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
11
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
12
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
*
+
19
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%
21
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
22
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
23
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.
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 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
26
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