Disclosures. Planning Committee Member Julie Messick No Relevant Relationships. Faculty All faculty disclosures can be found in your meeting guide.

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2 Disclosures All faculty and staff involved in the planning or presentation of continuing education activities provided by Annenberg Center for Health Sciences at Eisenhower (ACHS) are required to disclose to the audience any real or apparent commercial financial affiliations related to the content of the presentation or enduring material. Full disclosure of all commercial relationships must be made in writing to the audience prior to the activity. John Bayliss, VP, Business Development, Annenberg Center, spouse is an employee of Amgen, Inc; all other staff at the Annenberg Center for Health Sciences at Eisenhower and the Gi Health Foundation have no relationships to disclose. Planning Committee Member Julie Messick No Relevant Relationships Faculty All faculty disclosures can be found in your meeting guide. 2

3 This program is supported by educational grants from Commonwealth Laboratories LLC and QOL Medical LLC 3

4 Learning Objectives Incorporate into clinical practice novel diagnostic tools to differentiate IBS from other common disorders and make a "positive" IBS diagnosis Individualize nonpharmacologic treatment plans for IBS patients using evidence-based recommendations Individualize pharmacologic treatment plans for IBS patients using evidence-based recommendations 4

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6 Welcome and Introduction Nicholas J. Talley, MD 6

7 Late-Breaking News from DDW 2016 Plecanatide in CIC Curable CSBM responders, % Curable CSBM responders, % P<0.001 P<0.001 Proportion of Durable CSBM Responders* Study-00 (N=1346, ITT population) Study-03 (N=1337, ITT population) 12.8 P=0.004 P= Placebo Plecanatide 3 mg QD Plecanatide 6 mg QD *Defined as weekly responders for at least 9 of 12 treatment weeks, for at least 3 of the last 4 weeks. Weekly responders had 3 CSBMs and an increase of 1 CSBM from baseline. Miner PB et al. Presented at DDW Presentations Sa1440 and Su

8 Change in Stool Consistency from Baseline Late-Breaking News from DDW 2016 Plecanatide in CIC Study * * * Post- * * 1.6 * * * * * * * Treatment 1.4 * * * * * * * * * * * 1.2 * 1.0 ** Treatment Time (Week) Effect on Stool Consistency * * * * Study-03 Treatment Time (Week) Placebo Plecanatide 3 mg QD Plecanatide 6 mg QD * * * * * * * * * * * * * * * * * * * Post- Post- Treatment Treatment * Value are LS mean Error bars represent standard error; *p<0.001; **p=0.46 Krause R et al. Presented at DDW Presentation Sa

9 Late-Breaking News from DDW 2016 Plecanatide in CIC Incidence of Diarrhea and Discontinuation Due to Diarrhea Placebo % Study 00 (N=1346) Study 03 (N=1337) Plecanatide % Placebo Plecanatide % 3 mg 6 mg % 3 mg 6 mg Diarrhea Discontinuation due to diarrhea Miner PB et al. Presented at DDW Presentations Sa1440 and Su

10 Late-Breaking News from DDW 2016 Prucalopride in Idiopathic Gastroparesis Change in gastric emptying time (min) Effect of Prucalopride on Gastric Emptying Time After 4 Weeks (N=28) Carbone F et al. Presented at DDW Presentaiton ± 13.1 P< ± 19.5 P< ± 17.1 Placebo Baseline Prucalopride 2 mg QD 10

11 Field Report: Advances in Symptom-Based Diagnosis of IBS Rome IV Update 11

12 Late Breaking News from DDW Rome IV Criteria Rome III 1 Rome IV 2 Recurrent abdominal pain or discomfort at least 3 days/month in the last 3 months associated with 2 of the following: 1. Improvement with defecation 2. Onset associated with change in stool frequency 3. Onset associated with change in stool form (appearance) Criteria should be fulfilled for the last 3 months with symptom onset 6 months prior to diagnosis Recurrent abdominal pain, on average, at least 1 day per week in the last 3 months, associated with 2 of the following: 1. Related to defecation 2. Associated with change in stool frequency 3. Associated with change in stool form (appearance) Criteria should be fulfilled for the last 3 months with symptom onset 6 months prior to diagnosis 1. Longstreth GF et al. Gastroenterology. 2006;130: Lacy BE et al. Gastroenterology. 2016;150:

13 Integrating Novel Diagnostic Strategies into Clinical Practice William D. Chey, MD Stanley A. Cohen, MD 13

14 Typical Patient HISTORY & PE MEDICATION LABS PROGRESS NOTES OTHER HPI Family History Pain, periumbilical or generalized, several times per week, intense at times, often accompanied by bloating Mother also troubled by similar symptoms and diagnosed with IBS Doesn t usually follow meals 15 year-old female with longstanding abdominal discomfort and diarrhea Occurs on weekends and vacations as well as school days Diarrhea varies from 0-3 mushy stools to 5-6 looser ones on the days with pain but no blood Admits to embarrassing flatulence Social History Academically high achiever 14

15 Typical Patient HISTORY & PE MEDICATION LABS PROGRESS NOTES OTHER PE Thin female, NAD Normal vitals 15th percentile Height, 8 th percentile Weight, with BMI 30% Entirely normal except for slightly distended abdomen, increased borborygmi No tenderness or organomegaly CBC, CRP, LFTs, TTG/IgA normal 15

16 Does she have IBS? 16

17 Searching for IBS: Differential Diagnoses Bile acid diarrhea Microscopic colitis Celiac disease Non-celiac wheat intolerance Food allergy Disaccharidase deficiency 17

18 Bile Acids and IBS-D Enterohepatic circulation of bile acids IBS with bile acid diarrhea (25-50% prevalence) Adapted from Camilleri M. Gut Liver. 2015;9:

19 Proportion of Responders (%) IBS-SSS Score Colestipol for Bile Acid Diarrhea in IBS Abnormal 75 SeHCAT retention and/or C4 level in 32% & 19% of IBS-D 75SeHCAT test correlates with hepatic bile acid synthesis, bowel habits & colonic transit time in IBS patients A Change in IBS Severity Score ** ** Symptom response to open-label colestipol in patients with abnormal 75SeHCAT retention supports a role of bile acids in IBS-D symptoms B Baseline Week 2 Week 4 Week 6 Week 8 Adequate Relief of IBS Symptoms **P<0.01 vs baseline. SeHCAT, 75Se-labelled homocholic acid-taurine. Bajor A et al. Gut. 2015;64:

20 Colonoscopy Findings in IBS Without Alarm Features Patients, % Prevalence of Structural Abnormalities in IBS Patients Compared with Controls IBS patients (n=466) Controls (n=451) P< Adenomas 11.5 Hyperplastic polyps Colorectal adenoma IBD N/A Microscopic colitis Chey WD et al. Am J Gastroenterol. 2010;105: Microscopic colitis more common in IBS-D patients aged 45 years 20

21 IBS vs Microscopic Colitis Favors IBS Meal-related diarrhea Intermittent symptoms Longstanding symptoms Symptoms with stress Family history of IBS Favors Microscopic Colitis Nocturnal diarrhea Unrelenting symptoms Short symptom duration New drug in last 1 to 3 months Other autoimmune disorders Majority of cases will be diagnosed with left colon biopsies alone McCaigne G, et al. Am J Gastroenterol. 2014;109:

22 Patients with celiac disease, % How Common Is Celiac Disease in IBS? International Meta-analysis 1 Prevalence of biopsy-proven celiac disease in IBS vs controls US Prospective Study 2 Non-constipated IBS patients (Rome II) biopsy-proven celiac disease 4.34 ( ) IBS patients (n=492) Controls (n=458) 1. Ford et al. Archives Int Med. 2009;169: Cash BD and Chey WD. Gastroenterology. 2011;141:

23 IBS and Celiac Disease Most IBS patients who associate their symptoms with wheat will have non-celiac wheat intolerance, NOT celiac disease 1. Ford et al. Archives Int Med. 2009;169: Cash BD and Chey WD. Gastroenterology. 2011;141:

24 Non-Celiac Wheat Intolerance: Fact or Fad? Encompasses a collection of medical conditions in which gluten leads to an adverse effect 1, 2 True population prevalence is unknown 1-3 Can be clinically indistinguishable from celiac disease but testing is negative or inconclusive 2 Not associated with increased intestinal permeability Innate immunity markers TLR2 & FOXP3 altered in gluten sensitivity but not celiac disease Improves with a gluten-free diet Volta U et al. Best Pract Res Clin Gastroenterol. 2015;29: Green PHR et al. J Allergy Clin Immunol. 2015;135: Lebwohl. B et al. BMJ. 2015;351:h Czaja-Bulsa G et al. Clin Nutr. 2015;34:

25 Understanding Food Allergy Immune-mediated adverse reaction to food 1-3 Acute onset IgE-mediated Urticaria/angioedema Oral allergy syndrome Rhinitis/asthma (wheat) Anaphylaxis Food-associated, exerciseinduced anaphylaxis (wheat) IgE-associated/ cell-mediated Delayed/chronic Atopic dermatitis Eosinophilic gastroenteropathies Cell-mediated Dietary protein enterocolitis/ proctitis True food allergies are rare in IBS 4 1. Valenta R et al. Gastroenterology. 2015;148: Brandtzaeg P. Nat Rev Gastroenterol Hepatol. 2010;7: Soares-Weiser K et al. 2013;3: Turnbull JL et al. Aliment Pharmacol Ther. 2015;41:

26 Diagnosing Food Allergy Skin prick test Serum immunoassays (IgE) Oral challenge Important to understand complexity and variety of nuances, eg: + Skin/blood test may suggest sensitization Cross-reactivity Cooked vs raw antigens IgG serum antibodies have not been adequately validated 1. Sicherer SH and Sampson HA. J Allergy Clin Immunol. 2014;133(2): Valenta R et al. Gastroenterology. 2015;148:

27 Understanding Carbohydrate Malabsorption Polysaccharides Disaccharides Monosaccharides Amylase starch glycogen Palatinase (isomaltase) lactose isomaltose maltose sucrose Lactase Maltase Sucrase fructose glucose galactose 1. Treem WR. J Pediatr Gastroenterol Nutr. 2012;55(Suppl 2):S7-S Canani RB et al. Nutrients. 2016;8:

28 Key Intestinal Disaccharidases Maltase Palatinase Lactase Sucrase Used to approximate glucoamylase Not explicit to maltase, more related to SI (75%) than MGAM (only 25%) Used to approximate isomaltase SI responsible for most isomaltase activity (>70%) Specific to lactose, but lactase deficiency can be as high as 50% after 5 years of age 85% specific to sucrose Digests starch Digests milk sugar Digests table sugar MGAM, maltase-glucoamylase; SI, sucrase-isomaltase. Quezada-Calvillo R et al. J Nutr. 2008;138:

29 Clinical Consequences of Carbohydrate Malabsorption Pain Diarrhea Gas Luminal fluid Bloating 1. Treem WR. J Pediatr Gastroenterol Nutr. 2012;55(Suppl 2):S7-S Canani RB et al. Nutrients. 2016;8:

30 How Common Is Disaccharidase Deficiency? Analysis of Mucosal Biopsies (N=27,875) 55% No disaccharidase deficiency 45% 1 disaccharidase deficiency 4% Other 21% 75% Sucrase deficiency (9.4% of biopsies) Lactase deficiency (34.7% of biopsies) Nichols BL et al. J Pediatr Gastroenterol Nutr. 2012; (Suppl 2):S28-S30. 30

31 How Common Is Disaccharidase Deficiency in IBS? Patients with lactose intolerance, % Lactose Intolerance By Lactose Breath Testing OR=2.57 (95% CI: ) 0 IBS patients (n=251) Controls (n=174) ACG Task Force on IBS. Am J Gastroenterol. 2009;104(suppl 1):S1-S35. 31

32 Potential Etiologies of Key Disaccharidase Deficiencies Congenital lactase deficiency Genetic 1,2 Genetic Sucrase-Isomaltase Deficiency (GSID) Autosomal recessive (CSID) Symptomatic heterozygous carriers Compound heterozygotes Secondary causes 2 Celiac disease Bacterial overgrowth IBD Allergic enteropathy Acute gastroenteritis Giardiasis Other (eg, mucositis) CSID, congenital sucrase isomaltase deficiency; IBD, inflammatory bowel disease. 1. Cohen S. Molecular Cellular Pediatr. 2016;3:5. 2. Naim HY et al. J Pediatr Gastroenterol Nutr. 2012; 55(Suppl 2):S13-S20. 32

33 The Spectrum of GSID Phenotypes Phenotypes IV, VI Enzymatic activity Active sucrase, active isomaltase V Active isomaltase, absent sucrase VII Decreased sucrase, absent isomaltase I, II, III Completely inactive Naim HY et al. J Pediatr Gastroenterol Nutr. 2012; 55(Suppl 2):S13-S20. 33

34 Patients, % Presenting Symptoms of GSID Presenting Symptoms in GSID (N=65) Diarrhea Bloating/ gas Abdominal pain Irritability Diaper rash Failure to thrive Nausea/ vomiting IBS Treem WR. J Pediatr Gastroenterol Nutr. 2012;55(Suppl 2):S7-S13. 34

35 Symptoms of GSID: Infants vs. Adults more severe Shorter length of GI tract Increased consumption of highcarbohydrate diet (juices, baby food, fruits/vegetables, cereals) More rapid intestinal and colonic transit time available for alternative carbohydrate digestion pathways Symptom severity Changes in bowel flora may alleviate symptoms Diet control Carrier status, milder variants Ileal hyperproliferation less severe May be misdiagnosed as IBS, lactose intolerance 1. Treem WR. J Pediatr Gastroenterol Nutr. 1995;21: Treem WR. J Pediatr Gastroenterol Nutr. 2012;55(Suppl 2):S7-S13. 35

36 Methods to Diagnose GSID z Small bowel Sacrosidase biopsy 1,2 Genetic test 2 response dose 2,3 Breath tests 2 Stool tests 1,2 Definitive diagnosis Often sent to specialty lab Buccal or saliva Detects 37 polymorphisms in SI gene Determined by decrease in GI symptoms Hydrogenmethane or 13 C-sucrose ph, osmolality, reducing sugars Not specific for sucrose malabsorption SI, sucrase isomaltase 1. Treem WR. J Pediatr Gastroenterol Nutr. 2012;55(Suppl 2):S7-S Cohen S. Molecular Cellular Pediatr. 2016;3:5. 3. Puntis JW and Zamvar V. Arch Dis Child. 2015;100(9):

37 Hydrogen-Methane Breath Test for GSID Colonic fermentation Sucrose load H 2 &/or methane Indirect test for CHO malabsorption (not specific for GSID) 1-3 Reduced CHO diet 24 hours before test and 12 hours of fasting 4 Catch breath into 6 tubes over 3 hours after ingesting sucrose solution 4 May produce symptoms in GSID patients due to consumption of sucrose 1,2 CHO, carbohydrate; GSID, genetic sucrase-isomaltase deficiency. 1. Ghoshal UC. J Neurogastroenterol Motil. 2011;17(3): de Lacy Costello BPJ et al. J Breath Res. 2013;7: Simren M and Stotzer P. Gut. 2006;55: Sucrose tolerance/malabsorption breath test. Commonwealth Laboratories Inc. Salem, MA. 37

38 Patient Follow-Up PROGRESS NOTES HISTORY MEDICATION LABS OTHER EGD/colonoscopy visually and histologically normal Disaccharidases Lactase 7.9 (abnormal < 17) Sucrase 18.6 (abnormal < 25) Maltase 62.0 (abnormal < 100) Palatinase 2.6 (abnormal < 5) Patient diagnosed with pan-disaccharidase deficiency 38

39 Options for Managing GSID Elimination diet (2 weeks) 1,2 Induction diet establish tolerance to sucrose and starch 1 Sacrosidase may allow for nearly normal sucrose intake Starch tolerance will vary and will not be improved by sacrosidase Sacrosidase oral solution with every meal or snack (half at beginning of meal/snack and other half during meal/snack) 3 1 ml if 15 kg 2 ml if > 15 kg 1. McMeans AR. J Pediatr Gastroenterol Nutr. 2012;55 (Suppl 2):S37-S Treem WR. J Pediatr Gastroenterol Nutr. 2012;55(Suppl 2):S7-S Canani RB et al. Nutrients. 2016;8:

40 Integrating Novel Diagnostic Strategies into Practice Key Points Most IBS patients who associate their symptoms with wheat will have non-celiac wheat intolerance, not celiac disease Bile acid malabsorption and microscopic colitis are under-recognized masqueraders for IBS-D True food allergies in IBS are rare Lactase and sucrase deficiencies are relatively common and can mimic IBS Different genotypes of sucrase-isomaltase deficiencies result in variable symptom patterns Testing for disaccharidase deficiencies is best accomplished by breath testing or duodenal biopsies 40

41 Field Report: Facilitating Patient-Physician Communication About GI Symptoms MyGIHealth Mobile App 41

42 Advances in Management of IBS-D Mark Pimentel, MD Philip Schoenfeld, MD 42

43 Patient Case HISTORY & PE MEDICATION LABS PROGRESS NOTES OTHER 32-year-old female presents complaining of 10+ years of bloating on most days Passes 3-4 loose stools per day with fecal urgency Intermittent LLQ cramping Worry about having an accident is very anxiety-provoking when at work 43

44 Patient Case HISTORY MEDICATIONS LABS PROGRESS NOTES OTHER Prior EGD/colonoscopy: normal Normal stool studies, TSH, CBC, CRP, celiac serologies No other medical problems No family history of GI diseases No danger signs of weight loss, BRBPR, etc. 44

45 Does she have IBS? Are other diagnostic tests needed? What treatments would you try? 45

46 Diagnostic Testing for Patients with Suspected IBS and No Concerning* Features CRP or fecal calprotectin IgA TtG ± quantitative IgA When colonoscopy performed, obtain random biopsies SeHCAT, fecal bile acids, or serum C 4 where available Anti-CdtB/anti-vinculin antibodies 2 All IBS Subtypes 1 CBC Age-appropriate CRC screening IBS-D 1,2 IBS-M 1 IBS-C 1 CRP or fecal calprotectin IgA TtG ± quantitative IgA Stool diary Consider abdominal plain film to assess for fecal loading If severe or medically refractory, refer to specialist for physiologic testing *Alarm features include age 50 years old, blood in stools, nocturnal symptoms, unintentional weight loss, change in symptoms, recent antibiotic use, and family history of organic GI disease. CBC, complete blood count; CRC, colorectal screening; CRP, C-reactive protein; SeHCAT, selenium homocholic acid taurine; Ttg, tissue transglutaninase. 1. Chey WD, et al. JAMA. 2015;313(9): Pimentel M, et al. PLoS ONE. 2015;10(5):e

47 Biomarkers for IBS-D? The IBS Microbial Hypothesis At Work Food poisoning Bacterial toxin Autoimmunity Gut nerve damage Bacterial overgrowth IBS E. Coli C. jejuni Shigella Salmonella Cytolethal Distending toxin (CDT B) Pimentel M, et al. PLoS ONE. 2015;10(5):e Anti-vinculin Reduced ICC Reduced MMC Breath testing Culture qpcr Deep sequencing Antibiotics 47

48 Anti-CdtB and Anti-Vinculin May Help Distinguish IBS-D from IBD Validation study of serum biomarker in IBS-D patients (N=2,375) Comparison groups Crohn s disease (n=73) Ulcerative colitis (n=69) Celiac disease (n=121) Healthy subjects (n=43) Anti-CdtB and anti-vinculin titers significiantly higher in IBS-D compared with other groups (P<0.001) Accuracy for Diagnosing IBS-D vs IBD Optical Density Specificity % Sensitivity % CdtB (cutoff 2.80) Vinculin (cutoff 1.68) CdtB, cytolethal distending toxin. Pimentel M, et al. PLoS ONE. 2015;10(5):e

49 Anti-CdtB and Anti-vinculin Antibodies Vary By IBS Subtype Patients with positive test,% Percentage of Patients with Positive Antibody Testing IBS-D (n=2375) IBS-M (n=25) IBS-C (n=30) Healthy (n=43) Anti-CdtB Anti-vinculin Any positive CdtB, cytolethal distending toxin. Rezaie A et al. Presented at DDW

50 Advances in Nonpharmacologic Treatment of IBS-D 50

51 Patient Case HISTORY & PE MEDICATION LABS PROGRESS NOTES OTHER Patient notes that some foods seem to trigger symptoms Can t eat out at restaurants because those foods usually trigger symptoms Tried gluten-free diet and lactose-free diet without much success PCP has asked her to increase fiber in her diet Used psyllium which helped diarrhea, but made her bloating worse Has not tried FODMAP diet 51

52 Diet Therapies: Food for Thought All IBS treatments have their problems Medications are sometimes not effective Complementary therapies are not evidence-based Behavioral therapies can be difficult to obtain Patients often institute dietary therapy on their own, but. Most aren t evidence-based Some can be dangerous if not properly administered Some diets are expensive Cash BD. 52

53 Food and IBS Symptoms: The Patient s Perspective Patients, % 100 IBS Patients Reporting Symptom Improvement With Intervention (N=1,242) % of patients report worsening of symptoms after meals Small meals Avoiding fat Increasing fiber Avoiding milk products 1. Simren M et al. Digestion. 2001;63: Halpert et al. Am J Gastroenterol. 2007; 102:

54 Dietary Considerations in IBS FODMAPS are an important trigger of meal-related symptoms in IBS 1 Low FODMAP diet found to improve overall symptom scores compared with typical diet in IBS patients 2 Gluten-free diet found to be beneficial in some patients with IBS-D 3,4 Wheat contains fructans and other proteins that may also cause symptoms in IBS patients 5 Food antigens found to cause changes in the intestinal mucosa* of IBS patients that are associated with patient responses to exclusion diets 6 *Breaks in intestinal mucosal, increased intervillous spaces, and increased intraepithelial lymphocytes demonstrated via confocal laser endomicroscopy in 22 of 36 patients with IBS. 1. Shepherd SJ et al. Am J Gastroenterol. 2013;108: Halmos EP et al. Gastroenterology. 2014;146: Biesiekierski JR et al. Gastroenterology. 2011;106: Vazquez-Roque MI et al. Gastroenterology. 2013;144: e3. 5. Chey WD, et al. JAMA. 2015;313(9): Fritscher-Ravens A et al. Gastroenterology. 2014;147:

55 Low FODMAP Diet Reduces Functional GI Symptoms Mean change from baseline Mean Daily Symptom Scores Over Treatment Weeks 3 and Abdominal pain Bloating Frequency Consistency (BSF) Urgency P= P=0.013 P= P= P= Control (n=38) Low FODMAP (n=45) BSF, Bristol Stool Form. Eswaran S et al. Presented at DDW

56 Is A Low FODMAP Diet More Effective Than Traditional Dietary Advice? Patients, % Single-blind study of patients with Rome III IBS (N=75) Randomized to low-fodmap diet or traditional dietary advice Traditional advice focused on how and when to eat rather than on specific food choices Symptoms assessed with IBSS Patients completed 4-day food diary before and after intervention Patients with >50% Reduction in IBSS at Week Low FODMAP diet (n=38) P=NS Traditional dietary advice (n=37) IBSS, IBS severity score. Böhn L et al. Gastroenterology. 2015;149: e2. 56

57 Advances in Pharmacologic Treatment of IBS-D 57

58 Patient Case HISTORY & PE MEDICATION LABS PROGRESS NOTES OTHER She tried loperamide which helped her diarrhea a little but did not improve bloating or cramping, and dicyclomine which was not helpful Has not tried other treatments What treatments would you try? 58

59 Overview of IBS-D Therapies: Mechanisms of Action Modulation of gut flora Rifaximin Probiotics Bile Acid Binders Cholestyramine/ Colestid/Colesevelam Antidepressants TCAs 5-HT 3 antagonists Alosetron Ondansetron µ-opioid receptor agonist Eluxadoline 59

60 Alosetron Improves Multiple IBS-D Symptoms In patients with IBS-D, alosetron is superior to placebo for Global IBS symptoms Abdominal pain Stool frequency Fecal urgency Lotronex (alosetron) [prescribing information]. San Diego; Prometheus Laboratories;

61 Alosetron in the Clinic Dosage/Indication 0.5 mg BID, for female patients with chronic, severe IBS-D who have not responded adequately to conventional therapy 1 REMS program modified in January 2016 to eliminate requirements for patient attestation form and affixing prescribing program stickers to prescriptions for Lotronex/generic alosetron 2 Ischemic colitis 0.95 cases per 1000 patient-years 3 Rare Adverse Effects Associated with Alosetron Serious complications of constipation 0.36 cases per 1000 patient-years 3 REMS, Risk Evaluation and Mitigation Strategy. 1.US National Library of Medicine Daily Med. Lotronex (alosetron hydrochloride) tablet. Available at Accessed February 29, FDA. Lotronex (alosetron) tablets and authorized generic tablets. Risk evaluation and mitigation strategy (REMS). Available at Accessed February 29, Chang L, et al. Am J Gastroenterol. 2010;105:

62 Ondansetron for IBS-D: Improves Stool Frequency Bristol Stool Form Score Effect of Ondansetron 4-8 mg TID for 5 Weeks in Patients with Rome III IBS-D (N=120)* Crossover Placebo Ondansetron Treatment 1 Washout Treatment 2 endpoint weeks endpoint weeks *Randomized, double-blind, dose-titration study. Primary endpoint was average stool consistency in last 2 weeks of treatment. Improvements in urgency, frequency, bloating but NOT pain. Garsed K, et al. Gut. 2014;63:

63 Patients, % Patients, % Rifaximin Improves Global IBS Symptoms and Bloating Outcomes at 4 Weeks 80 Adequate Relief of Global IBS Symptoms 80 Adequate Relief of IBS-Related Bloating 60 P=0.01 P=0.03 P< P=0.005 P=0.02 P< n=309 n=314 n=315 n=320 n=624 n=634 TARGET 1 TARGET 2 Combined 0 n=309 n=314 n=315 n=320 n=624 n=634 TARGET 1 TARGET 2 Combined Rifaximin Placebo Pimentel M, et al. N Engl J Med. 2011;364:

64 TARGET 3: Study Design and Patient Disposition 2,438 patients were treated and completed 2 weeks of rifaximin 550 mg in the open-label phase 1 44 % n=1,074 responded to open-label treatment 1 36 % n=382 Of open label responders didn t experience a reoccurrence of symptoms for up to an 18-week followup period were excluded due to symptom inactivity 2 59 % n=636 entered the double-blind phase after symptom reoccurrence 328 patients randomized to rifaximin 550 mg TID patients randomized to placebo 2 Xifaxan [prescribing information]. Salix Pharmaceuticals, Inc Median time to recurrence of 10 weeks (range of 6-24 weeks) 2 64

65 TARGET 3: Study Design and Patient Disposition 2,438 patients were treated and completed 2 weeks of rifaximin 550 mg in the open-label phase 1 44 % n=1,074 responded to open-label treatment 1 36 % n=382 Of open label responders didn t experience a reoccurrence of symptoms for up to an 18-week followup period were excluded due to symptom inactivity 2 59 % n=636 entered the double-blind phase after symptom reoccurrence 328 patients randomized to rifaximin 550 mg TID patients randomized to placebo 2 Xifaxan [prescribing information]. Salix Pharmaceuticals, Inc Median time to recurrence of 10 weeks (range of 6-24 weeks) 2 65

66 TARGET 3: Study Design and Patient Disposition 2,438 patients were treated and completed 2 weeks of rifaximin 550 mg in the open-label phase 1 44 % n=1,074 responded to open-label treatment 1 36 % n=382 Of open label responders didn t experience a reoccurrence of symptoms for up to an 18-week followup period were excluded due to symptom inactivity 2 59 % n=636 entered the double-blind phase after symptom reoccurrence 328 patients randomized to rifaximin 550 mg TID patients randomized to placebo 2 Xifaxan [prescribing information]. Salix Pharmaceuticals, Inc Median time to recurrence of 10 weeks (range of 6-24 weeks) 2 66

67 TARGET 3: Study Design and Patient Disposition 2,438 patients were treated and completed 2 weeks of rifaximin 550 mg in the open-label phase 1 44 % n=1,074 responded to open-label treatment 1 36 % n=382 Of open label responders didn t experience a reoccurrence of symptoms for up to an 18-week followup period were excluded due to symptom inactivity 2 59 % n=636 entered the double-blind phase after symptom reoccurrence 328 patients randomized to rifaximin 550 mg TID patients randomized to placebo 2 Xifaxan [prescribing information]. Salix Pharmaceuticals, Inc Median time to recurrence of 10 weeks (range of 6-24 weeks) 2 67

68 Patients, % TARGET 3: Efficacy of First and Second Retreatments Efficacy of First and Second Retreatments LOCF Analysis 33 P= First repeat treatment 36.9 P= n=328 n=308 n=295 n=283 Second repeat treatment Urgency and bloating improved significantly with both repeat treatments Abdominal pain and stool consistency improved significantly with first retreatment At time of recurrence, IBS-D symptoms were less severe compared to symptoms at onset of study Rifaximin Placebo LOCF, last observation carried forward. Responder defined as subjects responding to IBS-related Abdominal Pain and Stool Consistency for 2 of 4 weeks. Recurrence defined as a loss of response for 3 of 4 weeks. Chey WD, et al. Effects of Rifaximin on Urgency, Bloating, and Abdominal Pain in Patients with IBS-D: A Randomized, Controlled, Repeat Treatment Study. Presented at DDW, May 16-19, 2015; Washington, D.C. [Abstract No. 313]. 68

69 Rifaximin in the Clinic Most Common Reported Adverse Events ( 2%)* 2 Dosage 550 mg TID for 14 days, with up to 2 retreatments with the same regimen 1 *Pooled analysis of Phase 2b and 3 trials of rifaximin in non-ibs C TID, three times daily; URT, upper respiratory tract. 1. XIFAXAN (rifaximin) [prescribing information]. Salix Pharmaceuticals; Raleigh, NC: May 2015; 2. Schoenfeld P, et al. Aliment Pharmacol Ther. 2014;39: Adverse Events Rifaximin 550 mg (n=1,008) n (%) Placebo (n=829) Headache 55 (5.5) 51 (6.2) URT infection 45 (4.5) 47 (5.7) Nausea 41 (4.1) 31 (3.7) Abdominal pain 40 (4.0) 39 (4.7) Diarrhea 35 (3.5) 26 (3.1) Urinary tract infection 32 (3.2) 18 (2.2) Pooled safety analysis demonstrated no difference between rifaximin and placebo for any adverse event 2 69

70 Eluxadoline in IBS-D Mixed opioid receptor activity Mu (μ) opioid receptor agonist Delta (δ) opioid receptor antagonist and kappa (κ) opioid receptor agonist 1,2 Low systemic exposure after oral administration 2 Animal studies suggest eluxadoline can improve the diarrheal and hyperalgesia symptoms of IBS-D. 1,2 μ opioid receptor Activation reduces pain, gastric propulsion δ opioid receptor Inhibition restores G-protein signaling; reduces μ agonist-related desensitization 1. Fujita W, et al. Biochemical Pharmacology Wade PR, et al. British Journal of Pharmacology. 2012;167: ; 3. VIBERZI (eluxadoline) [package insert] Cincinnati, OH: Forest Pharmaceuticals, Inc.; May

71 Responders, % Responders, % Eluxadoline in IBS-D: Primary Composite Endpoint IBS-3001 and IBS-3002 Pooled Weeks 1 12 Weeks 1 26 P<0.001 P< P<0.001 P< n=809 n=808 n=806 0 n=809 n=808 n=806 Placebo BID Eluxadoline 75 mg BID Eluxadoline 100 mg BID Primary composite endpoint defined as reduction in abdominal pain > 30% compared to baseline AND stool consistency < 5 on same day. In order to be a responder, need to achieve this daily endpoint for > 50% of days in trial. Lembo AJ et al. N Engl J Med. 2016;374:

72 Eluxadoline in IBS-D: Percentage of Daily Composite Responders Over Time Daily composite responders (%) Percentage of Daily Composite Responders* Over Time Pooled Data from Studies IBS-3001 and IBS Placebo Eluxadoline 75 mg Eluxadoline 100 mg Time (weeks) *Composite responders met criteria of daily pain responder and daily stool consistency responder on the same day, with 50% of days demonstrating a response. Daily pain responder defined as 30% improvement in WAP scores by in the past 24 h compared with average baseline pain. Daily stool consistency responder defined as BSS score <5 (or in absence of BM, if accompanied by 30% improvement in WAP compared with average baseline pain). Lembo AJ et al. N Engl J Med. 2016;374:

73 Eluxadoline Improves Multiple IBS-D Symptoms In patients with IBS-D, eluxadoline 100 mg bid is superior to placebo for Global IBS symptoms 50% reduction in abdominal pain Stool frequency Fecal urgency Bloating Adequate Relief of IBS Symptoms Lembo AJ et al. N Engl J Med. 2016;374:

74 Eluxadoline Safety Profile Constipation occurred 7.4% (75 mg bid) and 8.6% (100mg bid)of patients receiving eluxadoline 1 Discontinuation of eluxadoline due to constipation reported in 1.1% (75 mg bid) and 1.7% (100 mg bid) of patients receiving eluxadoline 1 Symptomatic Sphincter of Oddi spasm events: 2 In clinical trials, 0.5% (10/1839) Only occurred in patients with cholecystectomy. Pancreatitis 2 In clinical trials, 0.3% (5/1839) (3 associated with alcohol use, 1 with biliary sludge, 1 with sphincter of oddi spasm) 1. Lembo AJ et al. N Engl J Med. 2016;374: VIBERZI (eluxadoline) [prescribing information]. Forest Pharmaceuticals, Inc; Cincinnati, OH: May

75 Eluxadoline in the Clinic Dosage 100 mg BID taken with food 75 mg BID with food in patients who do not have a gallbladder are unable to tolerate 100 mg BID using OATP1B1 inhibitors Compensated cirrhosis Contraindications Sphincter of Oddi disease or dysfunction Pancreatitis Patients who consume >3 alcoholic drinks/day Decompensated cirrhosis (Child-Pugh Class C) Severe constipation Bile duct obstruction VIBERZI (eluxadoline) [prescribing information]. Forest Pharmaceuticals, Inc; Cincinnati, OH: May

76 Symptom reduction, % Triple-Coated Peppermint Oil for IBS RCT of triple-coated peppermint oil microspheres in IBS-M or IBS-D (N=72) Randomized to peppermint oil 180 mg TID or placebo for 4 weeks 0 Symptom Reduction at Day 29 Abdominal Pain or Discomfort Abdominal Bloating or Distension Pain at Evacuation Primary analysis based on Total IBS Symptom Score Peppermint oil improved Total IBS Symptom Score (P<0.02) and frequency and intensity of individual IBS symptoms over 4 weeks * Placebo TID (n=37) * Peppermint oil 180 mg TID (n=35) * *P<0.05. AEs, adverse events; TISS, Total IBS Symptom Score; URT, upper respiratory tract. Cash BD, et al. Dig Dis Sci. 2016;61:

77 Antidepressants in IBS Meta-analysis of 16 RCTs demonstrate that TCAs and SSRIs reduce global IBS symptoms and abdominal pain in IBS patients 1 TCAs are associated with constipation and may be best for IBS-D patients SSRIs likely to increase small bowel and colonic transit and may be preferred in IBS-C 2-4 Potential Antidepressant Actions in IBS 3 Antidepressant action Visceral analgesia Changes in motility Smooth muscle relaxation RCTs, randomized, controlled trials; SNRIS, serotonin norepinephrine reuptake inhibitors; SSRIs, selective serotonin reuptake inhibitors; TCAs, tricyclic antidepressants. 1. Ford AC et al. Am J Gastroenterol. 2014;109: Grover M, Drossman DA. Gastroenterol Clin N Am. 2011;40: Chey WD, et al. Gut Liver. 2011;5: Gorard DA, et al. Aliment Pharmacol Ther. 1994;8:

78 General Approach to Prescribing Antidepressants in IBS Consider specific symptoms 1-4 TCAs in IBS-D, SSRIs in IBS-C SSRI/SNRI for anxiety Consider side effect profiles 1,3 SSRIs may be better tolerated than TCAs Start with low dose and titrate slowly (every 1-2 weeks) by response; allow 4-8 weeks for maximal response 1,2 If ineffective or not tolerated, consider switching to different class of agent 1 Continue at minimum effective dose for 6-12 months 1 RCTs, randomized, controlled trials; SNRIS, serotonin norepinephrine reuptake inhibitors; SSRIs, selective serotonin reuptake inhibitors; TCAs, tricyclic antidepressants. 1. Grover M, Drossman DA. Gastroenterol Clin N Am. 2011;40: Dekel R et al. Expert Opin Invest Drugs. 2013;22 : Chey WD, et al. Gut Liver. 2011;5: Gorard DA, et al. Aliment Pharmacol Ther. 1994;8:

79 Advances in IBS Key Points IBS can be diagnosed confidently with symptom-based criteria. Celiac serologies, CRP, and/or fecal calprotectin are useful to rule out celiac disease and inflammatory bowel disease Anti-vinculin and anti-cdtb antibodies may be useful to diagnose post-infectious IBS-D Emerging evidence supports a primary role of diet in managing IBS patients (low FODMAP/carbohydrate, gluten-free, elimination diets) Evidence-based treatments that improve symptoms of IBS-D include alosetron, TCAs/SSRIs, rifaximin, eluxadoline, and peppermint oil 79

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