Trulance™ - Plecanatide Manufacturer: Synergy Pharmaceuticals Inc. FDA Approval Date: 1/19/17

Trulance™ - Plecanatide Objectives At the end of this presentation participants will be able to: Appropriately recommend Trulance™ - (plecanatide) Effectively educate patients on the purpose, proper use and potential adverse effects of Trulance™ - (plecanatide)

Trulance™ - Plecanatide Clinical Application Indications: Treatment of chronic idiopathic constipation (CIC) in adults Place in therapy: First uroguanylin analog to be approved for the treatment of CIC, thus, provides a differentiated therapeutic option for these patients Trulance [package insert].

Trulance™ - Plecanatide Clinical Application Contraindications: Patients less than 6 years of age Patients with known or suspected mechanical gastrointestinal obstruction Warnings and Precautions: Black box warning: Risk of serious dehydration in pediatric patients Diarrhea: If severe diarrhea occurs, suspend dosing and rehydrate Trulance [package insert].

Trulance™ - Plecanatide Clinical Application Pregnancy: Category B Available data on use is not sufficient to inform any drug-associated risks for major birth defects and miscarriage No evidence of harm in animal studies Lactation: No data available Trulance [package insert].

Trulance™ - Plecanatide Drug Facts Pharmacology: Guanylate cyclase-C (GC-C) agonist Structurally related to human uroguanylin Both plecanatide and its active metabolite bind to GC-C and act locally on the luminal surface of the intestinal epithelium. Activation of GC-C results in an increase in both intracellular and extracellular concentrations of cyclic guanosine monophosphate (cGMP). Elevation of intracellular cGMP stimulates secretion of chloride and bicarbonate into the intestinal lumen, mainly through activation of the cystic fibrosis transmembrane conductance regulator (CFTR) ion channel, resulting in increased intestinal fluid and accelerated transit. In animal models, plecanatide has been shown to increase fluid secretion into the gastrointestinal (GI) tract, accelerate intestinal transit, and cause changes in stool consistency. Trulance [package insert].

Trulance™ - Plecanatide Drug Facts Pharmacokinetics: A Minimally absorbed; AUC and Cmax cannot be calculated D Minimally distributed M Proteolytically degraded within intestinal lumen E No excretion studies conducted Trulance [package insert].

Trulance™ - Plecanatide Drug Interactions Drug Interactions – Object Drug/Precipitant Drug: Neither plecanatide nor its metabolite inhibited CYP2C9 and CYP3A4 Does not induce CYP3A4 in vitro Neither substrates nor inhibitors of P-gp or BCRP in vitro Based on drug interaction studies Trulance [package insert].

Trulance™ - Plecanatide Adverse Effects Common Adverse Effects: (Plecanatide%)[placebo%] Diarrhea (5%)[1%] Serious Adverse Effects: (Plecanatide%)[placebo%] Severe diarrhea (0.6%)[0.3%] Trulance [package insert].

Trulance™ - Plecanatide Monitoring Parameters Efficacy Monitoring: Frequency of bowel movements Toxicity Monitoring: No findings of toxicity observed in studies Trulance [package insert].

Trulance™ - Plecanatide Prescription Information Dosing: 3 mg by mouth once daily Cost: Not yet available Trulance [package insert].

Trulance™ - Plecanatide Literature Review Purpose: To assess the efficacy and safety of two plecanatide doses when administered to patients with CIC for 12 weeks Design: Phase III, multi-center, double-blind, placebo-controlled study Miner PB Jr, et al. Am J Gastroenterol. 2017.

Trulance™ - Plecanatide Literature Review Treatment Arms: 1:1:1 ratio Plecanatide 3 mg Plecanatide 6 mg Placebo Miner PB Jr, et al. Am J Gastroenterol. 2017.

Trulance™ - Plecanatide Literature Review Inclusion Criteria: Patients with CIC aged 18-80 years old Body mass index of 18-40 kg/m2 Rome III functional constipation criteria History of < 3 bowel movements per week No use of manual maneuvers to facilitate defecations At least two of the following for ≥25% of defecations: Straining Lumpy or hard stool Sensation of incomplete evacuation Sensation of anorectal blockage/obstruction Miner PB Jr, et al. Am J Gastroenterol. 2017.

Trulance™ - Plecanatide Literature Review Exclusion Criteria: Met Rome III criteria for irritable bowel syndrome Diseases or conditions associated with constipation Diseases of conditions that affect GI motility or defecation Medical history of cancer Other uncontrolled medical conditions Miner PB Jr, et al. Am J Gastroenterol. 2017.

Trulance™ - Plecanatide Literature Review Patient Characteristics: Female (80.8%) Black/African American (25.6%) Plecanatide 3 mg (n=453) Plecanatide 6 mg (n=441) Placebo (n=452) Age 45.1 46.4 45.0 Gender (% female) 81.2 82.1 79.0 Race (% black) 24.5 23.9 28.5 CSBMs/week 0.3 0.4 Miner PB Jr, et al. Am J Gastroenterol. 2017.

Trulance™ - Plecanatide Literature Review Efficacy Results: Endpoint Plecanatide 3 mg (n=453) Plecanatide 6 mg (n=441) Placebo (n=452) Durable overall CSBM responders 21.0% p<0.001 19.5% 10.2% The primary efficacy endpoint was the percentage of patients who were durable overall CSBM responders during the 12-week treatment period. A CSBM weekly responder was defined as a patient who had ≥3 CSBMs for a given week and an increase from baseline of ≥1 CSBM for that same week. An overall CSBM responder was a patient who was a weekly CSBM responder for at least 9 of the 12 treatment weeks, and a durable overall CSBM responder was also a weekly responder in at least 3 of the last 4 weeks. Miner PB Jr, et al. Am J Gastroenterol. 2017.

Trulance™ - Plecanatide Literature Review Treatment-Emergent Adverse Events: Plecanatide 3 mg (n=474) Plecanatide 6 mg (n=457) Placebo (n=458) Diarrhea 5.9% 5.7% 1.3% Nasopharyngitis 0.8% 2.4% 1.7% Sinusitis 2.1% 0.7% Miner PB Jr, et al. Am J Gastroenterol. 2017.

Trulance™ - Plecanatide Literature Review Conclusions: Plecanatide, orally administered once daily for 12 weeks, significantly improved constipation and its related symptoms Plecanatide was well-tolerated, exhibiting a limited adverse effect profile Miner PB Jr, et al. Am J Gastroenterol. 2017.

Trulance™ - Plecanatide Summary TrulanceTM, plecanatide, is a guanylate cyclase-C agonist indicated in adults for treatment of CIC Plecanatide is dosed 3mg once daily The most common adverse effect is diarrhea. If severe diarrhea occurs, suspend dosing and rehydrate. Plecanatide is contraindicated in patients less than 6 years old due to the risk of serious dehydration Plecanatide provides a new option for patients with CIC who have not found relief in other medications

Trulance™ - Plecanatide References www.trulancehcp.com Trulance [package insert]. New York, NY: Synergy Pharmaceuticals Inc.; January 2017. Miner PB Jr, Koltun WD, Wiener GJ, De La Portilla M, Prieto B, Shailubhai K, Layton MB, Barrow L, Magnus L, Griffin PH. A randomized phase III clinical trial of plecanatide, a uroguanylin analog, in patients with chronic idiopathic constipation. Am J Gastroenterol 2017. doi: 10.1038/ajg.2015.611. [Epub ahead of print]