Stephen B. Hanauer, MD

1
Stephen B. Hanauer, MD

• Professor of Medicine Clinical Pharmacology
• Chief, Gastroenterology
• University of Chicago

2
Credentials

• Clinician with 6000 patient database
• Crohns Colitis Foundation of America
• Scientific Cabinet, Chair Clinical Research
  Alliance, Research Initiatives
• American Gastroenterological Association
• Ex-Chair Immunology, Inflammation, IBD Section
• Ex-Chair Clinical Practice Section
• Chair, Consensus Conference on Biologics
  (Gastroenterology July 2007)
• American College of Gastroenterology
• Governing Board
• International Organization for Inflammatory Bowel
  Disease
• Chairman
• FDA GI Advisory Board
• Ex-Chair Member

3
Conflicts of Interest

• Elan/Biogen
• Consultant Clinical Research
• Millenium
• Consultant
• Centocor
• Consultant, Clinical Research, Lectures
• Abbott
• Consultant, Clinical Research, Lectures
• UCB
• Consultant, Clinical Research
• Genentech
• Consultant, Clinical Research

• BMS
• Consultant, Clinical Research
• PDL
• Consultant, Clinical Research
• GSK
• Consultant, Clinical Research
• Novartis
• Consultant
• PG, Shire, Prometheus Labs, Salix, TAP, Astra
  Zeneca
• Consultant, Clinical Resarch, Lectures

4
Presentation Summary

• Crohns Disease
• Crohns Patients
• Therapeutic Need
• Therapeutic Risks
• Likely Prescribers

5
The Spectrum of IBD1-2 Million Americans

• CROHNS DISEASE
• Patchy inflammation
• Mouth to anus involvement
• Full-thickness inflammation
• Variable involvement
• Fistulas
• Strictures
• Extraintestinal manifestations

• ULCERATIVE COLITIS
• Continuous inflammation
• Colon only
• Superficial inflammation
• Variable involvement
• Risk of cancer
• Strictures (cancer)
• Extraintestinal manifestations

Indeterminate colitis 10-15
6
Common Symptoms of Crohns Disease

• Diarrhea
• Abdominal pain and tenderness
• Loss of appetite and weight
• Fever
• Fatigue
• Rectal bleeding and anal ulcers
• Stunted growth in children

7
Crohns DiseaseColonoscopic Appearance
Cobblestone
Discrete Ulcer
Stricture (Narrowing)
8
Crohns DiseaseIntestinal Complications
Cancer
Perforation
Stricture
Fistula
Abscess
9
Traditional Clinical Parameters

CD
UC
CD/UC
IBD Subtype
4
1
2
3
1
4
3
2
Crohns Diseases Ulcerative Colitides
10
CD Activity Course
Active
25
Clinical Activity
53
22
Inactive
3
8
Diagnosis
Years
Munkholm et al. Scand J Gastroenterol.
199530699-706.
11
Long-term Evolution of Disease Behavior in CD
100
90
Progression Toward Surgery
80
70
60
Penetrating
50
Cumulative Probability ()
40
Inflammatory
30
Stricturing
20
10
0
240
228
216
204
192
180
168
156
144
132
120
108
96
84
72
60
48
36
24
12
0
Months
Patients at risk
95
2002
552
229
37
N
Cosnes J et al. Inflamm Bowel Dis. 20028244.
12
Cumulative Probability of Surgical Intervention
in CD
100
80
60
Probability ()
40
20
0
0
2
5
8
11
14
17
20
Dx
Years
Events (no.) 122 26 15 7 7 4 8 1 8 2 2 2 3 2 1
Munkholm P et al. Gastroenterology. 19931051716.
13
Postsurgical Recurrence of CD
N76.
McLeod RS, et al. Gastroenterology. 19971131823.
14
Crohns Patients
15
The Crohns Disease Activity Index
70
Liquid stools- 5x7 days35x2
70
Abdominal pain-2x7145
147
Well being-avg 3/d21x7
20
Perianal Fistula
TOTAL 307 CDAI
moderate CD
10 Liquid stools Moderate Pain Abdominal
Mass Arthralgias, Weight loss, Anemia 450 CDAI
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Definitions of CD Activity

• Severe-Fulminant
• Persistent symptoms despite outpatient oral
  corticosteroids
• High fever, persistent vomiting
• Obstruction, rebound tenderness
• Muscle mass wasting
• Abscess
• Toxic megacolon
• Fever, distention, frequent bloody bowel movement

• Moderate-Severe
• Non-responders to treatment for mild-moderate
  disease
• Fever, significant weight loss
• Abdominal pain/tenderness
• Intermittent nausea/vomiting without obstruction
• Anemia

Hanauer et al. Am J Gastroenterol.
200196635-643.
17

SF-36 Scale Scores for Medical Conditions(Standar
dized Scales)


Ware JE, JR., Kosinski M. SF-36(r) PHYSICAL AND
MENTAL HEALTH SUMMARY SCALES A MANUAL FOR USERS
OF VERSION 1. 2ND ed, Lincoln, RI QualityMetric
Incorporated, 2001. Baseline ENCORE data
Baseline AFFIRM data
18

SF-36 Scale Scores for Medical Conditions(Standar
dized Scales)
General Population
Ware JE, JR., Kosinski M. SF-36(r) PHYSICAL AND
MENTAL HEALTH SUMMARY SCALES A MANUAL FOR USERS
OF VERSION 1. 2ND ed, Lincoln, RI QualityMetric
Incorporated, 2001.
19
Current Therapeutic Pyramid
Crohns Disease
Severe
Moderate
Mild
20
Clinical Remission Rates in CD Patients with
Conventional Therapies

• Aminosalicylates
• Mild-Moderate Disease 45-55
• Antibiotics
• Few controlled trials
• Mild-Moderate Disease 50
• Budesonide
• Mild-Moderate Disease 65-75
• Corticosteroids
• Moderate to Severe Disease70-80

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Corticosteroids Short Long Term Efficacy in
Crohns Disease
None 16 (n12)
Complete 58 (n43)
Partial 26 (n19)
30-Day Responses (n74)
Steroid Dependent 32 (n24)
Prolonged Response 28 (n21)
Surgery 38 (n28)
1-Year Responses (n74)

Faubion WA Jr., et al. Gastroenterology.
2001121255-260.
One patient lost to follow-up
22
Cumulative Incidence of Surgical Resection Over 1
Year in CD Patients Starting Corticosteroids
100
80
60
Cumulative Probability ()
40
20
0
60
0
30
90
182
365
Days
N77
Faubion WA Jr et al. Gastroenterology.
2001121255.
23
Infliximab vs. Placebo in Induction and
Maintenance of Remission of CD
NNT 3
NNT 5
NNT number needed to treat.
Adapted from Bebb JR, et al. Ailment Pharmacol
Ther. 200420151-9.
24
Corticosteroid ToxicityDose/Duration

• Moon face
• Acne
• Ecchymoses
• Hypertension
• Hirsutism
• Petechial bleeding
• Striae

• Diabetes
• Infection
• Osteonecrosis
• Osteoporosis
• Myopathy
• Cataracts
• Glaucoma
• Psychosis

25
Lymphoma Risk in IBD Patients on
AZA/6MPMeta-Analysis

• Study Setting N Obs Exp SIR (95 CI)
• Kinlen U.K. 321 2 0.16 12.5 (1.2 - 46)
• Connell London 755 0 0.52 0
• Farrell Dublin 238 2 0.05 37.5 (3.5 - 138)
• Fraser Oxford 626 3 0.65 4.6 (0.9 - 13.7)
• Korelitz New York 486 3 0.61 4.9 (0.9 - 14.5)
• Lewis GPRD 1465 1 0.64 1.6 (0.001
  - 9)
• Pooled 3891 11 2.63 4.2 (2.1 - 7.5)
• Sensitivity analyses when papers with highest or
  lowest SIRs were excluded,
• results remained significant (range, 3.5 - 5.2)
• population-based study

Kandiel et al, Gut 2005
26
Ex from Risk Factors for Opportunistic
Infections in IBD A Case-Control Study of 100
Patients (1998-2003)
Opportunistic infections and anti-TNF therapies

Odds Ratio (95 CI) Odds Ratio (95 CI) P value
Any medication (5-ASA, AZA/6MP, Steroids, MTX, Infliximab) 3.50 (1.98-6.08) lt0.0001
5-ASA 0.98 (0.61-1.56) 0.94
Corticosteroids 3.35 (1.82-6.16) lt0.0001
AZA/6MP 3.07 (1.72-5.48) 0.0001
MTX 4.00 (0.36-4.11) 0.26
Infliximab 4.43 (1.15-17.09) 0.03
One medication 2.65 (1.45-4.82) 0.0014
Two medications 9.66 (3.3128.19) lt0.0001
Toruner M, et al. Presented at DDW 2006.
27
Warning n2 Meta-analysis Risk of Malignancy
in RA

• Systematic review of pooled data from 9 clinical
  trials
• 3,493 RA patients treated with adalimumab or
  infliximab compared with 1,512 placebo controls
• Malignancy pooled OR 3.3 (95 CI 1.2-9.1)
• 11 lymphomas or leukemia
• 14 solid tumors
• 10 basal or squamous cell carcinomas
• The potential risks for these events are
  reflected in the product labeling for all TNF
  antagonists

Bongartz T, et al. JAMA. 2006
28
Standard Gamble Utility Scores in CD
gt20 life trade-off
Gregor JC et al. Inflammatory Bowel Dis.
19973265-276 unpublished data.
Median with interquartile range.
29
Utility Estimates for Chronic Diseases
Estimates obtained using time trade-off method.
Gregor JC et al. Inflammatory Bowel Dis.
19973265-276.
30
Indications Prescribers

• Patients with persisting moderate-severe symptoms
  with confirmed active inflammation (CRP /-
  endoscopy) not responding to conventional
  anti-TNF biologics
• Prescribers are most likely to be experienced IBD
  Tertiary Centers willing to pursue active
  safety efficacy monitoring