IBSi 2015 Wh t` N d IBS in 2015: What`s New and What Works?

Transcription

Brooks D. Cash, MD, FACG
IBS iin 2015
2015: What’s
Wh t’ New
N and
d
What Works?
American College of Gastroenterology
Nashville, TN, December 5, 2015
Professor of Medicine
University of South Alabama
Director, GI Physiology, USA Medical Center
Mobile, AL
Managing IBS:
What Do Your Patients Want?
• They want you to listen
– Understand their history (symptoms
(symptoms, work
work, home)
• Education about their condition
– Address questions or concerns
– Address uncertainty of IBS
• Reassurance
• A positive
iti di
diagnosis
i
– Review results with patients
• Symptom improvement
ACG 2015 Nashville Regional Postgraduate Course
Copyright 2015 American College of Gastroenterology
1
Rome III Criteria for IBS
Recurrent abdominal p
pain or discomfort
at least 3 days/month in the last 3 months
associated with ≥2 of the following:
Improvement with
defecation
d f
i
Onset associated with
a change in frequency of
stool
Onset associated with a
change in
form of stool
Criteria fulfilled for the last 3 months with symptom onset
at least 6 months prior to diagnosis
Longstreth GF, et al. Gastroenterology. 2006;130:1480-1491
Overview of IBS Pathophysiology
Luminal Factors
Dysbiosis
Neuroendocrine mediators
Bile Acids
Host Factors
Environmental
Factors
Altered GI Motility
Visceral hypersensitivity
Altered brain-gut interactions
Psychosocial distress
Food
Medications
Supplements
Antibiotics
Enteric infection
Increased intestinal permeability
Gut mucosal immune activation
Serotonin
Opioids
Chey WD, et al. JAMA. 2015;313(9):949-958.
2
Diagnostic Testing for Patients with
Suspected IBS and No Concerning* Features
All IBS Subtypes
CBC
A
Age-appropriate
i t CRC screening
i
IBS-D
CRP or fecal calprotectin
IgA TtG ± quantitative IgA
When colonoscopy performed,
p
obtain random biopsies
SeHCAT, fecal bile acids, or serum
C4 where available
IBS-M
CRP or fecal calprotectin
IgA TtG ± quantitative IgA
Stool diary
Consider abdominal plain film to
assess for fecal loading
IBS-C
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.
Chey WD, et al. JAMA. 2015;313(9):949-958.
Auto-immune IBS: An Emerging
Pathophysiological Construct
Food
poisoning
E. Coli
C. jejuni
Shigella
Salmonella
Bacterial
toxin
Cytolethal
Distending toxin
(CDT B)
Autoimmunity
Gut nerve
damage
Bacterial
overgrowth
Anti-vinculin
Reduced ICC
Reduced MMC
Breath testing
Culture
qPCR
Deep sequencing
IBS
Antibiotics
3
Blood Test for IBS
• D-IBS subjects (N=2,375)
• Subjects with IBD (n=142) which included
Crohn’s disease (n=73) and ulcerative colitis
(N=69)
• Subjects with celiac disease (n
(n=121)
121)
• Healthy subjects (n=43)
Pimentel M, et al. PLoS ONE. 2015;10(5):e0126438.
Potential Utility of Biomarkers for IBS-D
Antibody Titers in IBS Compared with Healthy Subjects and IBD
Anti-CdtB
Anti
CdtB
Anti-vinculin
Anti
vinculin
Healthy control
Healthy control
IBS
IBS
Crohn’s disease
Crohn’s disease
Ulcerative colitis
Ulcerative colitis
Celiac disease
Celiac disease
0
1
2
3
Anti-CdtB antibody titers
4
0
1
2
3
4
Anti-vinculin antibody titers
P<0.001 for titers in IBS subjects vs other groups.
CdtB, cytolethal distending toxin.
4
Anti-CdtB and Anti-Vinculin May
Distinguish IBS-D from IBD
Accuracy for Diagnosing
IBS-D vs IBD
ROC For Diagnosing IBS-D vs IBD
AUC
0 81 (95% CI,
0.81
CI 0.77-0.84)
0 77 0 84)
1
Sensitivity
Optical
Density
AUC
0.62 (95% CI, 0.58-0.67)
Specificity
%
Sensitivity
%
CdtB
(cutoff ≥2.80)
91.6
43.7
Vinculin
(cutoff ≥1.68)
83.8
32.6
0
0
1
1-Specificity
Anti-vinculin Ab
Anti-CdtB Ab
AUC, area under the curve; CdtB, cytolethal distending toxin; IBD, inflammatory bowel disease.
Potential Utility of Biomarkers for IBS-D
Anti-CdtB
99
0.1
99
0.2
98
0.2
98
95
0.5
90
1
0.5
1
2
5
10
56%
Ford, et al.
Anti-CdtB and Anti-vinculin
0.1
20
30
40
50
60
70
80
90
95
2000
1000
500
200
100
50
20
10
5
2
1
0.5
0.2
0.1
0.05
0.02
0.01
0.005
0.002
0.001
0.0005
98
99
Pre-Test
Probability (%)
Likelihood
Ratio
80
70
60
50
40
30
20
10
5
2
2
5
10
20
30
40
50
60
70
80
1
90
0.5
95
0.2
98
0.1
Post-Test
Probability (%)
99
Pre-Test
Probability (%)
2000
1000
500
200
100
50
20
10
5
2
1
95
95%
90
0.5
0.2
0.1
0.05
0.02
0.01
0.005
0.002
0.001
0.0005
80
70
60
50
40
30
20
24%
10
5
2
1
0.5
0.2
Likelihood
Ratio
0.1
Post-Test
Probability (%)
CdtB, cytolethal distending toxin.
5
Treatment Depends on Severity
•
•
•
Goal: improved function
Continuing care
Severe
(25%)
+
•
•
•
•
•
•
Psychological treatments
Follow-up visit
Moderate
Manage stress
(35%)
Drug therapy
+
Diet, lifestyle advice
Mild
Positive diagnosis
(40%)
Explain, reassure
Bulking Agents for IBS-C:
Systematic Review and Meta-analysis
RCTs
Fiber
Placebo
RR of
d
Unimproved
Symptoms
(95% CI)
48%
43%
0.86 (0.80-.94)
10 (5-100)
7 (3-50)
Response*
N
Overall
14
906
Ispaghula
7
499
48%
36%
0.83 (0.73-0.94)
Bran
6
441
46%
46%
0.90 (0.79-1.03)
NNT
(95%CI)
p
y p
*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 of 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: 1367-1374.
6
IBS & Probiotics: Global Symptoms
IBS & Antidepressants
7
General Approach to Prescribing
Antidepressants in IBS
• Consider specific symptoms1-3
TCA iin IBS
D SSRIs
SSRI
– TCAs
IBS-D,
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 (every 1-2 weeks)1
• If ineffective or not tolerated, consider
switching to different class of agent or
combination therapy with another agent
and/or psychological treatment1
• Continue at minimum effective dose for
6-12 months1
– Long-term therapy may be warranted
for some patients
– Gradual taper to prevent
withdrawal symptoms
y p
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;40:183-206; 2. Chey WD, et al. Gut Liver. 2011;5:253-266;
3. Gorard DA, et al. Aliment Pharmacol Ther. 1994;8:159-166.
Food & IBS Symptoms:
The patient’s perspective
• 60% of patients report worsening of
symptoms after meals1
• Survey of 1,242 IBS patients the following
interventions improved symptoms2
– small meals (69%)
– avoiding fat (64%)
– increasing fiber (58%)
– avoiding milk products (54%)
1Chey
et al, Am J Gastroenterol 2002; 2Halpert et al, Am J Gastroenterol 2007
8
IBS & Diet
• Elimination diet
• IgG elimination diet
• Low carbohydrate
• Low fructose/fructan
• Low gluten
• Low FODMAP
9
IBS & Low Gluten
•
•
•
•
R, DB, PC, re-challenge study
34 IBS patients (Rome III); celiac excluded
Prior improvement in Sx on gluten-free diet
16 gm of non-fermentable gluten
substitute/day vs. 16 grams of gluten
• Primary endpoint: adequate symptom relief
• Gluten-group had less improvement in Sx than
those on gluten-free (68% vs. 40%; p = .001)
Biesiekierski et al, Am J Gastro 2011
IBS & Low Gluten Diet
Biesiekierski et al, Am J Gastro 2011
10
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 HLADQ2/8 positive patients
Vazquez-Roque et al, Gastroenterology 2013; 144: 903-911
What Are FODMAPs?
Fermentable oligo-, di-, monosaccharides and polyols
Excess
Fructose
Honey, apples, pears, peaches, mangos,
fruit juice, dried fruit
Fructans
Wheat (large amounts), rye (large amounts),
onions, leeks, zucchini
Lactose
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;6:765-771; 2. Shepherd SJ, Gibson PR. J Am Diet Assoc. 2006;106:1631-1639; 3. Barrett JS,
Gibson PR. Ther Adv Gastroenterol. 2012;5:261-268.
11
Potential Role of FODMAPs in IBS
FODMAPS
Osmotic effects
Bacterial fermentation
SCFA
Gas production
(CH3, H2, CO2)
(butyrate, propionate, acetate)
Trophic effects
Luminal pH
Microbiome
changes
Osmotic load
Increased biomass
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;12:424-440.
•
•
•
•
•
Low FODMAP Diet: What is there
left to eat?
Lean proteins
Gluten-free breads, rolls, pasta
Rice, corn, oat products
Quinoa
Safe fruits and vegetables:
– Snow peas, bok choy, mandarin oranges
12
IBS: Prospective study to Evaluate Low
FODMAP diet
•
•
•
•
82 consecutive IBS patients (NICE criteria)
Detailed symptom and dietary evaluation
9 month evaluation – performed in UK
Individual symptoms and global IBS symptoms
measured
• 39 in the standard diet group
• 42 in the low FODMAP diet group
Staudacher et al, J Hum Nutr Diet, 2011
Patients With Improved
Symptom Response, %
Improvements in IBS Symptom Scores:
Low FODMAP vs Control Diet
100
90
80
70
60
50
40
30
20
10
0
*
†
†
Standard Diet
Low FODMAP Diet
*
†
†
*P≤0.001
† P<0.05
Staudacher HM, et al. J Hum Nutr Diet. 2011;24:487-495.
13
FODMAP Diet Reduces Functional
GI Symptoms
Effects of Diet on Functional GI Symptoms
in Controlled, Crossover Study (N=30)
VAS (0-100 mm)
V
60
Typical Australian diet
40
60
Typical Australian diet
40
Low FODMAP diet
20
Low FODMAP diet
20
0
7
14
Study Day
21
0
7
14
21
Study Day
FODMAP, fermentable oligo-di-monosaccharides and polyols.
Halmos EP et al. Gastroenterology. 2014;146:67-75.
IBS & Low FODMAP Diet:
Some Problems Exist
• What is the cut
cut-off
off for FODMAP content?
• Resources differ on low FODMAP diets
• Total meal FODMAPs should be counted, not
individual FODMAP
• Most patients can’t
can t stick to the diet
• Often requires significant time counseling
• Theoretical nutritional issues with long-term
use
14
Sucrase/Isomaltase Deficiency
Normal sucrose digestion
Sucrase-Deficient
Small intestines
Large intestines
Potential Role for Sucrase/Isomaltase
Deficiency in IBS
• Sucrase-isomaltase digests
75% of carbohydrates
(~40% of total Western diet)
– The high workload of
sucrase-isomaltase in total
carbohydrate digestion may
explain likelihood of
pathology if there is sucrase
deficiency
Frequency of Sucrase Deficiency in Small
Bowel Biopsies
(N=27,875 samples)
9.3%
Sucrase deficiency
• Sucrase deficiency is
common and can causes
diarrhea
Nichols BL, et al. J Pediatr Gastroenterol Nutr. 2012;55:S28-S30.
15
IBS-C
Osmotic Agents: PEG for IBS-C
•
•
•
•
•
•
•
Prospective, multi-center, R, DB, PC
R
Rome
III criteria
it i
139 patients (mean age = 41; 83% women)
28 day study; 13.8 gm/ sachet;
1-3 sachets/day vs. placebo
Primary endpoint: mean # of SBM/day
Results: At week 4, 4.4 SBM/week vs. 3.1
SBM/week (PEG vs. placebo; p < .0001)
16
PEG 3350+E Improves SBMs in IBS-C
5
*
4.5
4
Mean at Week 4
3.5
3
2.5
Placebo (n=71)
2
1.5
1
PEG 3350+E (n=68)
0.5
0
# SBMs
Pain Level
SBMs = spontaneous bowel movements; PEG = polyethylene glycol
PEG 3350+E is not approved for use in the US
*P < 0.0001
Chapman RW, et al. Am J Gastroenterol. 2013;108(9):1508-1515.
Efficacy of Linaclotide in IBS-C Patients
3
Treatment Period*
RW Period†
Mean Change From
Baseline +/- SEM
z
2
1
N=800
0
BL
1
2
3
4
5
6
7
8
9
10 11 12
Weeks
Treatment Period
Placebo
Linaclotide 290 µg
ANCOVA, analysis of covariance; RW, randomized
withdrawal.
Rao S, et al. Am J Gastroenterol. 2012;107:1714-1724.
13
14 15 16
Weeks
RW Treatment Sequence
Placebo/linaclotide 290 µg
Linaclotide 290 µg/linaclotide 290 µg
Linaclotide 290 µg/placebo
*P<0.0001 for linaclotide patients vs placebo patients (ANCOVA).
for linaclotide/linaclotide patients vs linaclotide/placebo
patients (ANCOVA).
†P<0.001
17
Linaclotide for IBS-C Over 12 Weeks
FDA Primary Endpoint
(≥6/12 Weeks)
% Responders
60
50
40
FDA Primary Endpoint:
≥30% reduction worst
abdominal pain and
increase ≥1 CSBM, both
for ≥6/12 weeks
33.7%*
30
20
13.9%
10
0
Placebo
(n=403)
Linaclotide
290 μg
(n=401)
*P<0.0001 for all analyses of linaclotide vs placebo groups, using Cochran-Mantel-Haenszel test
Chey WD, et al. Am J Gastroenterol. 2012; epub September 18.
Linaclotide Phase 3 IBS-C Trial:
Abdominal Pain Over 26 Weeks
% Change in Worstt
Abdominal Pain
0
Linaclotide 290 µg
-10
10
Placebo
-20
-30
-40
-50
-60
60
BL
2
4
6
8
10
12
14
16
18
20
22
24
Trial Week
ITT population, observed cases, LS-means presented: P-values based on ANCOVA at each
week. Bars represent 95% CI.
26
N=804
P=0.0007 for Week 1
P<0.0001 for Weeks 2-26
Diarrhea is the most common adverse event associated with linaclotide treatment; other AEs
were comparable between placebo and linaclotide treatment groups.
Chey WD, et al. Am J Gastroenterol. 2012; epub September 18.
18
IBS-D
Rifaximin: Most Extensively Studied
Antibiotic for IBS
•
•
•
•
•
Gut-directed
G
t di t d antibiotic
tibi ti
Not systemically absorbed
Doses studied for IBS: 400 mg BID to 550 mg TID
Generally well tolerated
Ad
Adverse
effects
ff
iinclude:
l d h
headache,
d h abdominal
bd i l
pain, and upper respiratory tract infection
Ford AC, et al. Clin Gastroenterol Hepatol. 2009;7:1279-1286. Pimentel M, et al. N Engl J Med. 2011;364:22-32.
19
Rifaximin Trials: Global Relief of IBS
Without Constipation
• 2 Phase 3 randomized
controlled trials; N=1260
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)
45
40
35
30
25
Rifaximin
20
Placebo
15
10
5
0
T-I
T-II
Comb
T-I, TARGET 1 trial; T-II, TARGET 2 trial; Comb, Combination of both trials.
Pimentel M, et al. N Engl J Med. 2011;364:22-32.
Retreatment with Rifaximin- Target 3
Screening/
Treatment 1
Phase
Treatment 2
Phase
Maintenance
Phase 1
Treatment 3
Maintenance
Phase/DBR
Phase 2
Treatment
Phase
Primary
2w
RFX
4w f/u
Up to 18w
2w
RFX
4w f/u
6w
2w
RFX 4w f/u
4w
1:1
*
Follow
up
Evaluation
Period
Study
Day 1
7-13 d
PBO
Treatment 4
Phase/SRT
Treatment
Phase
*
Responders
R
d with
ith
recurrent symptoms
NonResponders
Withdrawn
2w
PBO 4w f/u
*
Obtain Daily/Weekly Symptom Diary
6w
*
EOS
2w
PBO 4w f/u
*
* Stool sample collection
20
TARGET 3:
Study Design and Patient Disposition
36%
328
n=382
2,438
Of open label responders
didn’t experience a
reoccurrence of symptoms
for up to an 18-week followup period were excluded due
to symptom inactivity2
44%
46
patients
were treated and
completed 2 weeks
of rifaximin
550 mg in the
open-label phase1
patients
randomized to
rifaximin
550 mg TID2
n=1,074
responded
to open-label
treatment1
59%
n=636
entered the
double-blind phase
after symptom reoccurrence
308
patients
randomized
to placebo2
Median time to recurrence of
10 weeks (range of
6-24 weeks)2
Xifaxan [prescribing information]. Salix Pharmaceuticals, Inc. 2015.
TARGET 3:
Efficacy of First and Second Retreatments
Efficacy of First and Second Retreatments
LOCF Analysis
P 0 04
P=0.04
P=0.02
40
36.9
33
Patients, %
30
29.3
Abdominal pain and stool
consistency improved
significantly with first
retreatment
25
20
10
0
Urgency and
U
d bloating
bl ti improved
i
d
significantly with both repeat
treatments
n=328
n
328 n
n=308
308
n=295
n
295 n
n=283
283
First repeat
treatment
Second
repeat
treatment
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].
21
Eluxadoline for IBS-D: Rationale
• Mixed mu (μ) opioid receptor agonist / delta (δ) opioid receptor
antagonist
g
• 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
δ opioid receptor
Inhibition restores
G-protein signalling;
reduces
μ agonist-related
desensitization
Activation reduces
pain, gastric propulsion
Key inclusion and exclusion criteria
Key inclusion criteria
• IBS-D as defined by Rome III
• 1-week baseline
•
BSS ≥5.5 (scale 1–7)
•
WAP >3.0 (scale 0–10)
•
GSS ≥2.0 (scale 0–4a)
• Additional requirements:
•
Diary compliance
•
No rescue medications during baseline
Keyy exclusion criteria
• Prior pancreatitis, alcohol abuse, cholecystitis past 6
months, sphincter of Oddi dysfunction, IBD, intestinal
obstruction, GI infection or diverticulitis past 3 months
• Lipase >2x ULN; ALT or AST >3x ULN
a0=no
symptoms, 4=very severe symptoms
ALT, alanine transaminase; AST, aspartate aminotransferase; BSS, Bristol stool score; GI, gastrointestinal; GSS, global symptom
score: IBD, inflammatory bowel disease; ULN, upper limit of normal; WAP, worst abdominal pain in past 24 h
22
Phase 3 study design
IBS-3001
Prescreen
(≤1 wk)
Screening
(2–3 wks)
Double-blind treatment
(26 wks)
Randomization
(Day 1)
Efficacy
12 wks (FDA)
Double-blind safety
continuation (26 wks)
Efficacy
26 wks (EMA)
Post-Tx
(2 wks)
End of
treatment
IBS-3002
Prescreen
(≤1 wk)
Screening
(2–3 wks)
Double-blind treatment
(26 wks)
Randomization
(Day 1)
Efficacy
12 wks (FDA)
Blinded PBO
withdrawal
(4 wks)
Efficacy
26 wks (EMA)
Primary endpoint: composite responder
FDA guidance / EMA draft guidance
Responder must meet both criteria on same day:
Daily pain
responder:
WAP scores improved by ≥30%
compared to average baseline pain
•
•
•
AND
Daily stool
consistency responder:
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
23
Phase 3 baseline characteristics
Screened, n
3001
3002
2832
2521
Randomized n
Randomized,
1281
1146
Age, mean (SD)
44.9 (13.7)
45.9 (13.5)
Female, n (%)
838 (65.4)
768 (67.0)
115 (9.0)
126 (11.0)
Cholecystectomy, n (%)
272 (21.2)
224 (19.5)
Loperamide use, n (%)a
466 (36.3)
408 (35.6)
6 3 (0
6.3
(0.4)
4)
6 2 (0
6.2
(0.4)
4)
>65 years, n (%)
BSS mean (SD)
BSS,
WAP, mean (SD)
6.2 (1.5)
6.0 (1.5)
No. BMs/day, mean (SD)
4.9 (2.8)
4.8 (3.0)
GSS, mean (SD)
2.9 (0.5)
2.8 (0.5)
aIn previous year
SD, standard deviation
Primary endpoint: composite responders
35
Δ 11.5*
30
Δ 9.5*
Δ 10.3*
Δ 7.2*
Responders (%)
25
20
15
10
5
0
N=808
N=806
N=809
Weeks 1–12
N=808
N=806
N=809
Weeks 1–26
*p<0.001
24
Eluxadoline: Urgency-Free Days and Stool
Frequency
BM Frequency
Change from Baseline
≥75% Urgency-free Days
P<0.0001
27.9
26.6
20
Mean cchange from baseline
in nu
umber of daily BMs
Responders, %
R
30
Pooled Data
Week 26
1
P<0.0001
40
16.6
10
0.5
0
-0.5
-1
-1.5
1.5
-1.6
-2
-2.0
-2.5
0
-2.0
Weeks 1–26
Placebo BID
Eluxadoline 75 mg BID
Eluxadoline 100 mg BID
Chey WD, et al. Eluxadoline Demonstrates Sustained Efficacy for the Treatment of Diarrhea-predominant Irritable Bowel Syndrome in
Phase 3 Clinical Trials. Presented at DDW, May 16-19, 2015; Washington, D.C. [Abstract No. 316].
Eluxadoline: % of Daily Composite
Responders Over Time
Percentage of Daily Composite Responders* Over Time
Pooled Data from Studies IBS-3001 and IBS-3002
Daily
y composite responders
(%)
100
Placebo
Eluxadoline 75 mg
80
Eluxadoline 100 mg
60
40
20
0
0
1
2
3
4
5
6
7
8
9
10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26
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).
Chey WD, et al. Presented at DDW, May 16-19, 2015; Washington, D.C. [Abstract No. 316].
25
Eluxadoline Safety Profile
Most Common Adverse Events in Phase 3 Trials
(>4% in either treatment arm and > placebo)1
l b
Placebo
(n=808)
Sphincter of Oddi spasm
events
0.6% (10 /1666) patients
receiving eluxadoline
Eluxadoline Eluxadoline
75 mg
100 mg
(n=859)
(n=807)
n (%)
Adverse Events
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
(1.4)
4)
32 (4.0)
(4 0)
36 (4.2)
(4 2)
‡
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)
Gastroenteritis
Pancreatitis
4 additional cases
with eluxadoline
(3 associated with alcohol
use and 1
with biliary sludge)
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].
Ondansetron for IBS-D
Effect of Ondansetron 4-8 mg TID for 5 Weeks in
Patients with Rome III IBS-D (N=120)*
7
Crossover
Bristtol Stool Form Score
6
Placebo
Ondansetron
5
4
3
2
1
Treatment 1
Washout
endpoint weeks
Treatment 2
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;63:1617-1625.
26
Peppermint Oil SST (Site Specific Targeting) for
IBS-D/M
53
Peppermint Oil SST for IBS-D/M
Randomize
Peppermint oil SST
180 mg TID (n=35)
Screening
T-3 weeks
Placebo TID
(n=37)
Day 1
(Visit 2)
Safety and compliance assessments
Day 29
End of treatment
(Visit 7)
Days 2, 8,15, 22, and 29 (Visits 3–7)
TISS = Mean of frequency/intensity of 8 IBS
symptoms Days 2 and 29 (Visits 3 and 7)
Cash BD, et al. Dig Dis Sci. 2015 Aug 29 [Epub ahead of print].
27
PO-SST: Reduction in IBS Symptoms
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
0
10
20
-19.2
-22.6
-25.4
30
-26.1
-23.9
-26.2
-32.2
-34.1
34 1
-42.4
-35.6
-36.1
40
50
-23.9
-41.3
*
-48.1
*
-43
-44.2
*
*
Placebo (n=37)
Peppermint oil (n=35)
*P<0.05
Cash BD, et al. Dig Dis Sci. 2015 Aug 29 [Epub ahead of print].
Bile Acids and IBS-D
• Bile acid diarrhea
prevalence estimates 1%;
25-50% in IBS-D
• Excess bile acids in colon
– Stimulate enteroendocrine
cells and accelerates colonic
transit
– Activate visceral sensation and
fluid secretion (through
increased intracellular cAMP,
increased mucosal
permeability or chloride ion
secretion)
Camilleri M. Gut Liver. 2015;9:332-339.
28
Breaking BAD in IBS-D
• Empiric therapy currently; diagnostic tests pending
• Bile
Bil acid
id sequestrants/binders
t t /bi d
– Cholestyramine/Colestid/Colesevelam: small, uncontrolled
series suggest benefit
• Cellular mechanisms (investigational)
– FXR agonists (obeticholic acid, GW4064) to reverse FGF-19
deficiency and decrease enterocyte BA productions
Summary
• The field of IBS is constantly evolving
• Rome
R
IV 2016 – expectt changes
h
iin th
the d
definition
fi iti
• Our understanding of IBS physiology continues to
expand
• New diagnostic and treatment options have become
available
• Expect other new agents within the next few years
29

IBSi 2015 Wh t` N d IBS in 2015: What`s New and What Works?

Transcription

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