New Drug Review

Plecanatide (Trulance; Synergy Pharmaceuticals, Inc.) has been approved for treating chronic idiopathic constipation (CIC) in adults.

Plecanatide, an agonist of guanylate cyclase C in the GI tract, increases intracellular cGMP concentrations, which in turn promotes secretion of chloride and bicarbonate ions into the intestinal lumen via activation of the cystic fibrosis transmembrane conductance regulator ion channel. The effect is a rise in intraluminal fluid and improved GI transit.

Efficacy

Trulance was shown to be effective for  management of symptoms of CIC in two 12-week multicenter, double-blind, randomized, placebo-controlled trials.¹ Both studies included participants who had fewer than three defecations per week, who rarely experienced loose stool in the absence of laxatives, who did not use manual maneuvers to facilitate defecation, and who did not meet criteria for irritable bowel syndrome with constipation. Participants reported a minimum of two of the following conditions for at least 25% of their defecations: straining, lumpy, or hard stool; a sensation of incomplete evacuation; or a sensation of obstruction. During the last two weeks of a screening period, participants also had fewer than three complete spontaneous bowel movements (CSBM); a score of 6 or 7 on the Bristol Stool Form Scale (BSFS) in less than 25% of all spontaneous bowel movements; and at least one of the following: BSFS score of 1 or 2, straining, or a sense of incomplete evacuation at least 25% of defecations.  

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Participants were randomized to receive placebo or plecanatide, 3 mg daily. Change from baseline in CSBM and SBM served as the primary endpoints. Patients recorded information daily. Responders had at least three CSBMs in a week and one or more CSBM from baseline in the same week for 9 or more weeks of the 12-week treatment including at least 3 of the 4 final weeks of treatment.

There was a significant increase in responder rates in plecanatide recipients in both studies. (Study 1: 21% versus 10%, Study 2: 21% versus 13%, p<0.005 in each study).

Safety

Trulance carries a boxed warning about a serious risk of dehydration in pediatric patients. It is contraindicated in anyone under age 6 and use should be avoided in patients under 18; studies have not demonstrated, the safety and efficacy in this population. In animal models, plecanatide resulted in death due to dehydration in juvenile mice. Plecanatide therapy is contraindicated in patients with known or suspected GI obstruction.

Diarrhea is the most common adverse effect. In studies, severe diarrhea occurred in 0.6% of plecanatide recipients compared to 0.3% of placebo recipients. Other adverse events reported in fewer than 2% of recipients included: sinusitis, upper respiratory tract infection, abdominal distension and tenderness, flatulence, and increased ALT and AST levels (greater than 5 times the upper limit of normal).

Plecanatide should be used cautiously in patients over age 65. Studies have not sufficiently demonstrated safety and efficacy in this age group. If diarrhea occurs, patients should stop taking plecanatide and rehydrate.

Dosage

The approved dosage of plecanatide is 3 mg orally daily, without food. Tablets may be crushed for oral administration in water or applesauce. Trulance may also be mixed with water and administered via feeding tube.  

References
1. Trulance [package insert], New York, NY: Synergy Pharmaceuticals Inc., 2017. https://www.trulancehcp.com/clinical-results/.