brooks d. cash, md, facg€¦ · dan and lillie sterling professor of medicine mcgovern medical...

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Disclosures:

Brooks D. Cash, MD, FACGConsultant/Speakers’ Bureau: Salix, Allergan, Takeda, Ironwood, Alfasigma, Arena

DSMB: Vibrant

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

Current and Emerging Concepts in Irritable Bowel

Syndrome

Brooks D. Cash, M.D., FACP, FACG, FASGE, AGAFDan and Lillie Sterling Professor of Medicine

McGovern Medical SchoolChief, Gastroenterology, Hepatology, and Nutrition

University of Texas Health Science CenterHouston, TX

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American College of Gastroenterology

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

• DSMB: Vibrant

Disclosures

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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McGovern Medical School

Rome IV Criteria for IBS

Lacy BE, et al. Gastroenterology. 2016

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

Associated with a change

in stool frequency

Associated with a change

in stool form

Related to defecation

Recurrent abdominal painat least 1 day/week (on average) in the last 3 months

associated with ≥ 2 of the following


Multifactorial Pathophysiology of IBS

IBS Symptom Complex

Abnormal Motility

Visceral Hypersensitivity

Genetic Predisposition

Psychosocial Factors

Inflammation, Immune

Dysregulation

Microbiome

Malabsorption Issues

Diet

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


All IBS Subtypes1

• CRP or fecal calprotectin

• IgA TtG ± quantitative IgA

• Stool diary/App

• Consider abdominal plain film to assess for fecal loading

If severe or medically refractory, refer to specialist for physiologic testing

Diagnostic Testing for Suspected IBS and No AlarmFeatures*

• CRP or fecal calprotectin

• IgA TtG ± quantitative IgA

• When colonoscopy performed,

obtain random biopsies

• Serum 7‐C4 or fecal bile acids where available

IBS‐D1,2IBS‐D1,2IBS‐D1,2 IBS‐M1IBS‐M1IBS‐M1 IBS‐C1IBS‐C1IBS‐C1

CBCAge‐appropriate CRC screening

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

C4, 7α‐hydroxy‐4‐cholesten‐3‐one; CRC, colorectal cancer screening; CRP, C‐reactive protein; Ttg, tissue transglutaninase

*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

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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


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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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

Percent

Responders

52

41

0

20

40

60

80

LFD mNICE

Adequate Relief

27

13

0

20

40

60

80

LFD mNICE

FDA Composite Responder

>30% reduction in pain and decrease in BSFS >1 compared to baseline

P = 0.13

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

P = 0.31

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

Percent

Responders

n=45 n=45n=39 n=39


IBS Pharmacologic Options by Symptom1,2

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

Abdominalpain/

discomfort

Bloating/distension

Altered bowelfunction

Constipation Fiber* MOM/PEG solution* Lubiprostone Linaclotide Plecanatide Tegaserod Tenapanor Prucalopride*

Diarrhea Loperamide* Diphenoxylate‐

atropine* Cholestyramine* Alosetron Rifaximin Eluxadoline

Bloating

Rifaximin Lubiprostone Linaclotide Plecanatide Probiotics*

*Not currently FDA‐approved for IBS

Abdominal Pain/discomfort Antispasmodics* Antidepressants* Lubiprostone Linaclotide Plecanatide Alosetron Rifaximin Eluxadoline Tegaserod

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OTC Options

• Antidiarrheals: Imodium, clays/binders

• Anti‐spasmodics

• Peppermint oil

• Probiotics


Conventional Nonspecific Agents for IBS‐D

14

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

There is insufficient evidence to recommend

loperamide for use in IBS

There is insufficient evidence to recommend

antispasmodicsavailable in US*

Clinical trials

Patients treated

23

2,154

Clinical trials

Patients treated

2

42

Recommendation

Strong

Quality of evidence

Very Low

Recommendation

Weak

Quality of evidence

Low

*Recommendation revised to reflect evidence for products available in US

Recommendations from an American College of Gastroenterology monograph

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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. HenstromM et al. Gut. 2017;66(9):1725‐1727.


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


Rifaximin for IBS‐DTARGET 1 & TARGET 2 Trials

• Poorly absorbed antibiotic; inhibits protein synthesis

• Dosing 550 mg TID x 2 weeks• 7 RCT; 2654 patients • NNT= 8• AEs similar to placebo• 2/3 responders need repeat treatment

• No value in re‐treating non‐responders

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

Adequate Relief of IBS‐Related Bloating

TARGET 1 TARGET 2 Combined

40.8 40.6 40.7

31.2 32.2 31.7

0

20

40

60

80

Patients, %

P = .01

n=309 n=314 n=315 n=320 n=624 n=634

P = .03P < 0.001

Adequate Relief of Global IBS Symptoms

TARGET 1 TARGET 2 Combined

39.5 41 40.2

28.731.9 30.3

0

20

40

60

80

P = .005

n=309 n=314 n=315 n=320 n=624 n=634

P=.02 P < .001

Adequate Relief of Bloating

Rifaximin Placebo

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Urgency and bloating improved significantly with both repeat treatments

Abdominal pain and stool consistency improved significantly with first retreatment

Rifaximin for IBS‐DTARGET 3 Trial

33 36.9

2529.3

0

20

40

60

80

P = .04P = .02

n=328 n=308 n=295 n=283

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

Patients, %

First Repeat Treatment

Second Repeat Treatment

Rifaximin Placebo

Responder defined as • Responding to IBS‐related abdominal pain

and stool consistency for ≥2 of 4 weeksRecurrence defined as • Loss of response for ≥3 of 4 weeks

Data for last observation carried forward

Retreatment Efficacy


Eluxadoline for IBS‐DIBS‐3001 & IBS‐3002 Trials

• Mixed opioid receptor modulator

• μ/κ‐opioid receptor agonist; δ‐opioid antagonist 1,2

• Dosing: 100 mg BID


• NNT= 13

• AEs: Constipation, abdominal pain, SO spasm, pancreatitis

• Contraindicated if no GB or h/o pancreatitis, heavy ETOH users

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.

Placebo BID Eluxadoline 75 mg BID Eluxadoline 100 mg BI

Composite responder defined as

• 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

Composite Responder Rates

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Eluxadoline in Patients Who Failed LoperamideRELIEF Trial

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

22.7%27.9%

43.6%

10.3%

16.7%

31.0%

0%

10%

20%

30%

40%

50%

60%

Primary Composite Secondary: StoolConsistency

Secondary: WorstAbdominal Pain

Eluxadoline 100 mg BID (n=174) Placebo BID (n=172)

% R

esp

on

der

s

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.

• Phase IV multicenter DBRCT

• Subjects: Patients subjectively reporting loperamide use in prior 12 months failing to provide adequate control of IBS‐D symptoms

• AEs: Rates comparable in both groups; no SAEs

P < .05

P < .01

P < .05


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

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.

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

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AntidepressantsVariable Recs and Strength of Evidence

•18 RCT, 1127 patients •Antidepressants in general: NNT= 4; pain mostly

•TCAs: 12 RCT, 787 patients; NNT= 4; Strong rec, high evidence

•SSRIs: 7 RCT, 356 patients; NNT= 5; Weak rec, low evidence

•SNRIs not yet studied in large RCTs2

•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.

Antidepressant action

Visceral analgesia

Changes in motility

Smooth muscle relaxation


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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RCTs NResponse*

Fiber Placebo

RR of Unimproved Symptoms(95% CI)

NNT(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)

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

*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


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 guanylate‐cyclase C receptors to promote ion and fluid secretion into gut and ENS modulation


• IBS‐C dose:290 mcg daily

• NNT=6

• AEs: diarrhea*P<0.0001 for all analyses of linaclotide vs placebo groups, using Cochran‐Mantel‐Haenszel test

% Responders

Placebo

(n=403)Linaclotide

290 μg (n=401)

FDA Primary Endpoint: ≥30% reduction worst abdominal pain and increase ≥1 CSBM, both for ≥6/12 weeks

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


Linaclotide for IBS‐C

CSB

M M

ean

Chan

ge from

Baselin

e +/‐SEM

3

2

1

0

Weeks

BL 1 2 3 4 5 6 7 8 9 10 11 12

Treatment Period*

Treatment PeriodPlaceboLinaclotide 290 µg

12 13 14 15 16

RW Period†

RW Treatment SequencePlacebo/linaclotide 290 µgLinaclotide 290 µg/linaclotide 290 µgLinaclotide 290 µg/placebo

z

Weeks

N=800

*P < 0.0001 for linaclotide patients vs placebo patients (ANCOVA).†P < 0.001 for linaclotide/linaclotide patients vs linaclotide/placebo patients (ANCOVA).

ANCOVA = analysis of covariance; RW = randomized withdrawal

Rao S, et al. Am J Gastroenterol 2012;107(11):1714-1724.

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Linaclotide: Abdominal Pain Over 26 Weeks

Chey WD, et al. Am J Gastroenterol. 2012;107:1702-1712.

ITT population, observed cases, LS‐mean presented: P‐values based on ANCOVA at each week. Bars represent 95% CI.

P=0.0007 for week 1P<0.0001 for weeks 2-26

Chan

ge in

Worst

Abdominal Pain, %

‐60

‐50

‐40

‐30

‐20

‐10

0

Trial Week

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

Linaclotide 290 µg Placebo

N=804ITT, intention to treat; LS, least squares.


Plecanatide for IBS‐C

• 16 aa peptide structurally similar to uroguanylin

• 8x greater binding affinity at GC‐C receptors at pH <7

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

• IBS‐C dose: 3mg daily

• NNT=10

• AEs: diarrhea17.8 30.2 29.5

* *

Overall Responder Rates (%)

Plecanatide 3 mg

(n=351)

Plecanatide 6 mg

(n=349)

Placebo (n=354)

*

*

14.2 21.5 24.0

Plecanatide 3 mg

(n=377)

Plecanatid6 mg

(n=379)

Placebo (n=379)

Overall Responder Rates (%)

Study ‐05Study ‐04

*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 activator; increases balanced ion and water secretion into gut


• IBS‐C dose: 8 mcg BID only approved in women

• NNT=12.5• AEs: diarrhea and nausea

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

17.9

10.1

0

25

50

Lubiprostone 8 µg BID Placebo

Overall Responders (%)

N=780 N=387

• Monthly responder: At least moderate relief for 4/4 weeks or significant relief for

2/4 weeks• Overall responder: Monthly responder for

at least 2 of 3 months


Tegaserod for IBS‐C

Study B301 (n=325)

Study B358 (n=1181)

Study B307 (n=336)

Study B351 (n=359)

(N=2201)

Pooled, post hoc analysispatients with low CV risk

50

40

30

20

10

% Patients

Tegaserod(n=1122)

Placebo(n=1079)

OR 1.41 (1.19–1.68)

P<0.001

44

35

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

• 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

Considerable or complete relief at least 50% of last 4 weeks in 12‐week studyor at least somewhat relieved 100% of the last 4 weeks.

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No demonstrable risk of MACE events with tegaserod

Favors Tegaserod Favors Comparator

0.93 0.72–1.21

0.95 0.73–1.23

0.89 0.45–1.75

0.90 0.46–1.77

Hazard Ratio 95% Confidence Interval

Non‐adjusted†

Non‐adjusted†

Adjusted‡

Adjusted‡

CV Events*

Stroke Events

Risk of Event

Risk of CV and stroke events with tegaserod vs comparators

0.1 1.0 10.0

*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.


Tenapanor

• NHE3 Inhibitor: traps water and phosphate in GI lumen; pain modulation via TRPV‐1

• 50 mg BID resulted in significantly higher CSBM responder rate than placebo• Primary endpoint: Increase ≥1 CSBM/week from baseline for ≥6/12 treatment weeks

• FDA approved for IBS‐C 9/2019

• Most frequent AEs: diarrhea, headache, nausea, abdominal pain

Primary Endpoint

33.7

48.3

23.6

60.765.5

50

0

20

40

60

80

Placebo (n=308) Tenapanor 50 mg BID

Pa

tien

ts, %

P<0.001

≥1 CSBM increase ≥30% abdominal pain reduction

≥30% abdominal pain reduction and ≥1 CSBM increase in the same week

P<0.026

P<0.001

Secondary Endpoints

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.


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

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

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• 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

Ramosetron

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


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.


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.

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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.


Fecal Microbiota Transplant for IBSCharacteristics of randomized controlled trials of FMT versus placebo in IBSStudy, Year Study

population

Setting Study

Site

Sample

Size

IBS Criteria IBS Subtypes Primary outcome

Johnsen, 20171 Single

center

Primary care Norway 90 Rome III IBS‐D 53%

IBS‐C 47%

Decrease in IBS‐SSS > 75 points at

3 months

Holvoet 20182 Single

center

Tertiary care Belgium 64 Rome III Predominant

bloating and

non‐C

Yes to question of improvement in

overall symptoms and abdominal

bloating at 12 weeks

Aroniadis, 20183 Multi‐

center

Primary, secondary,

and tertiary care

USA 48 Rome III IBS‐D Decrease in IBS‐SSS ≥ 50 points at

12 weeks

Halkjaer, 20183,4 Two

centers

Tertiary care Denmark 52 Rome III All subtypes

33.3% IBS‐C

29.4% IBS‐D

37.3% IBS‐M

Decrease in IBS‐SSS ≥ 50 points at

3 months

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

Orally administrated vibrating capsule stimulates bowel motility by mechanically inducing vibrations in the large intestine

VIBRATING CAPSULE

PATIENT REPORTING APP Patients report bowel activity:• Allowing the physician to adjust the

treatment • Longitudinal, personalized data

collection for further development of treatment plans

ACTIVATING BASE UNIT The base unit activates the capsule prior to use. After placing a vibrating capsule into the designated groove , an activation signal is transmitted by the base unit to the capsule


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


Thank [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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brooks d. cash, md, facg€¦ · dan and lillie sterling professor of medicine mcgovern medical...

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