Plecanatide (Trulance)

Prescription

Plecanatide (brand name Trulance) is a synthetic 16-amino acid peptide that is structurally nearly identical to human uroguanylin, differing by only a single amino acid substitution (Asp3 to Glu3). Developed by Synergy Pharmaceuticals and approved by the FDA in January 2017 for chronic idiopathic constipation (CIC) in adults, with a subsequent approval in January 2018 for irritable bowel syndrome with constipation (IBS-C), plecanatide represents a physiologically designed approach to treating functional constipation disorders. It acts as a guanylate cyclase-C (GC-C) receptor agonist, mimicking the endogenous uroguanylin signaling pathway that regulates intestinal fluid and electrolyte homeostasis. The peptide acts locally in the gastrointestinal tract with negligible systemic absorption. Upon binding to GC-C receptors on the luminal surface of intestinal epithelial cells, plecanatide stimulates intracellular cyclic guanosine monophosphate (cGMP) production. Elevated cGMP activates the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel, driving chloride and bicarbonate secretion into the intestinal lumen. This creates an osmotic gradient that draws water into the gut, softening stool and accelerating intestinal transit. Importantly, unlike the related drug linaclotide (which is based on the heat-stable enterotoxin of E. coli), plecanatide's design based on human uroguanylin gives it pH-dependent activity — it binds GC-C most potently at pH 5.0–6.0, corresponding to the acidic environment of the proximal small intestine where uroguanylin naturally acts. Pivotal Phase III clinical trials demonstrated significant efficacy for both approved indications. In two CIC trials (Study 04 and Study 303), plecanatide 3 mg once daily produced durable responder rates of 21.0% and 21.5% versus 10.2% and 14.2% for placebo over 12 weeks. For IBS-C, two Phase III trials showed that plecanatide 3 mg achieved overall responder rates (composite endpoint of abdominal pain improvement plus increased complete spontaneous bowel movements) of 30.2% versus 17.8% placebo. The safety profile was favorable, with diarrhea being the most common adverse event (occurring in approximately 5% of patients at the 3 mg dose versus 1% placebo), and no clinically significant systemic side effects consistent with its locally acting mechanism. Plecanatide is administered as a 3 mg oral tablet taken once daily with or without food. Tablets can also be crushed in applesauce or administered in water via nasogastric or gastric feeding tubes for patients with swallowing difficulty. The drug is contraindicated in pediatric patients under 6 years of age due to risk of serious dehydration, and should be avoided in patients aged 6 through 17 years. Following Synergy Pharmaceuticals' bankruptcy, the Trulance brand was acquired by Salix Pharmaceuticals (a Bausch Health company), which continues to market and distribute the product.