41214272]