1. A Clinical Overview

2. Over 295,000 cumulative patient-years of experience globally2
Irritable Bowel Syndrome with Constipation (IBS-C)
CONSTELLA® (linaclotide) is indicated for the treatment of irritable bowel syndrome with constipation (IBS-C) in adults.1
Chronic Idiopathic Constipation (CIC)
CONSTELLA® (linaclotide) is indicated for the treatment of chronic idiopathic constipation (CIC) in adults.1
Over 295,000 cumulative patient-years of experience globally2

3. Irritable Bowel Syndrome with Constipation (IBS-C) Action and Clinical Pharmacology*
IBS-C is a functional bowel disorder1
In IBS-C, abdominal pain and discomfort are associated with altered defecation1
Etiology and pathophysiology are poorly understood and appear to be multifactorial resulting in:1
Visceral hypersensitivity
Alteration in GI motility
Psychosocial factors
Treatment is aimed at:1
Relief of abdominal symptoms – abdominal pain, discomfort and bloating
Normalization of bowel movements
Improvement of quality of life
* Clinical significance has not been established.

4. Chronic Idiopathic Constipation (CIC) Action and Clinical Pharmacology*
CIC is a functional GI disorder1
Patients with CIC report multiple bowel and abdominal symptoms:
Straining, gas, hard stools, abdominal discomfort, infrequent bowel movements, bloating, sense of incomplete evacuation, abdominal pain1
Treatment is aimed at:
Normalizing bowel movements – frequency and consistency
Relieving abdominal symptoms
* Clinical significance has not been established.

5. CONSTELLA®: A 14-Amino Acid Peptide That Acts Locally in the Bowel to Accelerate GI Transit and Reduce Intestinal Pain1*
CFTR=cystic fibrosis transmembrane conductance regulator; cGMP=cyclic guanosine monophosphate; GC-C=guanylate cyclase-C
* Clinical significance has not been established.

6. CONSTELLA® – Action and Clinical Pharmacology*
CONSTELLA® is –
minimally absorbed with low systemic availability following oral administration2
metabolized within the GI tract to its principle, active metabolite. Both linaclotide and the metabolite are proteolytically degraded within the intestinal lumen to smaller peptides and naturally occurring amino acids2
Patients with hepatic or renal impairment –
CONSTELLA® has not been specifically studied in patients with hepatic or renal impairment. No effect on metabolism or clearance of linaclotide or its metabolite is expected in patients with hepatic or renal impairment2
Pharmacokinetics –
No drug interaction studies have been performed. It is thought that linaclotide is unlikely to interact with concomitantly administered medications based on the observed:
Minimal systemic exposure to linaclotide or its principle metabolite
Extensive metabolism of both peptides within the GI tract
Lack of interaction with common drug metabolizing enzymes (e.g., cytochrome P450) and drug transporting enzymes (e.g., P-glycoprotein transporters)
* Clinical significance has not been established.

7. CONSTELLA®: Four Pivotal Phase 3 Clinical Trials in IBS-C and CIC1
Trial Number
Description
Duration
No. of Patients
(CONSTELLA®/placebo)
Trial 1: published in the AJG*
Multicentre, randomized, controlled trials
12+4 weeks
N=800 (405/395)
Trial 2: published in the AJG*
26 weeks
N=804 (401/403)
Trial 3: published in the NEJM†
N=642 (433/209)
Trial 4: published in the NEJM†
12 weeks
N=630 (415/215)
Study parameters are available at
* AJG=American Journal of Gastroenterology
† NEJM=New England Journal of Medicine

8. IBS-C: Demonstrated Early and Sustained Reduction in Abdominal Pain1
IBS-C: Demonstrated Early and Sustained Reduction in Abdominal Pain1* Statistically Significant Separation from Placebo Observed at Week 1 and Sustained across the 26-week Treatment Period1,2
Mean Percentage Improvement in Abdominal Pain by Week over 26 Weeks
(secondary endpoint)1,2
Week 1: Significant separation from placebo (p<0.001)1*
Weeks 6-9: Maximum effect was seen and maintained until the end of the study vs. baseline, p<0.001)1,2*
Week 26: 50% reduction vs. baseline1,2* (p<0.001)2
* Abdominal pain score based on 11-point numerical rating scale (0=none, 10=very severe).1

9. In IBS-C: Significant Improvement Reported in Abdominal Bloating1,2 At Week 12: 29% Reduction in Bloating from Baseline vs. 15% Placebo2
Mean Change from Baseline in Abdominal Bloating, Weeks 1-12 (secondary endpoint)1,2*†
* Analysis based on first 12 weeks of treatment, Trial 2.1
† Abdominal bloating was measured daily using an 11-point numerical rating scale (0=none, 10=very severe).1

10. IBS-C: Demonstrated Improvement in Bowel Movement Frequency – Weekly SBMs (secondary endpoint)1
SBMs/week, change vs. baseline at week 12:
Trial 1: 3.9 CONSTELLA® vs. 1.1 placebo; Trial 2: 4.0 CONSTELLA® vs. 1.3 placebo (p<0.0001)1
In Trial 1, 58% of CONSTELLA®-treated patients had an increase of ≥2 SBMs per week from baseline for at least 6 of 12 weeks vs. 29% placebo (p<0.0001, secondary endpoint)3
SBMs reported within 24 hours of first dose:
In a pooled analysis of Trials 1 and 2, 67% of patients had an SBM within 24 hours of the first dose of CONSTELLA® vs. 42% placebo (p<0.0001)1
SBM=spontaneous bowel movement (occurring in the absence of laxative use)1

11. CIC: Significant Improvement Reported in Abdominal Bloating and Discomfort
Lembo AJ, et al., New England Journal of Medicine 2011
Improvement Reported in Abdominal Discomfort (secondary endpoint)
Improvement Reported in Abdominal Bloating (secondary endpoint)
34% of patients treated with CONSTELLA® had a decrease in abdominal discomfort vs. 21% placebo (p=0.003)4*
Twice as many CONSTELLA®-treated patients had a decrease in bloating score: 30% CONSTELLA® vs. 15% placebo (p<0.001)4*
Trial 3
* Decrease of ≥0.5 points in score for 9/12 weeks.4

12. CIC: No Worsening Reported in SBM Frequency During the Randomized Withdrawal Period1,2
For CONSTELLA®-treated patients re-randomized to placebo, SBM frequency returned toward baseline within 1 week, with no evidence of rebound worsening1,2 Mean SBM Frequency by Week: 12-Week Treatment Period and 4-Week RW Period (secondary endpoint, Trial 3)1,2
CONSTELLA® 290 mcg is not recommended for the treatment of CIC
RW=randomized withdrawal; SBM=spontaneous bowel movement (occurring in the absence of laxative use)1

13. CIC: Significant Improvements Reported in Bowel Movement Frequency (SBMs)
Mean Number of SBMs/Week at Week 122 (secondary endpoint)
SBM frequency An increase of 3.4 SBMs/week was reported with CONSTELLA® vs. 1.1 with placebo (mean change from baseline, p<0.0001)1,2*
CONSTELLA®: SBMs from baseline vs placebo (p<0.0001)1,2
SBM=spontaneous bowel movement (occurring in the absence of laxative use)1
* Analysis based on Trial 4.

14. Quality of Life in IBS-C – Significant Improvements Reported with CONSTELLA® vs. Placebo (p<0.05 for QOL parameters assessed in IBS-C)1
IBS-C: QOL Results for CONSTELLA® (secondary endpoint, responder analyses, pooled ITT population)
IBS-QOL parameter*
0- to 100-point scale
CONSTELLA® 290 mcg
n=805
placebo
n=797
≥10-point improvement (%)
≥14-point improvement (%)
IBS-C-QOL overall score
64.3d
52.5
53.8d
39.0
Dysphoria
62.0b
53.6
56.2d
45.7
Body image
71.7d
59.5
62.1d
43.2
Health worry
67.6d
56.1
Food avoidance
57.4d
46.6
Social reaction
52.5b
44.5
42.4c
32.9
Sexual
54.2c
44.4
37.9d
26.9
Relationships
41.6b
34.7
Interference with activity
54.7a
48.5
47.5b
a p<0.05, b p <0.01, c p<0.001, d p< (vs. placebo, CMH test)
IBS-QOL=Irritable Bowel Syndrome – Quality of Life; ITT=intent-to-treat
* The Irritable Bowel Syndrome – Quality of Life (IBS-QOL) instrument evaluates eight dimensions on a 0- to 100-point scale: dysphoria, interference with activity, body image, health worry, food avoidance, social reaction, sexual, relationships. Assessments were made at baseline and at week 12 in the Phase 3 trials of CONSTELLA® 290 mcg vs. placebo in treatment of patients with IBS-C.1

15. ≥1-point improvement (%)
Quality of Life in CIC – Significant Improvements Reported with CONSTELLA® vs. Placebo (p<0.05 for QOL parameters assessed in CIC)1
CIC: QOL Results for CONSTELLA® (secondary endpoint, responder analyses, pooled ITT population)
PAC-QOL parameter*
0- to 4-point scale
CONSTELLA® 145 mcg
n=430
placebo
n=423
≥1-point improvement (%)
PAC-QOL overall score
43.6b
23.4
Satisfaction
53.8b
28.3
Physical discomfort
55.4b
30.8
Worries/concerns
48.1b
26.7
Psychosocial discomfort
24.7a
18.6
a p≤0.05, b p<0.0001(vs. placebo, CMH test)
PAC-QOL=Patient Assessment of Constipation – Quality of Life
* The Patient Assessment of Constipation – Quality of Life (PAC-QOL) instrument evaluates four dimensions on a 0- to 4-point scale: physical discomfort, psychosocial discomfort, worries/concerns and satisfaction.1

16. IBS-C and CIC: Safety Profile Evaluated in 4,370 Patients in Phase 2 and 3 Clinical Trials1

17. Adverse Reactions: Pooled IBS-C and CIC Clinical Trials
IBS-C and CIC Trials: Most Common Adverse Reactions (incidence ≥4% and greater than placebo)1
Adverse Reaction
IBS-C Trials
CIC Trials
CONSTELLA® 290 mcg/day
n=807
placebo
n=798
CONSTELLA® 145 mcg/day
n=430
n=423
Diarrhea (%)
19.8
3.0
16.0
4.7
Abdominal pain (%)
5.1
3.3
4.0
3.1
Flatulence (%)
4.3
1.9
5.6
5.2
IBS-C:
Severe diarrhea: 2.0% of IBS-C patients (vs. <1% placebo)1
Discontinuations due to diarrhea: 5.3% in IBS-C patients (vs. <1% placebo)1
Overall discontinuations: 9.4% of IBS-C patients (vs. 2.9% placebo)1
CIC:
Severe diarrhea: 1.8% of CIC patients (vs. <1% placebo)1
Discontinuations due to diarrhea: 4.2% in CIC patients (vs. <1% placebo)1
Overall discontinuations: 7.6% of CIC patients (vs. 4.3% placebo)1

18. CONSTELLA®: Simple, Once-Daily Dosing for IBS-C and CIC in Adults1
Taken orally once daily on an empty stomach, at least 30 minutes prior to the first meal of the day.1
Improvement of bowel symptoms should occur within the first week of CONSTELLA® treatment; improvement of abdominal symptoms may take longer.1  
No dosage adjustments required for patients with hepatic or renal impairment.1
Physicians should periodically assess the need for continued treatment with CONSTELLA®.1
* Exceeding the daily dose of 145 mcg for the treatment of CIC is not expected to increase efficacy. The 290 mcg dose is not recommended for the treatment of CIC.1

19. American Gastroenterological Association (AGA) Strong Recommendation for Linaclotide5
IBS-C
American Gastroenterological Association Institute Guideline on the Pharmacological Management of Irritable Bowel Syndrome
The AGA recommends using linaclotide (over no drug treatment) in patients with IBS-C.
Strong recommendation*
High-quality evidence5
Comment: Patients who place a high value on avoiding diarrhea and avoiding higher out-of-pocket expenses associated with linaclotide may prefer alternate treatments.5
Recommendations based on GRADE (Grading of Recommendations Assessment, Development and Evaluation).
* Implications of strong guideline recommendations for clinicians: most patients should receive the recommended course of action. Adherence to this recommendation according to guidelines could be used as a quality criterion or a performance indicator.5

20. American College of Gastroenterology (ACG) Strong Recommendations for Linaclotide6
IBS-C and CIC
American College of Gastroenterology Monograph on the Management of Irritable Bowel Syndrome and Chronic Idiopathic Constipation
Linaclotide is superior to placebo for the treatment of constipation-predominant IBS.
Recommendation: strong*
Quality of evidence: high6†
Linaclotide is effective in chronic idiopathic constipation.
Recommendations based on GRADE (Grading of Recommendations Assessment, Development and Evaluation).
* “Strong” recommendations represent a “recommendation that can apply to most patients in most circumstances and further evidence is unlikely to change our confidence in the estimate of treatment effect.”6
† Interpretation of high quality of evidence: further research is very unlikely to change our confidence in the estimate of effect.6

21. CONSTELLA®: For the Treatment of IBS-C and CIC in Adults
Demonstrated Efficacy in IBS-C and CIC
Demonstrated Safety Profile
The First-in-Class Guanylate Cyclase-C (GC-C) Agonist1*
A 14-amino acid peptide shown to act locally in the bowel to accelerate GI transit and reduce intestinal pain1†
Simple, Once-Daily Dosing1
IBS-C patients: 290 mcg
CIC patients: 145 mcg‡
Taken orally once daily on an empty stomach, at least 30 minutes prior to the first meal of the day
Strong Recommendations for Linaclotide:
For IBS-C – from the American Gastroenterological Association5
For IBS-C and CIC – from the American College of Gastroenterology6
* Comparative clinical significance has not been established.
† Clinical significance has not been established.
‡ Exceeding the daily dose of 145 mcg for the treatment of CIC is not expected to increase efficacy.

22. Clinical use:
Clinical studies of CONSTELLA® did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. 
CONSTELLA® is contraindicated in children under 6 years of age and is not recommended for use in children between 6 and 18 years of age as the safety and efficacy of CONSTELLA® in pediatric patients have not been established.
Contraindications: 
Pediatric patients under 6 years of age 
Patients with known or suspected mechanical gastrointestinal obstruction
Most serious warnings and precautions:
Children: Not recommended in children between 6 and 18 years of age
Other relevant warnings and precautions: 
Diarrhea most common adverse reaction; may cause serious diarrhea
Use in pregnant women only if the potential benefit justifies the potential risk to the fetus
Caution should be exercised when CONSTELLA® is administered to nursing women
For more information:
Please consult the Product Monograph at NR/rdonlyres/ D E-B C324A3CE8/0/ CONSTELLA_ProductMonograph.pdf for important information relating to adverse reactions, food interactions and dosing information not discussed in this piece. The Product Monograph is also available by calling Actavis Specialty Pharmaceuticals at

23. References: 1. CONSTELLA® (linaclotide) Product Monograph, Forest Laboratories Canada Inc., May 12, Data on file, Forest Laboratories Canada Inc. 3. Rao S, et al. A 12-week, randomized, controlled trial with a 4-week randomized withdrawal period to evaluate the efficacy and safety of linaclotide in irritable bowel syndrome with constipation. Am J Gastroenterol 2012;107: Lembo AJ, et al. Two randomized trials of linaclotide for chronic constipation. N Engl J Med 2011;365: Weinberg DS, et al. American Gastroenterological Association Institute guideline on the pharmacological management of irritable bowel syndrome. Gastroenterology 2014;147: Ford AC, et al. for the Task Force on the Management of Functional Bowel Disorders. American College of Gastroenterology monograph on the management of irritable bowel syndrome and chronic idiopathic constipation. Am J Gastroenterol 2014;109:S2-S26. CONSTELLA® is a registered trademark of Ironwood Pharmaceuticals, Inc. used under license by Allergan, Inc. or its affiliates. ©2015 Allergan. All rights reserved.