1

Stephen B. Hanauer, MD

Professor of Medicine & Clinical Pharmacology

Chief, Gastroenterology

University of Chicago

2

Credentials• Clinician with 6000+ patient database

• Crohn’s & 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

• P&G, Shire, Prometheus Labs, Salix, TAP, Astra Zeneca

– Consultant, Clinical Resarch, Lectures

4

Presentation Summary

• Crohn’s Disease

• Crohn’s Patients

• Therapeutic Need

• Therapeutic Risks

• Likely Prescribers

Indeterminate colitis

10-15%

The Spectrum of IBD1-2 Million Americans

CROHN’S 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

6

Common Symptoms of Crohn’s Disease

• Diarrhea

• Abdominal pain and tenderness

• Loss of appetite and weight

• Fever

• Fatigue

• Rectal bleeding and anal ulcers

• Stunted growth in children

7

Crohn’s Disease:Colonoscopic Appearance

CobblestoneDiscrete Ulcer Stricture(Narrowing)

8

Perforation

Stricture

Cancer

Fistula

Abscess

Crohn’s Disease:Intestinal Complications

9

+

IBD Subtype:

UC UC

1 23

412

3 41 2 3

CD/UCCD/UC

Individualized “Reagent Grade”

Intervention

Traditional Clinical Parameters:

“Crohn’s Diseases” & “Ulcerative Colitides”:

CDCD

Genetic Markers

Serum Immune Markers

Cytokine Profile

Enzyme Activity

Metabolite Levels

Genetic, Serologic, and Biochemical Profiles:

10

YearsYears

Clin

ical A

cti

vit

yC

lin

ical A

cti

vit

y

33 88DiagnosisDiagnosis

ActiveActive

InactiveInactive

25%25%

53%53%

22%22%

Munkholm et al. Munkholm et al. Scand J GastroenterolScand J Gastroenterol. 1995;30:699-706.. 1995;30:699-706.

CD Activity Course

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Long-term Evolution of Disease Behavior in CD

Cosnes J et al. Inflamm Bowel Dis. 2002;8:244.

24022821620419218016815614413212010896847260483624120

0

10

20

30

40

50

60

70

80

90

100

Cum

ulat

ive

Pro

babi

lity

(%)

Patients at risk:Months

2002 552 229 95 37N =

Penetrating

StricturingInflammatory

Progression Toward Surgery

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Cumulative Probability of Surgical Intervention in CD

Munkholm P et al. Gastroenterology. 1993;105:1716.

Years

Pro

babi

lity

(%)

Events (no.) 122 26 15 7 7 4 8 1 8 2 2 2 3 2 1

0

20

40

60

80

100

0 2 5 8 11 14 17 20

± 2 SD

Dx

13

Postsurgical Recurrence of CD

McLeod RS, et al. Gastroenterology. 1997;113:1823.

N=76.

20

40

80

100

0

60

Years

0 1 2 3 4 5 6

Radiologic/endoscopicrecurrence

Symptomaticrecurrence P

atie

nts

Wit

h R

ecu

rren

ce (

%)

14

Crohn’s Patients

The Crohn’s Disease Activity Index

moderate CD

TOTAL =307 CDAI

=20Perianal Fistula

=147Well being-avg 3/d=21x7

=70Abdominal pain-2x7=14=5

=70Liquid stools- 5x7 days=35x2

10 Liquid stoolsModerate PainAbdominal MassArthralgias, Weight loss, Anemia= 450 CDAI

Hanauer et al. Hanauer et al. Am J GastroenterolAm J Gastroenterol. 2001;96:635-643.. 2001;96:635-643.

Definitions of CD Activity

Moderate-Severe• Non-responders to treatment for

mild-moderate disease

• Fever, significant weight loss• Abdominal pain/tenderness• Intermittent nausea/vomiting

without obstruction• Anemia

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

SF-36 Scale Scores for Medical Conditions

(Standardized Scales)

25

30

35

40

45

50

55

60

PhysicalFunction

RolePhysical

Bodily Pain GeneralHealth

Vitality SocialFunction

RoleEmotional

MentalHealth

Mea

n S

cale

Sco

re

Healthy Population Kidney Disease Mod-Severe CDGeneral Population Rheumatoid Arthritis Multiple Sclerosis

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

*

+

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Current “Therapeutic Pyramid”

BudesonideAntibiotics

5-ASA

MTXAZA/6-MP

Systemic Steroids

Surgery

Anti-TNF

Severe

Moderate

Mild

Crohn’s Disease

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 Disease~70-80%

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Corticosteroids: Short & Long Term Efficacy in Crohn’s Disease

Faubion WA Jr., et al. Gastroenterology. 2001;121:255-260.

None 16%

(n=12)

Complete 58%(n=43)

Partial26%(n=19)

30-DayResponses(n=74)

1-YearResponses(n=74)*

Prolonged Response

28%(n=21)

Steroid Dependent

32%(n=24)

Surgery38%

(n=28)

*One patient lost to follow-up*One patient lost to follow-up

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Cumulative Incidence of Surgical Resection Over 1 Year in CD Patients Starting

Corticosteroids

Days

Cu

mu

lati

ve P

rob

ab

ility

(%

)

0

20

40

60

80

100

0 30 60

90 182 365

Faubion WA Jr et al. Gastroenterology. 2001;121:255.N=77

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Infliximab vs. Placebo in Induction and Maintenance of Remission of CD

NNT = number needed to treat.

GapRemission

12

41

22

43

88

5978

57

0

10

20

30

40

50

60

70

80

90

100

Placebo InfliximabInduction

Placebo InfliximabMaintenance

Rem

issi

on

(%

)

NNT = 3 NNT = 5

Adapted from Bebb JR, et al. Ailment Pharmacol Ther. 2004;20:151-9.

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Corticosteroid ToxicityDose/Duration

• Moon face

• Acne

• Ecchymoses

• Hypertension

• Hirsutism

• Petechial bleeding

• Striae

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

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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 0Farrell 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

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Ex: from Risk Factors for Opportunistic Infections in IBD

A Case-Control Study of 100 Patients (1998-2003)

Odds Ratio (95%

CI)P value

Any medication (5-ASA,

AZA/6MP, Steroids, MTX,

Infliximab)

3.50 (1.98-6.08) <0.0001

5-ASA 0.98 (0.61-1.56) 0.94

Corticosteroids 3.35 (1.82-6.16) <0.0001

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(3.31–

28.19)<0.0001

Toruner M, et al. Presented at DDW 2006.

Opportunistic infections and anti-TNF therapies :

Warning n°2 : 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

Standard Gamble: Utility Scores in CD

Gregor JC et al. Inflammatory Bowel Dis. 1997;3:265-276; unpublished data.*Median with interquartile range.

>20% life trade-off

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