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

2. 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)

3. 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].

4. 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].

5. 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].

6. 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].

7. 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].

8. 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].

9. 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].

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

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

12. 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

13. 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

14. Trulance™ - Plecanatide Literature Review
Inclusion Criteria:
Patients with CIC aged years old
Body mass index of 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

15. 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

16. 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

17. 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

18. 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

19. 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

20. 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

21. Trulance™ - Plecanatide References
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 doi: /ajg [Epub ahead of print]