Irritable Bowel Syndrome Benson Thomas FRCPC Gastroenterology St

Irritable Bowel Syndrome Benson Thomas FRCPC Gastroenterology St. Thomas Elgin General Hospital Objectives

•Understand the epidemiology, etiology and impact of IBS for the patients

•Review a simple diagnosis and management algorithm

•Understand the evidence to support the clinical utility of the latest Rx products Introduction to IBS

3 Epidemiology of “Common” GI Disorders

Prevalence

1. Lovell RM, Ford AC. Clin Gastroenterol Hepatol. 2012;10(7):712-721. 2. Suares NC, Ford AC. Am J Gastroenterology. 2011;106(9):1582-1591. 3. Tysk C, et al. Ann Gastroenterol. 2011;24(4):253-262. 4. Ye Y, et al. Int J Clin Exp Med. 2015;8(12):22529-22542. 5. Cash BD, et al. Gastroenterology. 2011;141(4):1187-1193. 4 What is Irritable Bowel Syndrome? • Functional GI disorder with multiple etiologies – no cure • Chronic symptoms attributable to middle or lower GI tract • Absence of organic cause (e.g., structural or biochemical) • In Canada, 5 million suffer from IBS (10% of people in literature) • 20-50% of GI referrals, 10% GP visits, #2 cause of missing work!

Rome IV Diagnostic Criteria for IBS • Recurrent abdominal pain associated • Pain occurring, on average, at least with two or more of the following: 1 day per week in the last 3 months – Change in frequency of stool • Symptom onset at least 6 months – Change in form (appearance) before diagnosis of stool – Related to defecation

Longstreth GF et al. Gastroenterology. 2006;130:1480; Lovell RM, Ford AC. Clin Gastroenterol Hepatol. 2012; 10:712; Lacy BE et al. Gastroenterology. 2016;150:1393; Fedorak RN et al. Can J Gastroenterol. 2012;26:252. 5 Subtypes of IBS

Lacy BE, et al. Gastroenterology. 2016;150(6):1393-1407.e5. Functional Bowel Disorders are a Spectrum

Type 1

Type 2 FC C

Type 3 Bloating Constipation Type 4 M IBS

Type 5 Distension Type 6 FDr D

Type 7 Pain

FC: Functional constipation FDr: Functional diarrhea IBS-C: Irritable bowel syndrome with predominant constipation IBS-D: Irritable bowel syndrome with predominant diarrhea IBS-M: Irritable bowel syndrome with mixed bowel habits (D and C)

Lacy BE, et al. Gastroenterology. 2016;150(6):1393-1407.e5. 7 Possible Causes of IBS

Visceral hyper- sensitivity

Altered Abnormal gut microbiome motility

IBS Altered Fluid Brain gut Homeostasis interaction

Genetics Post infection inflammation

Feldman, et al. Sleisenger and Fordtran’s Gastrointestinal and Liver Disease, 10th ed. 2016. (Adapted) Abdominal pain distinguishes CIC & IBS-C

Symptoms ≥3 months, onset ≥6 months prior to diagnosis

CIC* IBS-C Long term (≥6 months)

< 3 stools per week

Stool form that is mostly hard/lumpy†

Difficult stool passage (straining and/or incomplete evacuation)†

Abdominal pain

*No known underlying cause. †≥25% of the time. CIC=chronic idiopathic constipation. IBS-C=irritable bowel syndrome-constipation. Pare P et al. Can J Gastroenterol 2007;21(Suppl B): 3B-22B. 2. Irvine EJ et al. Am J Gastroenterol. 2002 Aug;97(8):1986-93. 3.Paré P et al. Clin Ther. 2006 Oct;28(10):1726-35; discussion 1710-1 9 The impact of IBS on patients

Burden on patients’ quality of life1–3 On average patients would sacrifice 10–15 years of remaining life expectancy for an immediate cure4 Regular visits to Disturbed sleep Reduced HCPs work productivity

Presence of Long-term Unnecessary comorbidities Anxiety/ Dietary medication use surgeries / can further depression restrictions investigations* reduce quality of life

*Hysterectomy and appendectomy were 2-fold higher, and cholecystectomy was 3-fold higher in patients with IBS vs. patient who did not have IBS3 1. Furnari M, et al. Ther Clin Risk Manag 2015;11:691–703; 2. Spiller R, et al. Gut 2007;56:1770–1798; 3. Longstreth GF, Yao JF. Gastroenterology 2004;126:1665−1673; 4. Canavan C, et al. Aliment Pharmacol Ther 2014;40:1023–1034. IBS Patients are Dissatisfied and Frustrated

80 74

A little bit satisfied 60 29% 48

39 40 37 34 Somewhat Not at all satisfied satisfied 28 29% 34% Respondents(%;=n 3,254) 20 20 18

4 4 1 0 Very Extremely satisfied satisfied 5% 3%

IFFGD. IBS Patients: Their Illness Experience and Unmet Needs; 2009. IBS in America summary findings, AGA: data extracted from full raw data set, December 2015. 11 Diagnosis and Management of IBS

12 Diagnosis and Management of IBS

IBS management algorithm1

Identify key patient 1 IBS diagnosis algorithm1 characteristics

Patient presents with Educate and reassure the defining symptoms 2 patient

1 Assess 3 Optimise treatment

2 Diagnose 4 Follow up

1. Moayyedi P, et al. United European Gastroenterol J 2017;5:773–788. Patient presenting with symptoms suggestive of IBS1

Typically, the first point Recurrent bothersome symptoms for at least 3 months at which patients with suspected IBS will consult a physician is when their symptoms are ABDOMINAL PAIN ALTERED BOWEL HABIT bothersome enough to + (constipation, diarrhoea or both) affect their daily life.1

The following tools can aid in establishing a diagnosis of IBS

ROME IV IBS Bristol Stool diagnostic subtypes Form Scale criteria

1. Moayyedi P, et al. United European Gastroenterol J 2017;5:773–788. Reaching a positive diagnosis of IBS1

Recurrent bothersome symptoms for at least 3 Patient meets months diagnostic criteria

ALTERED BOWEL ABDOMINAL PAIN HABIT + (constipation, diarrhoea or both)

ASSESS • Conduct a history and physical exam • Investigations should be minimal – (can be a challenge) 1 • If concerns exist for organic disease, conduct further investigations

1. Moayyedi P, et al. United European Gastroenterol J 2017;5:773–788. Features that may cause concern for organic pathology1

• Age 50 years or above • Abdominal mass • Blood in stools (unless of anal • Ascites origin – haemorrhoids or fissures) • Elevated white blood cell count • Unintended weight loss • Loss of appetite • Unexplained anaemia • Nocturnal symptoms • Family history of IBD, coeliac • Fever disease, or colon cancer • Recent change in symptoms

These features should be considered in the context of the supportive features, marked changes or the presence of multiple features

1. Moayyedi P, et al. United European Gastroenterol J 2017;5:773–788. Assessment and investigation: (history/physical exam)1

Identify symptom triggers (e.g. diet, stress) Limited laboratory studies to help distinguish IBS from other gastrointestinal conditions1

Complete blood count Assess impact on daily life If anaemia or an elevated white blood cell count is detected, further investigation should be conducted Assess for psychological comorbidities C-reactive protein and faecal calprotectin Assess for other physical To exclude IBD or other comorbidities inflammatory conditions in individuals with diarrhoea (e.g. gynaecological, urological)

Explore patient’s values and preferences

1. Moayyedi P, et al. United European Gastroenterol J 2017;5:773–788. Further questions to confirm a positive diagnosis of IBS1

Defining symptoms The nature and onset of symptoms is also Abdominal pain Altered bowel habit important (e.g. in (constipation, diarrhoea or both) + relation to episodes of gastroenteritis, stressful events etc.)1

Further features supportive of diagnosis Pattern, duration Pain relieved/worsened by bowel movements and location important

Abdominal symptoms Bloating, distention, flatulence Consistent with diagnosis but not always present Migraines, interstitial cystitis, Non GI symptoms dyspareunia, constant lethargy Presence of other functional GI disorders may support IBS diagnosis

1. Moayyedi P, et al. United European Gastroenterol J 2017;5:773–788. Reaching a positive diagnosis of IBS1

Recurrent bothersome symptoms for at least 3 months Patient meets diagnostic criteria

ABDOMINAL PAIN ALTERED BOWEL HABIT + (constipation, diarrhoea or both)

ASSESS • Conduct a history and physical exam 1 • Investigations should be minimal • If concerns exist for organic disease, conduct further investigations

DIAGNOSE 2 • If there are no concerns for organic pathology, give a POSITIVE diagnosis of IBS

1. Moayyedi P, et al. United European Gastroenterol J 2017;5:773–788. IBS management algorithm at a glance1

Identify key patient • Identify the predominant symptom(s) • Consider previous therapies, 1 characteristics preferences and patient expectations

Educate and reassure • NAME and EXPLAIN the condition 2 the patient • Provide reassurance

• Consider non-pharmacological and pharmacological treatments based on 3 Optimize treatment the predominant symptom, patient preferences and expectations

• Reassess at 4–8 weeks Follow up • Assess relief, satisfaction, 4 compliance and tolerability strategies

1. Moayyedi P, et al. United European Gastroenterol J 2017;5:773–788. 1 Identify key patient characteristics1

When deciding on an appropriate treatment strategy, it is important to understand the clinical profile of the patient:

Predominant Impact on Treatment Patient Patient Psychological symptom quality of history preferences goals comorbidities life

Including Symptom Over the counter E.g. for non- Expectation May pattern and impact on and prescription pharmacologic s for therapy contribute to severity daily medications al worsening of activities therapies symptoms

Adapted from Moayyedi P, et al. 20171

1. Moayyedi P, et al. United European Gastroenterol J 2017;5:773–788. 2 Educate and reassure the patient1

Providing patients with a written diagnosis of IBS rather than Establishing a strong patient- just verbal confirmation physician relationship at this early stage – getting to the root of the patient’s concerns and explaining their NAME and EXPLAIN IBS to patients using patient-friendly condition – is a crucial step terminology towards finding an effective management strategy.1 Build a strong patient-physician relationship Using active listening, not interrupting, empathy, setting realistic patient expectations, eye contact and open body posture

Use simple visual tools to simplify the complex pathophysiology of IBS

Teach patients simple self-management strategies Related to diet and stress management

Reassure the patients to reduce their symptom-related fears and anxiety

1. Moayyedi P, et al. United European Gastroenterol J 2017;5:773–788. Evidence Based Recommendations on IBS Management

23 Optimize treatment:1 3 Start with conservative management

3Regardless of subtype Conservative management or predominant 3symptoms, for many patients, the first-line Lifestyle and dietary modifications approach of lifestyle and (usually tried BEFORE pharmacological interventions and advanced management strategies) dietary modifications may provide relief from IBS without the need for Promoting increased Encouraging healthy eating habits further interventions1 physical activity

Modifying the intake of alcohol, caffeine, fat, spicy food, and gas-producing foods.

Investigating potential carbohydrate Restricting milk Modifying malabsorption and dairy products dietary fibre

Adapted from Moayyedi P, et al. 20171 1. Moayyedi P, et al. United European Gastroenterol J 2017;5:773–788. Diet • Fiber (RCT evidence) in IBS-C - May benefit constipation and provide some global symptom benefit - Not helpful for pain or diarrhea • Consider trial of Lactose and gluten avoidance • Reduce excess fructose, fatty foods, gas- producing foods, caffeine, alcohol • Specific diets: FODMAPs FODMAPs

•Fermentable Oligo- Di- and Mono- saccharides And Polyols

•Short chain carbohydrates that are poorly absorbed. As a result: – Osmotically active – Rapidly fermented 27 Probiotics • Mixed results, low quality studies • Probably most potential for benefit in IBS-D Antispasmodics • 2011 Meta-analysis: antispasmodics superior to placebo • Smooth Muscle Relaxants – Pinaverium (Dicetel) – Trimebutine (Modulon) • Anticholinergic – Dicyclomine – Buscopan Antidepressants

• TCAs (amitriptyline, desipramine) – Meta-analyses have included low-quality studies, report NNT 3-4 for improvement in global well-being – Large RCT - Desipramine vs. placebo – in female patients 60% vs. 47% response – May be most beneficial in diarrhea-predominant IBS – Up to 40% discontinue use because of intolerance • SSRIs / SNRIs – Fewer side effects, RCTs report more mixed results Herbal Medicines

Peppermint oil = active ingredient is menthol – Has antispasmodic properties – Ibgard – slow release formulation, has some RCT data to support its use – Meta-analysis of 5 RCTs showed significant global improvement of IBS-Sx compared with placebo Antibiotics

• Two Phase 3 RCTs (1260 pts) for non-constipation IBS: rifaximin 550mg tid x 14d improved global Sx and individual Sx (bloating, AP, stool consistency) vs. placebo – Benefits persisted up to 3 months – alteration of flora? – Side effects: Safe – no C diff – Long term prognosis (>10 weeks) unknown Optimize treatment:1 3 Target therapy towards predominant symptoms

3 Conservative management 3 Lifestyle and dietary modifications (usually tried BEFORE pharmacological interventions and advanced management strategies)

If patients do not respond or are refractory to these measures, base the sequence of treatments on:

Individual Predominant Quality of Preference and patient symptoms evidence availability assessment

Management targeted at predominant symptom (order of use according to IBS subtype) Diarrhea Constipation Laxative user IBS-D Bloating IBS-C Bloating IBS-M Loperamide user Pain Pain Pain

Figure adapted from Moayyedi P, et al. 20171

1. Moayyedi P, et al. United European Gastroenterol J 2017;5:773–788. Optimize treatment:1 3 IBS management options at a glance

If patients do not respond or are refractory to lifestyle/dietary modifications, base the sequence of treatments on: Predominant Individual Preference Quality of evidence symptoms patient assessment and availability Diarrhea Bloating Pain • Loperamide • Rifaximin • Antispasmodics • Eluxadoline • Eluxadoline • Eluxadoline IBS-D • Cholestyramine • Low-FODMAP diet • TCAs • Ondansetron • Probiotics • Psychological therapy • Rifaximin • Bile acid sequestrants • Probiotics Constipation Bloating Pain • Water soluble fibre • Linaclotide • Linaclotide IBS-C • Laxatives • Lubiprostone • Antispasmodics • Linaclotide • Low-FODMAP diet • SSRIs • Lubiprostone • Probiotics • Psychological therapy • Prokinetics • Probiotics Laxative user Loperamide user Pain • Stop laxative • Stop loperamide • Antispasmodics IBS-M • Low-FODMAP diet • SSRIs or TCAs • Psychological therapy • Probiotics

Figure adapted from Moayyedi P, et al. 20171 Some classes of drug referred to may not be licensed for use in IBS. Refer to the relevant Product Monograph of each product for their approved indication. Eluxadoline is indicated in adults for the treatment of IBS-D.6 Linaclotide is indicated for the treatment of IBS-C and CIC in adults.11 Eluxadoline: Mechanism of Action Eluxadoline: Mechanism of Action

Patients with IBS-DEluxadoline: experience:

IncreasedSlows GI transit 1 Lumen + + – DecreasesIncreased secretionsecretion 2 κ µ δ Mucosa Submucosa EluxadolineEluxadolineEluxadoline agonizes binds δ Reduces Visceralvisceral pain 3 opioidκantagonizesandantagonism receptorsµ opioid δ opioidinPainmodulates receptorsthe GIreceptors tract fibresµ agonism

Dove LS et al. Gastroenterology. 2013;145:329; Fujita W et al. Biochem Pharmacol. 2014;92:448; Wade PR et al. Br J Pharmacol. 2012;167:1111; Viberzi (eluxadoline) [prescribing information]. Parsippany, NJ: Actavis Pharma, Inc., 2016. 36 Pivotal, Double-Blind, Phase 3 Trials

EFFICACY SAFETY CONTINUATION

RANDOMIZATION EFFICACY EFFICACY END OF TREATMENT 1:1:1 (day 1) 12 weeks (FDA) 26 weeks (EMA) 52 weeks

PTX Placebo (n=427) BID IBS-3001 (2 weeks)

PRE-SCREEN SCREENING PTX (≤1 week) (2–3 weeks) Eluxadoline (n=427) 75 mg BID (2 weeks)

PTX Eluxadoline (n=426) 100 mg BID (2 weeks)

PBO Placebo (n=382) BID IBS-3002 (4 weeks)

PRE-SCREEN SCREENING PBO (≤1 week) (2–3 weeks) Eluxadoline (n=381) 75 mg BID (4 weeks)

PBO Eluxadoline (n=382) 100 mg BID (4 weeks)

Time (weeks) 0 12 26 39 52

BID, twice a day; EMA, European Medicines Agency; FDA, US Food and Drug Administration; PBO, placebo withdrawal period; PTX, post treatment. Lembo AJ et al. N Engl J Med. 2016;374:242. 37 SECONDARY ENDPOINT Adequate Relief

Placebo Eluxadoline 75 mg Eluxadoline 100 mg

IBS-3001 IBS-3002 IBS-3001 IBS-3002 Weeks 1–12 Weeks 1–26 75 75

* 60.1 * 58.4 * * * 54.2 * 53.7 52.9 * 52.8 49.2 49.5 50 50 45.7 43.8 43.7 40.0 Responders(%) Responders(%)

25 25

0 0 n=427 n=427 n=426 n=382 n=381 n=382 n=427 n=427 n=426 n=382 n=381 n=383

*p<0.05 vs. placebo; Cochran-Mantel-Haenszel analysis of the intention-to-treat population. Adequate Relief Responders were patients who reported adequate relief for ≥50% of weeks, based on response to the following question asked each week (1-26): “Have you had adequate relief of your IBS symptoms?” Lembo AJ et al. N Engl J Med. 2016;374:242; TRUBERZI (eluxadoline) [summary of product characteristics]. Courbevoie, France: Aptalis Pharma SAS, 2016. 38 SECONDARY ENDPOINT Urgency-Free Days: Post Hoc Analysis

Placebo Eluxadoline 75 mg Eluxadoline 100 mg

Pooled IBS-3001 and IBS-3002 data

50% urgency- 75% urgency- 50% urgency- 75% urgency- free days free days free days free days 75 Weeks 1–12 75 Weeks 1–26

50 50 * * 45.5 * * 44.6 40.6 40.7

34.1 Responders(%) 29.3 Responders(%) * * * 26.6 27.9 23.8 * 25 23.2 25

16.6 14.3

0 0

At baseline, patients reported a mean of 3.5 urgency episodes/day and 1.0–1.4 incontinence episodes/day.

*p<0.0001 vs. placebo. An urgency-free day was any day on which a patient recorded a “zero” for the number of urgency episodes (sudden, almost irresistible need to have a bowel movement) in the past 24 hours, regardless of the number of bowel movements. Lembo A et al. Presented at: ACG 2014, Philadelphia, PA. 39 Eluxadoline: Safety and Tolerability

40 Anatomy of the Bile Duct

41 Sphincter of Oddi Spasm and Pancreatitis Events in Clinical Trials

Eluxadoline 75 mg Eluxadoline 100 mg (n=807)* (n=1,032)†

Sphincter of Oddi 2 (0.2%) 8 (0.8%) spasm (SOS)‡

All events resolved upon • 1 patient had abdominal pain • 7 patients had abdominal pain treatment discontinuation, typically improving by the and elevated hepatic enzymes and elevated hepatic enzymes following day; 80% of cases occurred within • 1 patient had abdominal pain • 1 patient had pancreatitis, occurring 1 week of treatment, and the and lipase elevation <3x ULN within minutes of taking treatment rest within 1 month.

Pancreatitis 2 (0.2%) 3 (0.3%)

• 3 patients had excessive alcohol intake All pancreatic events resolved with lipase normal- ization upon treatment • 1 patient had biliary sludge discontinuation; 80% of cases resolved within 1 week. • 1 patient discontinued treatment prior to symptom onset

*Of whom 165 did not have a gallbladder; †Of whom 184 did not have a gallbladder; ‡Occurred only in patients without a gallbladder. ULN, upper limit of normal Viberzi (eluxadoline) [prescribing information]. Parsippany, NJ: Actavis Pharma, Inc., 2016. 42 Common Adverse Reactions

Placebo Eluxadoline 75 mg Eluxadoline 100 mg Adverse reaction (%) (n=975) (n=807) (n=1,032) Constipation 2 7 8 Nausea 5 8 7 Abdominal pain* 4 6 7 Upper respiratory tract infection 4 3 5 Vomiting 1 4 4 Nasopharyngitis 3 4 3 Abdominal distension 2 3 3 Bronchitis 2 3 3 Dizziness 2 3 3 Flatulence 2 3 3 Rash† 2 3 3 Increased ALT 1 2 3 Fatigue 2 3 2 Viral gastroenteritis 2 3 1

The table shows ADE reported in phase 2 and 3 studies in >2% of eluxadoline-treated patients at either dose and at an incidence greater than in placebo-treated patients. During the 4-week single-blind withdrawal period in Study 2, no evidence of worsening of diarrhea or abdominal pain compared to baseline was demonstrated at either dose. *Includes abdominal pain, abdominal pain lower, and abdominal pain upper; †Includes dermatitis, dermatitis allergic, rash, rash erythematous, rash generalized, rash maculopapular, rash papular, rash pruritic, urticaria, and idiopathic urticaria. Viberzi (eluxadoline) [prescribing information]. Parsippany, NJ: Actavis Pharma, Inc., 2016. 43 Common Adverse Reactions

Placebo Eluxadoline 75 mg Eluxadoline 100 mg Adverse reaction (%) (n=975) (n=807) (n=1,032) Constipation 2 7 8 Nausea 7 8 5 Abdominal pain* 7 6 4 • Most constipation events occurred within the first 3 months Upper respiratory tract infection 5 3 4 of therapy, with ~50% occurring within the first 2 weeks Vomiting 4 4 1 Nasopharyngitits• Rates of constipation3 were similar between4 active and 3 Abdominal distensionplacebo arms beyond3 3 months of treatment3 2 Bronchitis • Severe constipation 3occurred in <1% 3of eluxadoline patients2 Dizziness 3 3 2 • No serious complications from constipation were reported Flatulence 3 3 2 Rash† 3 3 2 Increased ALT Eluxadoline should3 be discontinued2 in patients who 1 Fatigue develop severe constipation2 for more3 than 4 days. 2 Viral gastroenteritis 1 3 2

The table shows ADE reported in phase 2 and 3 studies in >2% of eluxadoline-treated patients at either dose and at an incidence greater than in placebo-treated patients. During the 4 week single-blind withdrawal period in Study 2, no evidence of worsening of diarrhea or abdominal pain compared to baseline was demonstrated at either dose. *Includes abdominal pain, abdominal pain lower, and abdominal pain upper; †Includes dermatitis, dermatitis allergic, rash, rash erythematous, rash generalized, rash maculopapular, rash papular, rash pruritic, urticaria, and idiopathic urticaria. Lembo AJ et al. N Engl J Med. 2016;374:242; Viberzi (eluxadoline) [prescribing information]. Parsippany, NJ: Actavis Pharma, Inc., 2016. 44 Linaclotide Mechanism of Action

Alignment with Functional GI Disease Pathophysiology

45 Linaclotide Mechanism of Action

Lumen Serosa

GC-C = guanylate cyclase-C; GTP = guanosine triphosphate; cGMP = cyclic guanosine monophosphate; NHE-3 = sodium-hydrogen exchanger 3; PKGII = protein kinase G type II; CFTR = cystic fibrosis transmembrane conductance regulator

*Based on findings from animal studies; clinical relevance in humans has not been established.

1. Vaandrager AB. Mol Cell Biochem. 2002; 230(1-2):73-83. 2. Eutamene H et al. Neurogastroenterol Motil. 2010; 22: 312–e84. 46 3. Castro J et al. Gastroenterol 2013 ;145(6):1334-46. Canadian Constella® (linaclotide) indications

Irritable Bowel Syndrome with Constipation (IBS-C) Constella® (linaclotide) is indicated for the treatment of irritable bowel syndrome with constipation in adults

Chronic Idiopathic Constipation (CIC) Constella® (linaclotide) is indicated for the treatment of chronic idiopathic constipation in adults

Constella® (linaclotide) Product Monograph. Forest Laboratories Canada Inc. May 12, 2014. 47 Constella® in IBS-C

Chey WD et al. Am J Gastroenterol. 2012 Nov;107(11):1702-12 Rao S et al. Am J Gastroenterol 2012; 107(11):1714-24 48 Phase 3 Trials in IBS-C: Baseline Characteristics

Trial 302 Trial 31 Placebo Linaclotide Placebo Linaclotide (N=403) 290 ug (N=401) (N=395) 290 ug (N=405) Mean age 44 44.6 43.7 43.3 Age ≥65 (%) 17 (4.2%) 23 (5.7%) 26 (6.6%) 19 (4.7%) Female (%) Mean352 CSBM (87.3%) frequency368 (91.8%) was 0.2 CSBMs/week357 (90.4%) 367 (90.6%) White (%) 76%311 (77.2%) of patients 316had (78.8%) 0 CSBMs301during (76.2%) 314 (77.5%) 2 week pretreatment period BMI 27.7 27.8 27.6 28.3 CSBMs/week 0.2 0.2 0.2 0.2 SBMs/week 1.7 1.7 1.9 1.9 Stool consistency (BSFS) 2.3 2.4 2.4 2.3 Straining score 3.5 3.6 3.4 3.6

Constipation severity score 3.8 3.8 3.7 3.8

IBS symptom severity 3.7 3.7 3.7 3.7

Rao S et al. Am J Gastroenterol 2012; 107(11):1714-24 Chey WD et al. Am J Gastroenterol. 2012 Nov;107(11):1702-12 49 Constella® - Significant sustained IBS-C: Study 2 improvement in bowel functioning SBM Week / SBM

Week

• 76% of linaclotide-treated patients experienced a weekly increase of ≥ 1 SBM/week (vs. 46% of placebo treated patients, P<0.0001) • 54% had an increase of ≥ 3 SBMs/week (vs.15% of placebo treated patients, P<0.0001)

Mean SBM / week p < 0.0001 for each of the 26 weeks based on ANCOVA at each week Chey WD et al. Am J Gastroenterol. 2012 Nov;107(11):1702-12 SBM = spontaneous bowel movement 50 Constella® - Significant sustained IBS-C: Study 2 improvement in abdominal pain % Change in Worst AbdominalPain % Changein Worst

Week • 70% of linaclotide-treated patients had a clinically relevant reduction in abdominal pain (vs. ~50% of placebo treated patients, P<0.005)

Chey WD et al. Am J Gastroenterol. 2012 Nov;107(11):1702-12 Least-squares mean percent change in worst abdominal pain 51 Castro et al Gastroenterol, 2013; 145:1334-1346 p < 0.001 for each of the 26 weeks based on ANCOVA at each week Constella® in CIC

Lembo A et al. N Engl J Med 2011;365:527-36. 52 Weekly Mean CSBM Frequency Rate – Randomized Withdrawal Period

Randomized Treatment Period Withdrawal Period 3

1 Weekly CSBMs Weekly

BL 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 Study Week p-values <0.0001 for all treatment period weeks

RW Treatment Sequence  145 μg → 145 μg 145 μg → Placebo Treatment Period  Placebo → 290 μg  145 μg  Placebo

Lembo A et al. N Engl J Med 2011;365:527-36.; Constella® (linaclotide) Product Monograph. Forest Laboratories Canada Inc. May 12, 2014. 53 Phase 3 Trials in CIC and IBS-C: Adverse Event Profile

Adverse reactions reported in ≥1% of linaclotide-treated patients and at an incidence greater than in the placebo group

CIC IBS-C

Linaclotide Linaclotide Linaclotide 145 µg 290 µg Placebo 290 µg Placebo N=430 N=422 N=423 N=807 N=798 % % % % % Diarrhea 16.0 14.2 4.7 Diarrhea 19.8 3.0 Flatulence 5.6 5.0 5.2 Abdominal pain 5.1 3.3 Abdominal pain 4.0 4.7 3.1 Flatulence 4.3 1.9 Nausea 3.5 4.3 3.5 Abdominal distention 2.2 1.1 Abdominal distention 3.5 3.6 2.4 Vomiting 1.7 1.3 Abdominal pain upper 3.0 1.2 1.7 Gastroesophageal 1.2 0.9 Dyspepsia 1.9 0.7 0.7 reflux Gastroenteritis viral 1.9 0.5 0.5 Fatigue 1.5 1.4 Dizziness 0.9 1.4 0.5 Gastroenteritis viral 2.6 1.4

Constella® (linaclotide) Product Monograph. Forest Laboratories Canada Inc. May 12, 2014. 54 Dosing and Administration

IBS-C CIC 290 μg 145 μg

• Constella® (linaclotide) is recommended to be taken orally once daily on an empty stomach, at least 30 minutes prior to the first meal of the day

• Exceeding the daily dose of 145μg for the treatment of CIC is not expected to increase efficacy

• No dose adjustment required for patients with hepatic or renal impairment

• No systemic drug to drug interactions expected

• Constella® is contraindicated in patients under 6 years of age or patients with known or suspected gastrointestinal obstruction

Constella® (linaclotide) Product Monograph. Forest Laboratories Canada Inc. May 12, 2014. 55 The key stages to successful IBS management1

Make a confident positive diagnosis of IBS and explain the underlying causes to the patient in relatable terms

Establish a strong patient–physician relationship to instil patient confidence

Identify potential dietary and lifestyle triggers that can be modified as the first stage of IBS management

If these measures are unsuccessful, base the subsequent treatment approach on predominant symptoms, quality of evidence and individual patient characteristics and preferences

1. Moayyedi P, et al. United European Gastroenterol J 2017;5:773–788. Follow up:1 4 Key factors to optimise management

Once a patient is started on a specific management strategy, reassess after FOUR to EIGHT weeks for their response to treatment. What does treatment success mean to the patient? • What level of improvement is acceptable for them (overall and individual symptoms) • Is the patient achieving satisfactory relief from their most bothersome symptoms?

Consider strategies to optimise treatment tolerability • Encourage patients to report any adverse events as soon as they occur • Be contactable to the patient (e.g. phone, email) to facilitate this • Determine the minimum effective dose to minimise the potential for adverse events • Assess the need to continue or to interrupt treatment

• Assess patient compliance (frequency, timing etc.)

• As most pharmacological therapies used for IBS management target specific symptoms, combining therapies may be a valid approach to target multiple symptoms

• Consider the need for further investigations if there is no response to therapy

1. Moayyedi P, et al. United European Gastroenterol J 2017;5:773–788.

HCV and Alcohol: Risk of Cirrhosis

100 80

60 HCV 40 HCV + alcohol

Cirrhosis (%) 20 0 10 20 30 40 Years Following Exposure Excessive alcohol intake characterized as > 40 g/day for women and > 60 g/day for men.

Wiley TE, et al. Hepatology 1998:28:805-9. Signs and Symptoms Are Not Usually Helpful for Identification of HCV . Most patients with HCV infection (60% to 75%) are asymptomatic – If a patient does exhibit symptoms, they may already have advanced liver disease

. Liver enzyme tests (e.g., ALT, AST): patients with HCV often have normal liver enzymes . HCV-specific screening is crucial

ALT, alanine transaminase; AST, aspartate transaminase.

Adapted from Wong T, et al. CMAJ. 2006;174:649-59; Centers for Disease Control and Prevention. www.cdc.gov/hepatitis/resources/professionals/pdfs/abctable.pdf; and Seeff LB. Hepatology. 2002;36(Suppl 1):S35-46. Risk Factors Associated With Chronic HCV Infection1

Receipt of contaminated blood transfusions Receipt of medical or dental care in settings Injection drug use with substandard infection control

Hemodialysis in low- Intranasal drug use HCV Risk and middle-income countries

Persons with HIV, in particular men who Being born to an have unprotected sex infected mother with men

Current or previous Tattoos, piercings, or incarceration scarification procedures

WHO. Guidelines for the screening, care and treatment of persons with hepatitis C infection. April 2014. ISBN 978 92 4 154875 5. Groups to Prioritize for HCV Screening .Birth between 1945 and 1975 .Any history of injection drug use .Living or having lived in an endemic area .Contaminated blood or blood products or organ transplantation before 1992 in Canada .High-risk sexual behaviour

Adapted from Wong T, et al. CMAJ. 2006;174:649-59. Evaluation: Laboratory Testing

Virological tests to diagnose Abdominal ultrasound and confirm HCV infection • Evaluate for cirrhosis and • Anti-HCV exclude HCC • HCV-RNA • HCV genotype Tests to rule out Other bloodwork coinfections • CBC • Hepatitis A (HAV-Ab) • Liver enzyme & function tests: • Hepatitis B (HBsAg, HBsAb, • ALT, AST, GGT, ALP, bilirubin, INR, HBcAb) albumin • HIV (Anti-HIV) • Normal ALT is not a contraindication to treatment (⅓ have normal test results)2 • Creatinine Fibrosis is the Key

• Fibrosis stage can be evaluated with a FibroScan

• Biopsies are no longer required in the majority of cases