Current and Emerging Concepts in Irritable Bowel Syndrome

9/17/2020

Disclosures:

Brooks D. Cash, MD, FACG Consultant/Speakers’ Bureau: Salix, Allergan, Takeda, Ironwood, Alfasigma, Arena DSMB: Vibrant

Brian E. Lacy, MD, PhD, FACG No conflicts of interest.

Brooks D. Cash, M.D., FACP, FACG, FASGE, AGAF Dan and Lillie Sterling Professor of Medicine McGovern Medical School Chief, Gastroenterology, Hepatology, and Nutrition University of Texas Health Science Center Houston, TX

American College of Gastroenterology 1 9/17/2020

Disclosures

• Consultant/Speakers’ Bureau: Salix, Allergan, Takeda, Ironwood, Alfasigma, Arena • DSMB: Vibrant

Objectives

1.Discuss the pathophysiology and diagnostic criteria for IBS 2.Explore the data for lifestyle and over the counter therapies for IBS symptoms 3.Review the mechanisms of action, efficacy, and safety profiles of FDA approved IBS therapies 4.Examine emerging therapies for IBS

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Rome IV Criteria for IBS

Recurrent abdominal pain at least 1 day/week (on average) in the last 3 months associated with ≥ 2 of the following

Related to defecation Associated with Associated with a change a change in stool form in stool frequency

Criteria fulfilled for the last 3 months with symptom onset at least 6 months prior to diagnosis

Lacy BE, et al. Gastroenterology. 2016

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Multifactorial Pathophysiology of IBS

Inflammation, Psychosocial Immune Factors Dysregulation

Genetic Predisposition Microbiome

Visceral Malabsorption Hypersensitivity Issues IBS Abnormal Symptom Diet Motility Complex

Chey WD, et al. JAMA. 2015;313:949‐958. Drossman DA. Gastroenterology. 2016;150:1262‐1279. Holtmann G, et al. Dig Dis. 2017:35:5‐13. Radovanovic‐Dinic B, et al. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2018;162:1‐9.

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Principles of IBS Management • Exclude organic GI disease • Make a positive diagnosis • Establish a rapport; educate and reassure • Categorize IBS subtype based on prevalent stool form (BSFS) • First line: lifestyle and dietary modifications and OTC therapies targeting abnormal stool form/most bothersome symptoms • Escalate to FDA approved/validated therapies • Non‐FDA/off‐label/psychological therapies

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Diagnostic Testing for Suspected IBS and No Alarm Features*

All IBS Subtypes1 CBC Age‐appropriate CRC screening IBS‐D1,2 IBS‐M1 IBS‐C1 • CRP or fecal calprotectin • CRP or fecal calprotectin If severe or medically refractory, • IgA TtG ± quantitative IgA • IgA TtG ± quantitative IgA refer to specialist for physiologic • When colonoscopy performed, • Stool diary/App testing obtain random biopsies • Consider abdominal plain film to assess for fecal loading • Serum 7‐C4 or fecal bile acids where available

*Alarm Features include age ≥50 years old, blood in stools, nocturnal symptoms, unintentional C4, 7α‐hydroxy‐4‐cholesten‐3‐one; CRC, colorectal cancer weight loss, change in symptoms, recent antibiotic use, and family history of organic GI disease screening; CRP, C‐reactive protein; Ttg, tissue transglutaninase

1. Chey WD et al. JAMA. 2015;313(9):949‐958. 2. Pimentel M et al. PLoS ONE. 2015;10(5):e0126438.

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Lifestyle Modifications (all have some evidence of benefit) • Dietary • Low FODMAP • Gluten restriction • Keto/Mediterranean • Low fat • Activity • Exercise • Sleep hygiene • Minimize/eliminate ETOH • Best evidence for IBS‐D, likely due to decrease in metabolic byproducts

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Dietary Considerations in IBS

• FODMAPS are an important trigger of meal‐related symptoms in IBS1 • Low FODMAP diet found to improve overall symptom scores compared with typical diet in IBS patients2 • Gluten‐free diet found to be beneficial in some patients with IBS‐D3,4 –Wheat contains fructans and other proteins that may also cause symptoms in IBS patients5 –Most patients who associate their symptoms with wheat will have wheat sensitivity, not celiac disease6 • Food antigens found to cause changes in the intestinal mucosa of IBS patients that are associated with patient responses to exclusion diets7

1. Shepherd SJ et al. Am J Gastroenterol. 2013;108:707‐717. 2. Halmos EP et al. Gastroenterology. 2014;146:67‐75.3. Biesiekierski JR et al. Gastroenterology. 2011;106:508‐514. 4. Vazquez‐ Roque MI et al. Gastroenterology. 2013;144:903‐911.e3. 5. Chey WD, et al. JAMA. 2015;313(9):949‐958. 6. Leonard MM et al. JAMA. 2017;318(7):647‐656. 7. Fritscher ‐Ravens A et al. Gastroenterology. 2014;147:1012‐1020.

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Low FODMAP versus mNICE Diet for IBS‐D: Adequate Relief & FDA Endpoint

84 patients with IBS‐D randomized to LFD or mNICE x 4 weeks and completed study ‐ median age was 43 years (range 19‐68); 65 were women

Adequate Relief FDA Composite Responder 80 80

P = 0.31 P = 0.13

60 52 60 41 40 40 Percent 27 Percent Responders 20 Responders 20 13

0 0 LFD mNICE LFD mNICE n=45 n=39 n=45 n=39 >30% reduction in pain and decrease in BSFS >1 compared to baseline

Eswaran SL et al. Am J Gastroenterol. 2016;111(12):1824‐1832.

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IBS Pharmacologic Options by Symptom1,2

Abdominal Pain/discomfort Bloating  Antispasmodics*  Rifaximin  Antidepressants*  Lubiprostone  Lubiprostone  Linaclotide  Linaclotide  Plecanatide  Plecanatide Abdominal  Probiotics*  Alosetron pain/ Bloating/  Rifaximin discomfort distension  Eluxadoline Constipation Diarrhea  Tegaserod  Fiber*  Loperamide*  MOM/PEG solution*  Diphenoxylate‐  Lubiprostone Altered bowel atropine*  Linaclotide function  Cholestyramine*  Plecanatide  Alosetron  Tegaserod  Rifaximin  Tenapanor  Eluxadoline  Prucalopride* *Not currently FDA‐approved for IBS

1. Brandt LJ, et al. Am J Gastroenterol. 2002;97(11 suppl):S7‐S26. 2. Drossman DA et al. Gastroenterology. 2002;123:2108‐2131.

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OTC Options

• Antidiarrheals: Imodium, clays/binders • Anti‐spasmodics • Peppermint oil • Probiotics

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Conventional Nonspecific Agents for IBS‐D

Recommendations from an American College of Gastroenterology monograph

There is insufficient 2 Recommendation evidence to Clinical trials Strong recommend loperamide for 42 Quality of evidence use in IBS Patients treated Very Low

There is insufficient Recommendation evidence to 23 Weak Clinical trials recommend antispasmodics 2,154 Quality of evidence available in US* Patients treated Low

*Recommendation revised to reflect evidence for products available in US

Ford AC et al. Am J Gastroenterol. 2014;109(Suppl 1):S2‐S26.

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Peppermint Oil

• Active ingredients: L‐menthol, rosmarinic acid, limonene1 • Primary effect: Ca+2 channel smooth muscle relaxation • Possible mediation via TRPM8, k‐opioid agonist, antibacterial, anti‐inflammatory, carminative2 • Dose unclear; typically 90‐180 mg up to TID • 7 RCT, 634 patients • NNT = 4 • AEs similar to placebo: GERD, dyspepsia reported

Cash BD et al. Dig Dis Sci. 2016;61:560‐571. Henstrom M et al. Gut. 2017;66(9):1725‐1727. McGovern Medical School

•. Probiotics

• 53 RCT, 5545 patients; 50% trials at low risk for bias • Significant heterogeneity • Evidence of publication bias • Probiotics superior to placebo • NNT=7 • Combination probiotics: RR = 0.79 (0.68‐0.91) • IBS dose/brand: unknown • Symptoms most likely to improve pain, bloating, flatulence • Low rate of AEs

Ford AC et al. Am J Gastroenterol. 2018;113(Suppl 2):1‐18.

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FDA Approved Therapies for IBS‐D

• Rifaximin • Eluxadoline • Alosetron

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Rifaximin for IBS‐D TARGET 1 & TARGET 2 Trials Adequate Relief Adequate Relief • Poorly absorbed antibiotic; of Global IBS Symptoms of Bloating inhibits protein synthesis 80 80 • Dosing 550 mg TID x 2 weeks P < 0.001 • 7 RCT; 2654 patients 60 P = .01 P = .03 60 PAdequate = .005 ReliefP of=.02 P < .001 IBS‐Related Bloating %

• NNT= 8 40.8 40.6 40.7 39.5 41 40.2 • AEs similar to placebo 40 40 31.2 32.2 31.7 31.9 • 2/3 responders need 28.7 30.3 Patients, repeat treatment 20 20 • No value in re‐treating non‐ responders 0 0 n=309 n=314 n=315 n=320 n=624 n=634 n=309 n=314 n=315 n=320 n=624 n=634 TARGET 1TARGET 2 Combined TARGET 1 TARGET 2 Combined

Pimentel M et al. N Engl J Med. 2011;364(1):22‐32. Rifaximin Placebo

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Rifaximin for IBS‐D TARGET 3 Trial Retreatment Efficacy 80 First Second Repeat Treatment Repeat Treatment Responder defined as Data for last observation carried forward • Responding to IBS‐related abdominal pain 60 and stool consistency for ≥2 of 4 weeks P = .02 P = .04 Recurrence defined as

% • Loss of response for ≥3 of 4 weeks 40 33 36.9 29.3 25 Urgency and bloating improved 20 significantly with both repeat treatments Patients,

Abdominal pain and stool consistency 0 improved significantly n=328 n=308 n=295 n=283 with first retreatment Rifaximin Placebo

Lembo A et al. Gastroenterology. 2016;151(6):1113‐1121.

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Eluxadoline for IBS‐D Composite Responder Rates IBS‐3001 & IBS‐3002 Trials • Mixed opioid receptor modulator • μ/κ‐opioid receptor agonist; δ‐ opioid antagonist 1,2 • Dosing: 100 mg BID • 3 RCT, 3235 patients • NNT= 13 • AEs: Constipation, abdominal pain, SO spasm, pancreatitis Placebo BID Eluxadoline 75 mg BID Eluxadoline 100 mg BI • Contraindicated if no GB or h/o Composite responder defined as pancreatitis, heavy ETOH users • 30% reduction in worst abdominal pain score AND improvement in stool consistency of <5 on the Bristol Stool Scale • Daily improvement in BOTH symptoms on at least 50% of days in the trial

Fujita W et al. Biochemical Pharmacology. 2014;92(3):448‐4565.; Wade PR et al. British Journal of Pharmacology. 2012;167(5):1111‐1125; ; Viberzi. Allergan; 2018. Accesses May 26, 2020. https://www.allergan.com/assets/pdf/viberzi_pi.; Lembo AJ et al. N Engl J Med. 2016;374(3):242‐253.

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Eluxadoline in Patients Who Failed Loperamide RELIEF Trial 60% • Phase IV multicenter DBRCT P < .05 50% • Subjects: Patients 43.6% 40% P < .05 subjectively reporting P < .01 31.0% loperamide use in prior 12 30% 27.9% 22.7% months failing to provide 20% 16.7% adequate control of IBS‐D 10.3% 10% symptoms Responders % 0% • AEs: Rates comparable in Primary Composite Secondary: Stool Secondary: Worst both groups; no SAEs Consistency Abdominal Pain Eluxadoline 100 mg BID (n=174) Placebo BID (n=172) Primary Composite = Patient met composite response criteria on ≥50% of days, defined as ≥40% improvement in WAP c/w BL and BSS <5 OR absence of a BM if accompanied by ≥40% improvement in WAP. Secondary Stool Consistency defined as BSS <5 on ≥50% of days. Secondary WAP defined as ≥40% improvement in WAP compared to BL, on ≥50% of days.

Brenner DM et al. Am J Gastroenterol 2019:114(9):1502‐1511.

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Alosetron for IBS‐D

• Partially selective 5‐HT3 antagonist • 8 RCT, 4341 patients (predominantly women) • NNT=7.5 • AEs: constipation, colon ischemia: 1/1000 patient‐yrs • 0.5 mg BID starting dose; may increase to 1 mg BID if well tolerated • Current indication: Female patients with severe IBS‐D not responding adequately to conventional therapy1

Ford AC et al. Am J Gastroenterol. 2014;109(Suppl 1):S2‐S26. US National Library of Medicine Daily Med. Alosetron hydrochloride tablet. https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=7a6c2fbb‐a76a‐497e‐8cf2‐ a6dca8945a9d. Accessed May 26, 2020.

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Antidepressants Variable Recs and Strength of Evidence Antidepressant action •18 RCT, 1127 patients •Antidepressants in general: NNT= 4; pain mostly Visceral analgesia •TCAs: 12 RCT, 787 patients; NNT= 4; Strong rec, high evidence

•SSRIs: 7 RCT, 356 patients; NNT= 5; Weak rec, low Changes in motility evidence Smooth muscle •SNRIs not yet studied in large RCTs2 relaxation •AEs more common with antidepressants; NNH= 8.5

1. Ford AC et al. Am J Gastroenterol. 2014;109(9):1350‐1365. 2. Grover M, Drossman DA. Gastroenterol Clin N Am. 2011;40(1):183‐206. 3. Chey WD et al. Gut Liver. 2011;5(3):253‐266. 4.Gorard DA et al. Aliment Pharmacol Ther. 1994;8(2):159‐166.

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General Approach to Prescribing Antidepressants in IBS

• Consider specific symptoms1,2 – TCAs in IBS‐D, SSRIs in IBS‐C – SSRI/SNRI for anxiety • Consider side effect profiles1,2 – SSRIs may be better tolerated than TCAs • Start with low dose and titrate slowly by response; allow 4‐8 weeks for maximal response1‐3 • Continue at minimum effective dose for 6‐12 months1,2 – Long‐term therapy may be warranted for some patients – Gradual taper to prevent withdrawal symptoms

1. Sobin WH et al. Am J Gastroenterol. 2017;112 (5):693‐702. 2. Grover M, Drossman DA. Gastroenterol Clin N Am. 2011;40(1):183‐206. 3. Dekel R et al. Expert Opin Invest Drugs. 2013;22(3) :329‐339.

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Bulking Agents for IBS‐C: Systematic Review and Meta‐ analysis: Strong rec, weak evidence

RR of Response* Unimproved NNT RCTs N Symptoms (95%CI) Fiber Placebo (95% CI) Overall 12 591 48% 43% 0.87 (0.76‐1.0) 11 (5‐100) Ispaghula 6 321 48% 36% 0.78 (0.63‐0.96) 6 (3‐50) Bran 5 221 46% 46% 1.02 (0.82‐1.27)

*Improved or resolved symptoms.

• Insoluble fiber was not more effective and sometimes worsened symptoms • Soluble fiber improved global symptoms • 4 out of 5 bran studies of poor quality CI = confidence interval; NNT = number needed to treat; RCTs = randomized, controlled trials; RR = relative risk

Ford, Quigley, Lacy et al, Am J Gastroenterol 2014

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FDA Approved Therapies for IBS‐C

• Linaclotide • Plecanatide • Lubiprostone • Tegaserod • Tenapanor

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Linaclotide for IBS‐C

• 14 aa peptide structurally similar to quanylin/uroguanylin; binds to FDA Primary Endpoint: ≥30% reduction worst guanylate‐cyclase C receptors abdominal pain and to promote ion and fluid increase ≥1 CSBM, both secretion into gut and ENS for ≥6/12 weeks Responders

modulation % • 4 RCT, 2867 patients

• IBS‐C dose:290 mcg daily Placebo Linaclotide (n=403) 290 μg (n=401) • NNT=6 *P<0.0001 for all analyses of linaclotide vs placebo groups, using Cochran‐Mantel‐Haenszel test • AEs: diarrhea

Chey WD, et al. Am J Gastroenterol. 2012; epub September 18.

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Linaclotide for IBS‐C

Treatment Period* RW Period† 3 z from

2 Change SEM

+/ ‐ 1 Mean

N=800 CSBM Baseline 0 BL12345678910111212 13 14 15 16 Weeks Weeks

Treatment Period RW Treatment Sequence Placebo Placebo/linaclotide 290 µg Linaclotide 290 µg Linaclotide 290 µg/linaclotide 290 µg Linaclotide 290 µg/placebo ANCOVA = analysis of covariance; RW = randomized withdrawal *P < 0.0001 for linaclotide patients vs placebo patients (ANCOVA). †P < 0.001 for linaclotide/linaclotide patients vs linaclotide/placebo patients Rao S, et al. Am J Gastroenterol 2012;107(11):1714-1724. (ANCOVA).

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Linaclotide: Abdominal Pain Over 26 Weeks

0 Linaclotide 290 µg Placebo

‐10

‐20 Worst Pain,

in ‐30

‐40 Change Abdominal ‐50

‐60 BL 2 4 6 8 10 12 14 16 18 20 22 24 26

Trial Week P=0.0007 for week 1 ITT population, observed cases, LS‐mean presented: P‐values based on P<0.0001 for weeks 2-26 ANCOVA at each week. Bars represent 95% CI. ITT, intention to treat; LS, least squares. Chey WD, et al. Am J Gastroenterol. 2012;107:1702-1712. N=804

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Plecanatide for IBS‐C

• 16 aa peptide structurally similar Study ‐05 to uroguanylin Study ‐04 * * • 8x greater binding affinity at GC‐C ** (%) receptors at pH <7 (%)

Rates Rates

• 3 RCT, all at low risk for bias, n=2612 Responder Responder

• IBS‐C dose: 3mg daily Overall Overall • NNT=10 17.8 30.2 29.5 14.2 21.5 24.0

• AEs: diarrhea Placebo Plecanatide Plecanatide Placebo Plecanatide Plecanatid (n=354) 3 mg 6 mg (n=379) 3 mg 6 mg (n=351) (n=349) (n=377) (n=379)

*P<0.001 vs placebo.. Brenner D, et al. Am J Gastroenterol 2018; In press.

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Lubiprostone for IBS‐C

• Type 2 chloride channel 50 • Monthly responder: At least moderate activator; increases balanced relief for 4/4 weeks or significant relief for (%)

2/4 weeks ion and water secretion into gut • Overall responder: Monthly responder for at least 2 of 3 months • 3 RCT, 1366 patients 25 • IBS‐C dose: 8 mcg BID only

Responders 17.9 approved in women 10.1

• NNT=12.5 Overall • AEs: diarrhea and nausea 0 Lubiprostone 8 µg BID Placebo N=780 N=387

Drossman DA et al. Aliment Pharmacol Ther. 2009;29:329‐341.

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Tegaserod for IBS‐C • Mixed 5-HT (serotonin) agonist (prokinetic) • Approved for women < 65 yo with ≤ 1 CV risk factor • Dose: 6 mg PO BID • AEs: Diarrhea, abdominal pain, headache, nausea

Pooled, post hoc analysis patients with low CV risk OR 1.41 (1.19–1.68) Study B301 (n=325) 50 P<0.001

40 44 Study B358 (n=1181) (N=2201) 30 35 Patients

% Study B307 (n=336) 20

Study B351 (n=359) Tegaserod Placebo (n=1122) (n=1079) Considerable or complete relief at least 50% of last 4 weeks in 12‐week study or at least somewhat relieved 100% of the last 4 weeks.

*Defined as patients who do not have a history of ischemic cardiovascular disease and who have no more than one cardiovascular disease risk factor. McGovern Medical School

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No demonstrable risk of MACE events with tegaserod

Risk of CV and stroke events with tegaserod vs comparators

CV Events* Hazard Ratio 95% Confidence Interval Non‐adjusted† 0.93 0.72–1.21 Adjusted‡ 0.95 0.73–1.23 Stroke Events Non‐adjusted† 0.89 0.45–1.75

Adjusted‡ 0.90 0.46–1.77

0.1 1.0 10.0 Favors Tegaserod Risk of Event Favors Comparator

*CV events include acute coronary syndrome, MI, coronary revascularization. †Unadjusted by Cox proportional hazards regression. ‡Adjusted for age, sex, region, calendar year, and baseline history of hypertension, treated hypertension, hyperlipidemia, statins, diabetes, treated diabetes, obesity, smoking, stroke, fibrates, angina, acute coronary syndrome, history of MI, and acute MI by Cox proportional regression. Loughlin J, et al. J Cardiovasc Pharmacol Ther. 2010;15(2):151‐157.

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Tenapanor

• NHE3 Inhibitor: traps water and phosphate in GI lumen; pain Primary Endpoint Secondary Endpoints 80 P<0.001 P<0.026 modulation via TRPV‐1 65.5 60.7 60 P<0.001 • 50 mg BID resulted in significantly 48.3 50 higher CSBM responder rate 40 33.7

than placebo % Patients, 23.6 • Primary endpoint: Increase ≥1 CSBM/week 20 from baseline for ≥6/12 treatment weeks 0 ≥1 CSBM increase ≥30% abdominal pain ≥30% abdominal pain reduction and • FDA approved for IBS‐C 9/2019 reduction ≥1 CSBM increase in the same week • Most frequent AEs: diarrhea, headache, nausea, abdominal pain Placebo (n=308) Tenapanor 50 mg BID

Chey WD et al. Am J Gastroenterol 2017; 112:763–774

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Emerging and Alternative IBS Therapies

• Bile acid sequestrants ‐ small, uncontrolled trials suggest benefit in IBS‐D

• Ramosetron – selective 5HT3 antagonist (IBS‐D) • Tachykinin antagonists • Peripheral cannabinoids –olorinab • Mast cell stabilizers • Glutamine • TRPV agents • Human milk oligosaccharrides • FMT

Peters SL et al. Aliment Pharmacol Ther. 2016;44(5):447‐459. Holvoet T et al. 2018 Digestive Disease Week Annual Scientific Meeting. Abstract 617. Lackner JM et al. 2018 Digestive Disease Week Annual Scientific Meeting. Abstract 455. Camilleri M. Gut Liver. 2015;9(3):332‐339.

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Bile Acid Sequestrants

• BAM: prevalence estimates 1%; 25‐50% in IBS‐D • Excess bile acids in colon • increase visceral sensation and fluid secretion via intracellular cAMP, mucosal permeability and/or Cl‐ secretion • Uncontrolled trials of bile acid sequestrants suggest benefit in IBS; 4‐16 gm/day • Availability of 7C4 serum test may identify likely responders; needs more study

Camilleri M. Gut Liver. 2015;9(3):332‐339.

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Ramosetron

• High 5‐HT3 binding affinity: potent and prolonged receptor blockade and antiemetic effects compared with older 5‐HT3 antagonists • Approved in Asia • Meta‐analysis of 4 IBS RCTs; 1623 patients (ramosetron vs placebo) • Overall IBS relief OR 1.70 (95% CI: 1.48 to 1.95) • Relief of abdominal pain/discomfort OR 1.41 (95% CI: 1.24 to 1.59) • Improvement in diarrhea OR 1.71 (95% CI: 1.40 to 2.08) • Higher rates of constipation; no colon ischemia

Qi Q et al. BMC Gastroenterology 2018;18(1):5.

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Mast cell stabilizers

• Ketotifen • Up to 6 mg BID increased discomfort threshold with visceral hypersensitivity, improved abdominal pain bloating, flatulence, diarrhea, incomplete evacuation, HRQOL (n=15)1 • No effect on release of tryptase and histamine from rectal biopsies demonstrated, mechanisms other than mast cell stabilization H1 receptor antagonism may be involved1 • Cromolyn(disodium cromoglycate) • Significantly decreased abdominal pain behaviors induced by colorectal distension in animal model independent of mast cell mediator release2

1. Klooker TK et al. Gut 59(9):1213‐1221. 2. Carroll SY et al. PLoS One. 2013;8(12):e84718.doi: 10.1371.

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TRPV Agents • Up‐regulation/sensitization of receptors on peripheral nerve terminals of nociceptors is an important mechanism of visceral hypersensitivity • Transient reporter potential channel V1 (TRPV1), is involved in this process • Responsive to capsaicin, heat, acidosis, and endovanilloids)

• Ebastine: H1RA • Small placebo‐controlled study (n=55) showed 20 mg/d reduced visceral hypersensitivity and abdominal pain in patients with IBS

Wouters MM et al. Gastroenterology. 2016;150(4):875‐887.

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Human Milk Oligosaccharides (HMOs)

HMOs in infant health1 • Primary determinant of gut microbiota • Involved in maturation of gut barrier and gut immune function; bind pathogens HMOs in IBS2,3 • Specifically increase bifidobacteria abundance • Increase concentration of metabolites essential for gut barrier functioning and immune modulation

1. Bode L. Glycobiology 2012:22(9):1147‐1162. 2. Iribarren C et al. 2019 Digestive Disease Week Annual Scientific Meeting. Abstract 1145. 3. Vigsnæs LK et al. 2017 11th Vahouny Fiber Symposium. Presentation 2. McGovern Medical School

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HMOs: Change in Total % of Stool Consistency (BSFS)

Significantly reduced total % of abnormal stools (diarrhea + constipation) compared to baseline at P < .001

Simrén M et al. 2019 American College of Gastroenterology Annual Scientific Meeting. Abstract 43.

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Fecal Microbiota Transplant for IBS Characteristics of randomized controlled trials of FMT versus placebo in IBS Study, Year Study Setting Study Sample IBS Criteria IBS Subtypes Primary outcome population Site Size Johnsen, 20171 Single Primary care Norway 90 Rome III IBS‐D 53% Decrease in IBS‐SSS > 75 points at center IBS‐C 47% 3 months Holvoet 20182 Single Tertiary care Belgium 64 Rome III Predominant Yes to question of improvement in center bloating and overall symptoms and abdominal non‐C bloating at 12 weeks Aroniadis, 20183 Multi‐ Primary, secondary, USA 48 Rome III IBS‐DDecrease in IBS‐SSS ≥ 50 points at center and tertiary care 12 weeks Halkjaer, 20183,4 Two Tertiary care Denmark 52 Rome III All subtypes Decrease in IBS‐SSS ≥ 50 points at centers 33.3% IBS‐C 3 months 29.4% IBS‐D 37.3% IBS‐M FMT, fecal microbiota transplantation; IBS‐QOL, Irritable Bowel Syndrome‐Quality of Life Measure; HADS; IBS‐Hospital Anxiety and Depression Scale

1. Johnsen PH et al. Lancet Gastroenterol Hepatol.2018;3(1):17‐24. 2. Holvoet T et al. Gastroenterology. 2018;154:S130. 3. Aroniadis OC et al. 2018 American College of Gastroenterology Annual Scientific Meeting. Abstract 742. 4. Halkjaer SI et al. Gut. 2018;67(12):2107‐2115.

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Vibrating Capsule

VIBRATING CAPSULE

Orally administrated vibrating capsule stimulates bowel motility by ACTIVATING BASE PATIENT REPORTING APP mechanically inducing vibrations in the UNIT Patients report bowel activity: • large intestine The base unit activates the Allowing the physician to adjust the capsule prior to use. After treatment • placing a vibrating capsule into Longitudinal, personalized data the designated groove , an collection for further development activation signal is transmitted of treatment plans by the base unit to the capsule

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Vibrating Capsule Proof of Concept Trial • 24 patients with CIC (Rome III) randomized to vibrating vs sham capsule (2/week x 8 weeks) • Endpoints: • Primary: Vibrating capsule vs sham colonic geometric center at 48 hours and t1/2 of ascending colon emptying • Secondary: colonic geometric center at 8 and 24 hours and slope of progression of colonic geometric center over the 48 hours of the transit study • Phase III trials ongoing for CIC with modified stimulation regimen

Nelson AD, et al. Neurogastroenterol Motil 2017; Jul;29(7). doi: 10.1111/nmo.13034. Epub 2017 Feb 8.

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Management of IBS: Take Home Points

• Make a positive diagnosis with judicious diagnostic testing • Diet, lifestyle modifications, OTC (loperamide, fiber) therapies first line • Best clinical trial evidence • IBS‐D: Rifaximin, Eluxadoline, Alosetron • IBS‐C: Linaclotide, Plecanatide, Lubiprostone, Tegaserod, Tenapanor • Adjunctive therapies (use at any point) • Peppermint oil (for all subtypes); TCAs, SNRIs (for IBS‐D/M with pain)‐allow 4 weeks minimum; antispasmodics; CBT; Diet; Probiotics; Bile acid sequestrants • Rich pipeline targeting specific etiologies/symptoms • Serotonergics, HMOs, tachykinin antagonists, mast cell stabilizers, FMT, glutamine, TRP agonists, cannabanoids

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Thank You! [email protected] 713‐500‐6672

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Questions?

Brooks D. Cash, MD, FACG

Brian E. Lacy, MD, PhD, FACG

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