Treatment of IBS - Diet or Drugs?

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1 Treatment of IBS - Diet or Drugs? Brooks D. Cash, MD, FACG Professor of Medicine University of South Alabama Director, GI Physiology, USA Medical Center Mobile, AL Learning objectives Review the evolving pathophysiologic concepts surrounding IBS Understand existing and emerging treatment options for IBS Page 1 of 21

Overview of IBS Pathophysiology Luminal Factors Dysbiosis Neuroendocrine mediators Bile Acids Host Factors Altered GI Motility Visceral hypersensitivity Altered

Antibiotics Enteric infection Serotonin Opioids Chey WD, et al. JAMA. 2015;313(9):949-958.

2 Overview of IBS Pathophysiology Luminal Factors Dysbiosis Neuroendocrine mediators Bile Acids Host Factors Altered GI Motility Visceral hypersensitivity Altered brain-gut interactions Increased intestinal permeability Gut mucosal immune activation Environmental Factors Psychosocial distress Food Medications Supplements Antibiotics Enteric infection Serotonin Opioids Chey WD, et al. JAMA. 2015;313(9): Treatment Depends on Severity Psychological treatments Goal: improved function Continuing care + Follow-up visit Manage stress Drug therapy + Diet, lifestyle advice Positive diagnosis Explain, reassure Severe (25%) Moderate (35%) Mild (40%) Page 2 of 21

Why are Foods and Diets so Topical? To improve overall health To be more natural To be in charge/take control To lose weight To prevent diabetes, HTN, etc.

3 Why are Foods and Diets so Topical? To improve overall health To be more natural To be in charge/take control To lose weight To prevent diabetes, HTN, etc. To avoid taking medications To treat/minimize specific symptoms Why might Food cause Symptoms? Stimulation of mechanoreceptors Stimulation of chemoreceptors Release of hormones/peptides Alterations in secretion Changes in osmolarity Fermentation of foods Subsequent luminal distention Page 3 of 21

4 Food & IBS Symptoms: The patient s perspective 60% of patients report worsening of symptoms after meals 1 Survey of 1,242 IBS patients the following interventions improved symptoms 2 small meals (69%) avoiding fat (64%) increasing fiber (58%) avoiding milk products (54%) 1 Chey et al, Am J Gastroenterol 2002; 2 Halpert et al, Am J Gastroenterol 2007 IBS Specific Diets: What s the Evidence? Low carbohydrate Low fructose/fructan Low gluten IgG food avoidance Low FODMAP (Fermentable Oligosaccharides, Disaccharides, Monosaccharides, and Polyols) Page 4 of 21

Potential Role of FODMAPs in IBS Osmotic effects FODMAPS Bacterial fermentation Trophic effects Microbiome changes SCFA (butyrate, propionate, acetate) Luminal ph Increased biomass Osmotic load Gas

5 Potential Role of FODMAPs in IBS Osmotic effects FODMAPS Bacterial fermentation Trophic effects Microbiome changes SCFA (butyrate, propionate, acetate) Luminal ph Increased biomass Osmotic load Gas production (CH 3, H 2, CO 2 ) Effects on Motility Visceral sensation Immune activation Permeability Acceleration of transit time GI symptoms (pain, gas/bloating, altered bowel movements) Cognitive and emotional factors Spencer M, et al. Curr Treat Options Gastroenterol. 2014;12: Low Carbohydrate Diet Prospective, randomized, controlled study 17 moderate-severe IBS-D patients 4-week very low carbohydrate diet (VLCD) 51% fat; 45% protein; 4% carbohydrate Endpoint: adequate relief for >2 weeks 13 completed the study All 13 met the responder definition 10 experienced adequate relief for all 4 weeks Austin et al, Clin Gastro & Hepatol 2009 Page 5 of 21

6 Low Carbohydrate Diet Secondary Endpoints also improved Decrease in stool frequency Improvement in stool consistency Decreased abdominal pain Improvement in quality-of-life Austin et al, Clin Gastro & Hepatol 2009 IBS & Low Fructose/Fructan Diet 26 IBS patients with fructose malabsorption (Rome II; + breath test; mean age = 38) Prior response to low fructose/low fructan diet Randomly re-challenged with offending foods 70% of those receiving fructose, 77% receiving fructans, and 79% receiving a mixture noted return/worsening of symptoms compared to glucose (14%; p < 0.002) Sheperd et al, Clin Gastroenterol Hepatol 2008; 6: Page 6 of 21

7 R, DB, PC, re-challenge study 34 IBS patients; CD excluded Improvement on GFD 16 gm of gluten substitute vs. 16 grams of gluten/day Endpoint: Adequate symptom relief Gluten-group had less improvement than those on gluten-free (68% vs. 40%; p =.001) Low Gluten Diet Biesiekierski et al, Am J Gastro 2011 IBS and Gluten-free Diet 45 Pts with IBS-D (43 women); 4-weeks Gluten-free diet (23) vs. Gluten-diet (22) Genotype analysis performed Stool frequency, intestinal transit and intestinal permeability measured Results: Gluten diet was associated with increased SB permeability, especially in HLA-DQ2/8 positive patients Vazquez-Roque et al, Gastroenterology 2013; 144: Page 7 of 21

amounts), rye (large amounts), onions, leeks, zucchini Milk (cow, goat, or sheep), custard, ice cream, yogurt, soft unripened cheeses (eg, cottage cheese, ricotta)

Shepherd SJ, et al. Clin Gastroenterol Hepatol. 2008;6:765-771; 2. Shepherd SJ, Gibson PR. J Am Diet Assoc. 2006;106:1631-1639; 3. Barrett JS, Gibson PR.

8 What Are FODMAPs? Fermentable oligo-, di-, monosaccharides and polyols Excess Fructose Fructans Lactose Honey, apples, pears, peaches, mangos, fruit juice, dried fruit Wheat (large amounts), rye (large amounts), onions, leeks, zucchini Milk (cow, goat, or sheep), custard, ice cream, yogurt, soft unripened cheeses (eg, cottage cheese, ricotta) Sorbitol Apricots, peaches, artificial sweeteners, artificially sweetened gums Raffinose Lentils, cabbage, brussels sprouts, asparagus, green beans, legumes 1. Shepherd SJ, et al. Clin Gastroenterol Hepatol. 2008;6: ; 2. Shepherd SJ, Gibson PR. J Am Diet Assoc. 2006;106: ; 3. Barrett JS, Gibson PR. Ther Adv Gastroenterol. 2012;5: Prospective Study to Evaluate Low FODMAP diet 9 month evaluation performed in UK 82 consecutive IBS patients (NICE criteria) 39 in standard diet group 42 in low FODMAP diet group Detailed symptom and dietary evaluation Individual symptoms and global IBS symptoms measured Staudacher et al, J Hum Nutr Diet, 2011 Page 8 of 21

Improvements in IBS Symptom Scores: Low FODMAP vs Control Diet Patients With Improved Symptom Response, % 100 90 80 70 60 50 40 30 20 10 0 * * Standard Diet Low FODMAP Diet *P 0.001 P<0.

9 Improvements in IBS Symptom Scores: Low FODMAP vs Control Diet Patients With Improved Symptom Response, % * * Standard Diet Low FODMAP Diet *P P<0.05 Staudacher HM, et al. J Hum Nutr Diet. 2011;24: FODMAP Diet Reduces Functional GI Symptoms Effects of Diet on Functional GI Symptoms in Controlled, Crossover Study (N=30) 60 Typical Australian diet 60 Typical Australian diet VAS (0-100 mm) Low FODMAP diet Low FODMAP diet Low FODMAP diet 0 7 Study Day Study Day Halmos EP et al. Gastroenterology. 2014;146: Page 9 of 21

10 Low FODMAP Diet: Issues What is the cut-off for FODMAP content? Variable and inconsistent resources Total meal FODMAPs should be counted, not individual FODMAPs Most patients can t stick to the diet Unknown nutritional issues with long-term use IBS & Probiotics: Global Symptoms Page 10 of 21

IBS & Antidepressants Bulking Agents for IBS-C: Systematic Review and Meta-analysis RCTs N Fiber Response* Placebo RR of Unimproved Symptoms (95% CI) NNT (95%CI) Overall 14 906 48% 43% 0.86 (0.80-.

11 IBS & Antidepressants Bulking Agents for IBS-C: Systematic Review and Meta-analysis RCTs N Fiber Response* Placebo RR of Unimproved Symptoms (95% CI) NNT (95%CI) Overall % 43% 0.86 ( ) 10 (5-100) Ispaghula % 36% 0.83 ( ) 7 (3-50) Bran % 46% 0.90 ( ) *Improved or resolved symptoms. Insoluble fiber was not more effective and sometimes worsened symptoms Soluble fiber improved global symptoms 4 out of 6 bran studies poor quality CI = confidence interval; NNT = number needed to treat; RCTs = randomized, controlled trials; RR = relative risk Moayeddi P, Quigley EE, Lacy BE, et al. Am J Gastroenterol 2014; 109: Page 11 of 21

Lubiprostone 8 mcg Twice Daily: IBS-C Overall Responder Criteria Overall responders (primary endpoint) were defined as monthly responders for at least 2 months of the 3-month study Monthly responders

12 Lubiprostone 8 mcg Twice Daily: IBS-C Overall Responder Criteria Overall responders (primary endpoint) were defined as monthly responders for at least 2 months of the 3-month study Monthly responders - Only those responders reporting at least moderate relief for 4 weeks a month or significant relief for 2 weeks a month, provided that during that month: o There were no ratings of moderately worse or significantly worse o Percentage of days of rescue medication use did not increase compared with baseline o Subject did not discontinue treatment due to lack of efficacy Responder definition developed in an effort to minimize the placebo effect Drossman DA, et al. Aliment Pharmacol Ther. 2009;29(3): Lubiprostone 8 mcg Twice Daily: Phase 3 IBS-C Studies Used Balanced 7-Point Symptom Relief Scale In 2 clinical studies, patients were asked weekly how they felt about their relief 1,2 : How would you rate your relief of IBS symptoms (abdominal discomfort/pain, bowel habits, and other IBS symptoms) over the past week, compared with how you felt before you entered the study? Significantly Moderately A Little Bit A Little Bit Moderately Significantly Worse Worse Worse Unchanged Relieved Relieved* Relieved* Points * Significantly relieved and moderately relieved were considered to be responders Drossman DA, et al. Aliment Pharmacol Ther. 2009;29(3): AMITIZA [package insert]. Bethesda, MD: Sucampo Pharma Americas, LLC; Page 12 of 21

Lubiprostone 8 mcg Twice Daily for IBS-C: Overall Responder* Rates 20 Response Rates (%) 1,2 18 16 14 12 10 8 6 4 2 0 P=0.029 P=0.023 13.8% 12.1% 7.8% 5.

of any 3 months 3 AMITIZA had up to 2x overall response rate vs placebo 1. AMITIZA [packageinsert]. Bethesda, MD: Sucampo Pharma Americas, LLC; 2013. 2. Data on file, SucampoPharma Americas, LLC.

Linaclotide for IBS-C Over 12 Weeks FDA Primary Endpoint ( 6/12 Weeks) % Responders FDA Primary Endpoint: 30% reduction worst abdominal pain and increase 1 CSBM,

13 Lubiprostone 8 mcg Twice Daily for IBS-C: Overall Responder* Rates 20 Response Rates (%) 1, P=0.029 P= % 12.1% 7.8% 5.7% (n=193) (n=390) (n=192) (n=379) Phase 3 Study 1 Phase 3 Study 2 Placebo AMITIZA * Overall responders defined as subjects who were monthly responders for 2 out of any 3 months 3 AMITIZA had up to 2x overall response rate vs placebo 1. AMITIZA [packageinsert]. Bethesda, MD: Sucampo Pharma Americas, LLC; Data on file, SucampoPharma Americas, LLC. 3. Drossman DA, et al. Aliment Pharmacol. 2009;29(3): Linaclotide for IBS-C Over 12 Weeks FDA Primary Endpoint ( 6/12 Weeks) % Responders FDA Primary Endpoint: 30% reduction worst abdominal pain and increase 1 CSBM, both for 6/12 weeks Placebo (n=403) Linaclotide 290 μg (n=401) *P< for all analyses of linaclotide vs placebo groups, using Cochran-Mantel-Haenszel test Chey WD, et al. Am J Gastroenterol. 2012; epub September 18. Page 13 of 21

Efficacy of Linaclotide in IBS-C Patients 3 Treatment Period * RW Period z Mean Change From Baseline +/- SEM 2 0 1 N=800 BL 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 Weeks Weeks Treatment Period Placebo

14 Efficacy of Linaclotide in IBS-C Patients 3 Treatment Period * RW Period z Mean Change From Baseline +/- SEM N=800 BL Weeks Weeks Treatment Period Placebo Linaclotide 290 µg ANCOVA, analysis of covariance; RW, randomized withdrawal. Rao S, et al. Am J Gastroenterol. 2012;107: RW Treatment Sequence Placebo/linaclotide 290 µg Linaclotide 290 µg/linaclotide 290 µg Linaclotide 290 µg/placebo *P< for linaclotide patients vs placebo patients (ANCOVA). P<0.001 for linaclotide/linaclotide patients vs linaclotide/placebo patients (ANCOVA). Rifaximin: Global Relief of non-c IBS 2 Phase 3 randomized controlled trials; N=1260 patients Rifaximin 550 mg TID x 2 weeks; patients followed additional 10 weeks 40.7% vs. 31.7% with adequate relief of global symptoms (P<0.001) T-I, TARGET 1 trial; T-II, TARGET 2 trial; Comb, Combination of both trials Rifaximin Placebo T-I T-II Comb Pimentel M, et al. N Engl J Med. 2011;364: Page 14 of 21

Retreatment with Rifaximin- Target 3 Screening/ Treatment 1 Phase Study Day 1 Treatment 2 Phase Maintenance Phase 1 Treatment 3 Phase/DBR Treatment Phase Primary Evaluation Period Maintenance Phase 2

15 Retreatment with Rifaximin- Target 3 Screening/ Treatment 1 Phase Study Day 1 Treatment 2 Phase Maintenance Phase 1 Treatment 3 Phase/DBR Treatment Phase Primary Evaluation Period Maintenance Phase 2 Treatment 4 Phase/SRT Treatment Phase Follow up 7-13 d PBO 2w RFX 4w f/u Up to 18w 2w RFX 4w f/u 6w 2w RFX 4w f/u * * Responders with recurrent symptoms Non- Responders Withdrawn 1:1 2w PBO 4w f/u Obtain Daily/Weekly Symptom Diary 6w 2w PBO 4w f/u 4w EOS * * * Stool sample collection * TARGET 3: Study Design and Patient Disposition 2, % 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 patients were treated and n=1,074 completed 2 weeks of rifaximin responded 550 mg in the to open-label 59% open-label phase 1 treatment 1 n=636 entered the double-blind phase after symptom reccurrence 328 patients randomized to rifaximin 550 mg TID patients randomized to placebo 2 Xifaxan [prescribing information]. Salix Pharmaceuticals, Inc 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. Median time to recurrence of 10 weeks (range of 6-24 weeks) 2 Page 15 of 21

TARGET 3: Efficacy of First and Second Retreatments Efficacy of First and Second Retreatments LOCF Analysis Patients, % 40 30 20 10 0 33 P=0.02 25 1 st repeat treatment P=0.04 36.9 29.

retreatment Rifaximin Placebo LOCF, last observation carried forward. Chey WD, et al.

16 TARGET 3: Efficacy of First and Second Retreatments Efficacy of First and Second Retreatments LOCF Analysis Patients, % P= st repeat treatment P= n=328 n=308 n=295 n=283 2 nd repeat treatment Urgency and bloating improved significantly with both repeat treatments Abdominal pain and stool consistency improved significantly with first retreatment Rifaximin Placebo LOCF, last observation carried forward. 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]. Eluxadoline for IBS-D Mixed mu (μ) opioid receptor agonist / delta (δ) opioid receptor antagonist Low systemic absorption and bioavailability Low potential for drug drug interactions Animal studies suggest eluxadoline should improve the diarrheal symptoms of IBS-D with limited constipation and durable analgesia μ opioid receptor Activation reduces pain, gastric propulsion δ opioid receptor Inhibition restores G-protein signalling; reduces μ agonist-related desensitization Page 16 of 21

17 Eluxadoline: Phase 3 study design IBS-3001 Prescreen ( 1 wk) Screening (2 3 wks) Double-blind treatment (26 wks) Double-blind safety continuation (26 wks) Post-Tx (2 wks) Randomization (Day 1) Efficacy 12 wks (FDA) Efficacy 26 wks (EMA) End of treatment IBS-3002 Prescreen ( 1 wk) Screening (2 3 wks) Double-blind treatment (26 wks) Blinded PBO withdrawal (4 wks) Randomization (Day 1) Efficacy 12 wks (FDA) Efficacy 26 wks (EMA) Primary endpoint: composite responder FDA guidance / EMA draft guidance Responder must meet both criteria on same day: Daily pain responder: AND Daily stool consistency responder: WAP scores improved by 30% compared to average baseline pain BSS score <5 (or in absence of BM, if accompanied by 30% improvement in WAP compared to average baseline pain) Above met on at least 50% of days in Weeks 1 12 (FDA), Weeks 1 26 (EMA) Minimum 60 days (FDA) / 110 days (EMA) diary compliance Bonferroni adjustment: to preserve the family-wise error rate for each active group vs placebo (p<0.025) BM, bowel movement Page 17 of 21

Primary endpoint: composite responders 35 11.5* 30 9.5* 10.3* 7.

1) 64 (7.5) Abdominal pain 33 (4.0) 47 (5.9) 62 (7.2) Vomiting 11 (1.4) 32 (4.0) 36 (4.2) Gastroenteritis 27 (3.4) 36 (4.4) 19 (2.

6% (10 /1666) patients receiving eluxadoline (0.

BID standard dose; 75 mg BID in patients without GB Avoid use in heavy ETOH users, cirrhotics URI, upper respiratory infection *All

18 Primary endpoint: composite responders * * 10.3* 7.2* 25 Responders (%) N=808 N=806 N=809 N=808 N=806 N=809 Weeks 1 12 Weeks 1 26 *p<0.001 Eluxadoline Safety Profile Most Common Adverse Events in Phase 3 Trials (>4% in either treatment arm and > placebo) 1 Placebo (n=808) Eluxadoline 75 mg (n=859) Eluxadoline 100 mg (n=807) Adverse Events n (%) Constipation * 20 (2.5) 60 (7.4) 74 (8.6) Nausea 41 (5.1) 65 (8.1) 64 (7.5) Abdominal pain 33 (4.0) 47 (5.9) 62 (7.2) Vomiting 11 (1.4) 32 (4.0) 36 (4.2) Gastroenteritis 27 (3.4) 36 (4.4) 19 (2.2) URI 32 (4.0) 27 (3.3) 47 (5.5) Nasopharyngitis 27 (3.3) 33 (4.1) 23 (2.7) Sphincter of Oddi spasm 0.6% (10 /1666) patients receiving eluxadoline (0.2% with 75 mg dose) Pancreatitis 5 additional cases with eluxadoline (3 associated with alcohol use, 1 biliary sludge, 1 SO spasm) 100 mg BID standard dose; 75 mg BID in patients without GB Avoid use in heavy ETOH users, cirrhotics URI, upper respiratory infection *All constipation events were non-serious 1.4% of patients receiving eluxadoline and 0.2% receiving placebo discontinued due to non-serious constipation; Abdominal pain = abdominal pain, abdominal pain upper, abdominal pain lower; Gastroenteritis = gastroenteritis and viral gastroenteritis Chey WD, et al. Presented at DDW, May 16-19, 2015; Washington, D.C. [Abstract No. 316]. Page 18 of 21

Ondansetron for IBS-D Bristol Stool Form Score 7 6 5 4 3 2 1 Effect of Ondansetron 4-8 mg TID for 5 Weeks in Patients with Rome III IBS-D (N=120)* Crossover Treatment 1 Washout Treatment 2 Placebo

19 Ondansetron for IBS-D Bristol Stool Form Score Effect of Ondansetron 4-8 mg TID for 5 Weeks in Patients with Rome III IBS-D (N=120)* Crossover Treatment 1 Washout Treatment 2 Placebo Ondansetron 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: Peppermint Oil SST (Site Specific Targeting) for IBS-D/M 38 Page 19 of 21

PO-SST: Reduction in IBS Symptoms 0 Abdominal Pain or Discomfort Abdominal Bloating or Distension Pain at Evacuation Urgency of BM Constipation Diarrhea Gas or Mucus Incomplete Evacuation Percent

05 Cash BD, et al. Dig Dis Sci. 2015 Aug 29 [Epub ahead of print].

20 PO-SST: Reduction in IBS Symptoms 0 Abdominal Pain or Discomfort Abdominal Bloating or Distension Pain at Evacuation Urgency of BM Constipation Diarrhea Gas or Mucus Incomplete Evacuation Percent reduction in individual IBS symptoms * * * * Placebo (n=37) Peppermint oil (n=35) *P<0.05 Cash BD, et al. Dig Dis Sci Aug 29 [Epub ahead of print]. Bile acid diarrhea prevalence estimates 1%; 25-50% in IBS-D Excess bile acids in colon Stimulate entero-endocrine cells and accelerates colonic transit Activate visceral sensation and fluid secretion (through increased intracellular camp, increased mucosal permeability or chloride ion secretion) Bile Acids and IBS-D Camilleri M. Gut Liver. 2015;9: Page 20 of 21

21 IBS & Diet: Conclusions Educate your patients Don t forget the obvious (lactose & fructose) Consider low FODMAP diet Discuss gluten-free diet For IBS-D, consider VLCD More research is desperately needed Summary Our understanding of IBS physiology continues to expand New diagnostic and treatment options have become available Not a diagnosis of exclusion Lifestyle/OTC management first line Prescription agents for non-responders (60-75%) IBS-C: Secretagogues IBS-D: antibiotics, mixed opioid receptor modulators Pain: TCAs, anti-spasmodics/peppermint oil Page 21 of 21

What s the Latest? Rome III Criteria for IBS

What s the Latest? Rome III Criteria for IBS Irritable Bowel lsyndrome: What s the Latest? American College of Gastroenterology Las Vegas, January 2014 Bi Brian E. Lacy, Ph.D., PhD M.D., MD FACG Professor of Medicine Geisel School of Medicine at