Improving Standards of Care in Irritable Bowel Syndrome

1
Improving Standards of Carein Irritable Bowel
Syndrome

2
Definition of Irritable Bowel Syndrome (IBS)

• IBS is a chronic, episodic medical condition
  characterized by abdominal pain or discomfort
  associated with altered bowel function
• IBS with constipation is abdominal
  pain/discomfort associated with at least 2 of the
  3- lt 3 bowel movements per week- Hard or lumpy
  stools- Straining with a bowel movement

Drossman et al, Gastroenterology 1997 112 2120

3
Overall prevalence of IBS greater in females
Prevalence ()
13.5
14
Female
13.0
Male
9.4
0
1534
3544
gt45
Ages (years)
Drossman et al, Dig Dis Sci 1993 38 1569
4
Prevalence by IBS subgroups
Survey respondents ()
Overall
8
Females
Males
3022 residents surveyed in Minnesota536
respondents
0
Adapted from Talley et al, Am J Epidemiol 1995
142 76
5
IBS patients suffer

• In a recent survey (n 350) conducted bythe
  International Foundation for FunctionalGastrointe
  stinal Disorders, it was found that
• 42 of respondents reported having symptomsfor
  10 years or more
• 43 reported symptoms as 'severe', 40 described
  them as 'moderate'
• two-thirds of IBS sufferers describe their
  symptoms as extremely or very bothersome

www.iffgd.org in press
6
IBS patients with constipation (abc-ibs) suffer
from abdominal pain/discomfort, bloating, and
constipation
Gas / gas pain
Constipation
Straining with BM
Abdominal pain / discomfort
Hard / lumpy stool
Incomplete evacuation after BM
Bloating / distension
Inability to have BM
Heartburn / acid reflux
IBS with constipation
Sudden urges to have BM
General US population
Rectal pain
0
10
20
30
40
50
60
70
IBS patients that suffer once a week or more
Lieberman Research Inc. 2000, GI Sufferer Study
7
Who treats IBS?
IBS is a common diagnosis in primary care and
gastroenterology practices
IBS
IBS
12
28
All other diagnoses 88
All other diagnoses 72
Primary care
Gastroenterology
Mitchell et al, Gastroenterology, 1987 92
1282 Drossman, Gastroenterology 1997 112 2120
8
Impact of IBS on work or school
13.4
IBS patients
Non-IBS
4.9
patients
0
5
10
15
Days missed from work or school in past year
plt0.0001
Adapted from Drossman et al, Dig Dis Sci 1993
38 1569
9
Mechanisms in IBS
Enhancedperception
Vagal nuclei
5-HT
Sympathetic
Alteredmotility
Visceralhypersensitivity
Adapted from Camilleri and Choi, Aliment
Pharmacol Ther 1997 113
10
Physiologic distribution of 5-HT
CNS 5
GI tract 95
Kim and Camilleri, Am J Gastroenterol 2000 95
2698
11
Summary of Hypotheses on the Pathophysiology of
IBS

• IBS is characterized by changes in motility in
  response to environmental or enteric stimuli1
• Visceral hypersensitivity is well documented in
  IBS patients2
• Serotonin, which has both motility and sensory
  modulating properties, could represent a common
  factor linking the symptoms of IBS3

1AGA Patient Care Committee Gastroenterology
19971122120-2137 2 Adapted from Camilleri and
Choi et al., Aliment Pharmacol Ther 1997 11 3
3Kim and Camilleri et al., Am J Gastroenterol
2000 95(10) 2698
12
Identify Red Flags

• Physical
• - Abnormal exams
• - Rectal bleeding/obstruction
• - Positive FOBT/flex.
• sigmoidoscopy or colonoscopy
• (gt50 years)

• History
• - Unintentional Weight loss
• Onset in older patient
• (gt50 years)
• - Family history of cancer or IBD

• Initial Labs
• - ? HGB
• - ? WBC
• - ? ESR
• - Abnormal chemistry
• - ? TSH

Red Flags
Adapted from A technical review, Gastroenterology
1997 112 2120 Paterson et al., Can Med Assoc J
1999 161 154 Camilleri et al., Aliment
Pharmacol Ther 1997 11 3
13
IBS An enduring diagnosis
112 consecutive Olmstead County residents first
diagnosed with IBS during 196163. Median
follow-up 29 years (range 132 years)
No change in diagnosis 97
Most have no change in diagnosis after initial
evaluation
Owens et al, Ann Intern Med 1995 122 107
14
Goals of Pharmacotherapy in IBS with
Constipation

• Overall Relief (including impact on patients
  overall well-being)4
• Multi-symptom relief4
• Abdominal pain
• Bloating
• Constipation

4Drossman DA, Corazziari E, Talley NJ, Thompson
WG, Whitehead,WE eds. Rome II The Functional
Gastrointestinal Disorders 2nd ed. McLean, Va
2000355,360,594-596
15
Dietary advice

• Patients often relate their functional
  symptomsto certain foods
• Dietary restrictions are common, but may be
  inappropriate
• dairy products, sorbitol, caffeine, alcohol,
  citrus fruit,gas-forming vegetables, grains

Jones et al, Gut 2000 47(suppl. II) 1
16
Traditional therapies focused on individual
symptoms of IBS with constipation

• Bloating and distention
• Dietary modifications
• Antispasmodics
• Antiflatulants
• Digestive enzymes
• Antibiotics

• Abdominal pain / discomfort
• Antispasmodics
• Tricyclics
• Analgesics

Abdominal pain /discomfort
Bloating /distention
Constipation

• Constipation
• Fiber
• Laxatives

• None of these medications effectively treat the
  multiple symptoms of IBS. May exacerbate
  individual symptoms e.g., fiber and bloating
  antispasmodics and constipation

17
Tegaserod Indication and Dosage

• Zelnorm (tegaserod maleate) is indicated for the
  short-term treatment of women with irritable
  bowel syndrome (IBS) whose primary bowel symptom
  is constipation
• The safety and effectiveness in men have not been
  established
• Recommended dosage tegaserod (Zelnorm) 6 mg
  twice daily orally before meals for 46 weeks
• For patients who respond to therapy at 46 weeks,
  an additional 46 weeks can be considered
• Efficacy of tegaserod beyond 12 weeks has not
  beenestablished

Novartis, data on file
18
Tegaserod A New Class of Compound
OH
NH
O
NH
NH2
N
NH
NH
NH
Serotonin (5-HT)
Tegaserod

• Tegaserod is a 5-HT4 receptor agonist
• new class of compound aminoguanidine indoles
• Structure similar to serotonin

Camilleri, Aliment Pharmacol Ther 2001 15 277
19
Tegaserod Pharmacological Effects

• Stimulates 5-HT4 receptors and improves GI
  function
• Stimulates the peristaltic reflex
• Alters the chloride secretion in the intestine
• Reduces visceral sensitivity

animal data
Camilleri M. Review article Tegaserod. Aliment
Pharmacol Ther. 2001 15 277-89.
20
Subjects Global Assessment of relief
Responders
B301
70









60


50
40
Tegaserod 6 mg bid (n 294)
Placebo (n 288)
30
0
1
2
3
4
5
6
7
8
9
10
11
12
0
Weeks
plt0.05 Responders are defined as at least
somewhat relieved ITT population
Müller-Lissner et al, Aliment Pharmacol Ther
2001 15 1655
21
Mean relief in abdominal pain / discomfort score
Change from baseline (pain score)
Baseline
Week
0
1
2
3
4
5
6
7
8
9
10
11
12
0
B301
-0.2

-0.4


-0.6







-0.8
Placebo (n 288)

Tegaserod 6 mg bid (n 294)
-1.0
plt0.05 (6 mg bid vs placebo) ITT analysis.
100mm Visual Analogue Scale with 6 descriptors
none to very severe Baseline pain score placebo
2.77 tegaserod 2.78
Müller-Lissner et al, Aliment Pharmacol Ther
2001 15 1655
22
Change in number of bowel movements
Change from baseline (number of weekly bowel
movements)


3
B301


2








1
0
0
1
2
3
4
5
6
7
8
9
10
11
12
Baseline
Week
plt0.05 (6 mg bid vs placebo) ITT analysis

• Improvement seen on Day 1

Müller-Lissner et al, Aliment Pharmacol Ther
2001 15 1655
23
Mean change in bloating score
Change from baseline (bloating score)
Week
Baseline
0
1
2
3
4
5
6
7
8
9
10
11
12
0
B301
-0.2
-0.4


-0.6







-0.8
Placebo
Tegaserod 6 mg bid
-1.0
plt0.05 (6 mg bid vs placebo) ITT analysis
6-point scale 0 none to 6 very severe
Baseline bloating score placebo 2.67
tegaserod 2.72
Müller-Lissner et al, Aliment Pharmacol Ther
2001 15 1655
24
Summary of Tegaserod Efficacy

• Significant improvement in Subject's Global
  Assessment of relief
• Relief of individual IBS symptoms
• - Abdominal pain / discomfort
• - Bloating
• - Constipation

Müller-Lissner et al., Aliment Pharmacol Ther
2001 15 1655
25
Zelnorm Safety Data

26
Adverse events occurring gt1
Placebo (n 1305)
Zelnorm 6 mg bid (n 1327)
System / adverse experience
11 4 7 5
12 9 8 6
Gastrointestinal system disorders Abdominal
pain Diarrhea Nausea Flatulence
12 3 1
15 4 2
Central and peripheral nervous system Headache Diz
ziness Migraine
2 lt1
3 1
Body as a whole general disorders Accidental
trauma Leg pain
4 1
5 2
Musculoskeletal disorders Back pain Arthropathy
Novartis, data on file
27
Overall Safety and Tolerability of Tegaserod

• Tegaserod was generally well tolerated. Side
  effects reported significantly more often with
  tegaserod than with placebo were headache (15 vs
  12) and diarrhea (9 vs 4)

Novartis, data on file
28
Overall Safety and Tolerability of Tegaserod

• Diarrhea
• tegaserod 9 vs placebo 4
• In most cases, diarrhea occurred within the first
  week of treatment
• Typically, diarrhea resolved with continued
  therapy
• Overall, the discontinuation rate from the
  studies due to diarrhea was 1.6 among the
  tegaserod-treated patients

Novartis, data on file
29
Summary of DrugDrug Interactions

• In vitro no inhibition of CYP2C8, CYP2C9,
  CYP2C19, CYP2E1 and CYP3A4
• No clinically relevant drugdrug interactions
  were observed in healthy volunteers with
• theophylline
• dextromethorphan
• Digoxin3
• Warfarin4
• oral contraceptives5
• Dose adjustment is not required for any of the
  above drugs co-administered with tegaserod

1Zhou, et al., Am J Gastroenterol 1999 94 2623
184 2Kalbag, et al., Gastroenterology 2000 118
(suppl. 2) A1179 5422 3Zhou, et al., J Pharm
Sci 1999 1 A2077 4Ledford, et al.,
Gastroenterology 2000 118 (suppl. 2) A1184
5445 5Zhou, et al., Gastroenterology 2000 118
(suppl. 2) A1207 5539
30
Conclusions

• Tegaserod is the first treatment proven to
  provide multi-symptom IBS relief of- Abdominal
  pain/discomfort- Bloating- Constipation
• Favorable tolerability demonstrated in
  well-controlled clinical trials with more than
  2,600 IBS patients

31
Digestive Diseases Week Key Findings Orlando,
FL May 17-22, 2003
32
Tegaserod Improves Gastric Emptying in Patients
with Gastroparesis and Dyspeptic Symptoms
Tougas G et al. Oral Presentation, DDW 2003
33
Objective

• To evaluate whether 8 weeks of tegaserod can
  improve abnormally delayed gastric emptying in
  patients with dyspeptic symptoms and delayed
  gastric emptying

Tougas G et al. Oral Presentation, DDW 2003
34
Gastric retention () of meal at 2 hours post
meal
60 50 40 30 20 10 0
normal gastricretention rate at2 hours is 40


Retention () at 2 hours post meal
? 24
? 35
? 15
? 6
24
18
12
Placebo
Tegaserod dose
p0.077 vs placebo p0.003 vs placebo
Tougas G et al. Oral Presentation, DDW 2003
35
Results and Conclusions

• Gastric retention was reduced consistently with
  tegaserod, especially at 2 and 4 hours after meal
• Tegaserod 18mg/day and 24mg/day decreased food
  retention in late phase emptying by 2x over
  placebo
• 80 of patients given 18mg/day developed normal
  gastric emptying vs. 50 of placebo patients
• Tegaserod improves gastric emptying in patients
  with gastroparesis and dyspeptic symptoms

Tougas G et al. Oral Presentation, DDW 2003
36
Efficacy and Safety of Tegaserod in Patients with
Chronic Constipation
37
Conclusions

• Significant improvement as compared to placebo
• Number of complete, spontaneous bowel movements
• Time to first complete, spontaneous bowel
  movement
• Straining
• Distention and bloating
• Abdominal discomfort/pain
• Satisfaction with bowel habits
• Bothersome constipation
• Additional evidence for safety
• Most frequent adverse effects leading to
  discontinuation included nausea, diarrhea,
  abdominal pain, headache
• No serious adverse events were noted with the use
  of tegaserod for up to 12 weeks in pts with CC.

Johanson J, et al. Oral presentation. DDW 2003.
38
Tegaserod provides rapid, effective relief of
abdominal pain/discomfort, bloating and
constipation in Chinese patients with irritable
bowel syndrome with constipation (IBS-C)
Lin S, et al. Poster S1017.DDW 2003.
39
Results and Conclusions

• Adverse events were reported in 10 of patients
  on tegaserod and 6 on placebo.
• The most common adverse events seen in tegaserod
  group were diarrhea, abdominal pain and dizziness
  (frequency lt3). They did not result in
  discontinuation.
• Tegaserod provided rapid relief of IBS-C symptoms
  including abdominal pain, bloating and
  constipation and was well tolerated in Chinese
  patients with IBS-C.

• Lin S, et al. Poster S1017. DDW 2003.

40
Tegaserod is an effective and safe therapy for
irritable bowel syndrome in a Nordic population
Nyhlin H, et al. Poster M1645. DDW 2003. In
press, Gastroenterology.
41
Results and Conclusions

• The overall frequency of adverse events (AE) was
  comparable between treatments.
• The most frequently reported AE was diarrhea
  9.2 tegaserod vs. 1.3 placebo.
• Discontinuations due to diarrhea were 2.8 for
  tegaserod vs. 0 for placebo .
• Tegaserod 6mg bid is an effective, safe and well
  tolerated therapy in a Nordic population of IBS
  patients with non-D IBS.

• Nyhlin H, et al. Poster M1645. DDW 2003. In
  press, Gastroenterology.

42
Results

• Tegaserod treated patients with less than 10 yrs
  duration of IBS symptoms had a gain in weekly
  therapeutic effect (range 10 to 26) each week
  (plt0.05) over weeks 1-12.
• Tegaserod significantly affected number of days
  with no bowel movements and days with gt3 bowel
  movements for weeks 1-4 (plt0.0001).

• Nyhlin H, et al. Poster M1645. DDW 2003. In
  press, Gastroenterology.

43
Relapse of Symptoms Following Withdrawal of
Tegaserod Treatment in Irritable Bowel Syndrome
with Constipation (IBS-C)
Munoz V, et al, Poster T1804. DDW 2003.
44
Conclusions

• IBS-C patients respond favorably to initial
  treatment with tegaserod for 1 month (82)
• IBS-C patients respond favorably to maintenance
  therapy with tegaserod for another 2 months (90)
• Upon discontinuation of tegaserod, 2/3 of
  patients will relapse within 3 weeks
• 10 of maintenance treatment patients relapsed
  (plt0.0001)
• Patients who continue treatment 18x less likely
  to relapse

Munoz V, et al, Poster T1804. DDW 2003.
45
Tegaserod Treatment for IBS A Model of Indirect
Costs
Smith D, et al. Poster T1303. DDW 2003.
46
Conclusions

• IBS has substantial impact on worker productivity
• Net annual savings of 1,497 for employer per
  employee treated for IBS
• Model can be tailored to match individual
  employers needs
• Treatment of IBS with tegaserod may be
  cost-effective in reducing indirect costs under a
  variety of scenarios, using a series of
  assumptions on wages, epidemiology, therapy, and
  costs
• Further validation of this model is warranted

• Smith D, et al. Poster T1303. DDW 2003.

47
Impact of IBS on Worker Productivity in an
Employed U.S. Population
Dean B, et al. Poster T 1302, DDW 2003.
48
Results and Conclusions

• 1,776 of 11,806 employees participated in both
  surveys
• 41 met Rome II criteria for IBS
• Participants with IBS more likely to be female
  and Caucasian or Hispanic, otherwise similar to
  those without IBS
• Participants with IBS had work productivity
  losses of 19.8 due to GI symptoms compared with
  5.6 among those without IBS
• This reduction is equivalent to working 4 days
  out of a 5-day work-week
• Reduced productivity of this magnitude may have
  substantial impact on employers.

Dean B, et al. Poster T 1302, DDW 2003.
49
Conclusions

• Employees with IBS
• 20 reduced work productivity due to GI Sx
• 14 reduced work productivity compared to
  non-IBS co-workers
• Work less than 4 days out of total 5 day work
  week
• May have substantial financial impact on employers

Bonnie Dean, Daniel Aguilar, et al. Poster
Presentation DDW 2003.
50
Tegaserod is Effective in the Retreatment of
Irritable Bowel Syndrome with Constipation (IBS-C)
Mueller-Lissner S., et al. Poster T1821. DDW 2003.
51
Conclusions

• High rate of recurrence of IBS symptoms was seen
  with discontinuation of tegaserod (84 of
  patients)
• Response rate achieved during re-treatment was
  similar to response rate achieved during initial
  treatment (85-88)
• Therapy with tegaserod is highly effective and
  well-tolerated for initial treatment, as well as
  re-treatment in patients with IBS-C

Mueller-Lissner S., et al. Poster T1821. DDW 2003.
52
Primary Efficacy Variable

• Increase 1 CSBM/Week

Johanson J, Tougas G, Chey W, et al. Oral
presentation. DDW 2003.
53
An Open Label Study to Determine the Efficacy and
Tolerability of Tegaserod in the Treatment of
Constipation Dominant Irritable Bowel Syndrome
(IBS-C)
Shah, S et al. Poster T1435. DDW 2003.
54
Conclusions

• Tegaserod 6mg BID is equally effective in male
  and females in relieving the symptoms of
  abdominal pain, bloating and straining at
  defecation.
• It increases the number of bowel movements per
  week in both sexes. This effect was more
  statistically more significant in males.
• This is the first study of tegaserod
  demonstrating significant efficacy in males.

• Shah, S et al. Poster T1435. DDW 2003.