Evidence Clinical relevance
Were do we stand with solid evidence for biologics in Crohn’s Disease
Biological plausibility
Biologic plausibility, pipeline
Do all patient equally benefit from available biologics
Goals of therapy
Do biologics change the course and natural history of CD
Problems and pitfalls in biologics therapy for CD
Biologic plausibility, pipeline
Do all patient equally benefit from available biologics
Goals of therapy
Do biologics change the course and natural history of CD
Problems and pitfalls in biologics therapy for CD
MacDonald TT & Monteleone G, Science 2005;307:1920-5
Dissecting mechanisms of inflammation in IBD by ex-vivo studies
JAK
Inhi
bito
rIm
mun
omod
ulat
or
Chemokine
inhibitors
Cell adhesionmoleculeInhibitors
Stem Celltherapies
TNFblockers
cytokineblockers
Therapeutic pipeline in Crohn’s disease
Adapted from Danese et al GUT 2012
Learning from other chronic inflammatory disorders
Presumed pathogenetic pathways involved in rheumatoid arthritis
Hueber et al. Gut 2012
Inhibition of IL-17A by anti-IL-17A monoclonal antibodysecukinumab is ineffective in moderate to severe Crohn’s disease
50
40
30
20
10
0
Resp
onse
at w
eek
6 (%
) (>
100
poin
ts d
rop
in C
DAI
Placebo
Secukinumab 2 x 10 mg/kg i.v.
30
18
50
40
30
20
10
0
Rem
issi
on a
t wee
k 6
(%)
(CD
AI <
150
)
1510
Augmentation of Tregs to treat human autoimmunity:In vivo and ex vivo approaches to enhance the relative numbers of Tregs
IFN/TNF
IL-4
IL-17
Different type cytokines are mutually antagonistic, and one or the other subtype may be dominant
at any one time during immune responses
Th2 Th2 Th2
Monteleone G et al Trends in Pharmacology 2011
IL-4
IL-17
Inhibition of IFN- enhances Th2 and Th17-type cytokines
Th17Th17
Th17
Th2Th2
Th2
Th1Th1 Th1
IFN-
Fontolizumab
Monteleone G et al Trends in Pharmacology 2011
IL-4
IL-17
Inhibition of IL-17A enhances Th1-type cytokines
Th17Th17
Th17
Th2Th2
Th2
Th1Th1 Th1
IFN-
Secukinumab
Monteleone G et al Trends in Pharmacology 2011
Targeting immune pathways in IBD: lessons from unsuccessful data
Redundancy of soluble Redundancy of soluble cytokines, chemokinescytokines, chemokines
and inflammatory pathways and inflammatory pathways
Positive effect of an anti-Positive effect of an anti-cytokine neutralizing strategy cytokine neutralizing strategy
in mice may not necessarily in mice may not necessarily be translated in humansbe translated in humans
Reconsider the use of murine models of colitis
Success of currently avaliable Success of currently avaliable biologics in CD is mostly biologics in CD is mostly
dependent on their killing dependent on their killing action against pro-action against pro-inflammatory cellsinflammatory cells
Target of available biologics are cells (T cells/ macrophages), not soluble cytokines
Block multiple signals simultaneously or sequentially
Chimeric monoclonal
antibody
InfliximabmAb
Human monoclonal
antibody
AdalimumabmAb
FcIgG1
Biologics for Crohn’s Disease
Biologic plausibility, pipeline
Do all patient equally benefit from available biologics
Goals of therapy
Do biologics change the course and natural history of CD
Problems and pitfalls in biologics therapy for CD
Were do we stand with solid evidence for biologics in Crohn’s Disease
Disease heterogeneity
Disease Disease complexitycomplexity
Uncertainty
Disagreement
TailoredTailoredtherapytherapy
Biomarkers& bio-profiling
Do all ptsneed
treatment?
Disease behaviour
Measuring intestinal damage
UNMET NEEDS FOR AN EBM BASED THERAPY IN CD
AVALABLE TOOLS FOR DISEASE ASSESSMENT IN CDDefining disease subtypes and treatment goals
a “VISUAL” approach
DB PTV 07
LC PTV 05
IS THE “VISUAL” APPROACH ADEQUATE FOR DEFINING TREATMENT OPTIONS AND
OUTCOME MEASURES?
Dis
ease
acti
vity
0 1010Years 0 Years
43% 19%
3% 32%
Management Must Be Tailored to the Individual Patient
IBSEN: disease course in Crohn’s disease over 10 years
Solberg IC, et al. Clin Gastroenterol Hepatol 2007;5:1430–8 Missing data, 3%
2400 12 24 36 48 60 72 84 96 108 120 132 144 156 168 180 192 204 216 228
0
100
90
80
70
60
50
40
30
20
10
Long-term evolution of Crohn’s disease behaviour
Cosnes J, et al. Inflamm Bowel Dis 2002;8:244–50
Penetrating
Stricturing
Cum
ulati
ve p
roba
bilit
y of
rem
aini
ng fr
ee o
f co
mpl
icati
ons
(%)
Inflammatory
Months372,002 552 229 95n =
Patients at risk:
Start therapy
Behaviour categories of the Vienna classification according to site
Evolution of Crohn’s disease behaviour over 10 years
AT DIAGNOSIS
L1 L2 L3
B1 76.9 72.1 69.7
B2 14.9 1.5 15.2
B3 8.3 26.5 15.2
AFTER 10 YEARS
L1 L2 L3
B1 37.3 28 22.9
B2 43 20 17
B3 19.6 52 60
adapted from Louis E et al Gut 2001;49:777–782
B1 non stricturing-non penetratingB2 stricturingB3 penetrating
L1 pure ilealL2 pure colonicL3 ileo-colonic
Remission and response from control arms of trials of biological therapies for active luminal Crohn’s disease
Tinè F et al Aliment Pharmacol Ther 27, 1210–1223
18 % remission 33 % response
When to Intervene early with aggressive therapy: Poor Prognosis Patients
We must intervene with immunosoppresive drugs early in:• Extensive small bowel disease
• Severe upper GI disease• Severe rectal disease
• Younger patients• Patients with perianal lesions
• Patients with early stricturing / penetrating disease• Patients with deep colonic (rectal) ulcers
Biologic plausibility, pipeline
Do all patient equally benefit from available biologics
Goals of therapy
Do biologics change the course and natural history of CD
Problems and pitfalls in biologics therapy for CD
What is Deep Remission?
Decision patterns in Crohn’s Disease
GROSS CHANGES
CLINICAL “ACTIVITY” *
HUMORAL “ACTIVITY” §
Pattern 1 − − −
Pattern 2 − − +
Pattern 3 + − −
Pattern 4 + − +
Pattern 5 − + −
Pattern 6 − + +
Pattern 7 + + −
Pattern 8 + + +
Torsoli A et al, Ital J Gastroenterol, 1983, 15, 138-139
* + = CDAI > 150 or Simple Index > 3
§ + = CRP > 1.5 mg/dl and/or ESR > 25
Based on 479 consecutive CD patients attendances
optimal
enough
acceptable ?
There is no validated definition of Mucosal Healing (MH) in CD patients
The “ideal„ definition of MH could be complete endoscopic healing of all inflammatory and ulcerative lesions of the gut mucosa in CD
No endoscopic indices have validated a cut-off value for MH
Pineton de Chambrun G et al. Nat Rev Gastroenterol Hepatol 2010Armuzzi A et al. JCC 2012
Mucosal Healing in CD
A new therapeutic end point in the management of CD
Rutgeerts P et al. Gastroenterology 2012
Deep Remission
Is a recently introduced end point, which includes corticosteroid free remission and mucosal healing
It has been introduced and applied to patients with CD on biologics or immunomodulators who have no symptoms and objective signs of inflammation
Mucosal Healing in CD
before anti TNF-α after anti TNF-α
Biologic plausibility, pipeline
Do all patient equally benefit from available biologics
Goals of therapy
Do biologics change the course and natural history of CD
Problems and pitfalls in biologics therapy for CD
DO BIOLOGIS IMPACT ON THE NATURAL HISTORY OF CROHN’S DISEASE ?
Early disease
Chronic uncomplicated disease course
Complicated disease
DO BIOLOGIS IMPACT ON THE NATURAL HISTORY OF CROHN’S DISEASE ?
Early disease
Chronic disease course free of either complications and major symptoms
Complicated disease
Inflammatory Activity and Progression of Damage in a Theoretical Patient with CD
Pariente B et al. Inflamm Bowel Dis. 2011;17(6):1415.
Inflamm
atory activity (C
DA
I, CD
EIS
, CR
P)
Surgery
Stricture
Stricture
Fistula/abscess
Diseaseonset
Dig
estiv
e da
mag
e
Diagnosis Earlydisease
Clinical remission
All randomized patients Week 54 results
Complete mucosal healing
ACCENT I – Hanauer SB, et al. Lancet 2002
Infliximab Improves Clinical Remission and Allows for Mucosal Healing
Patients with Corticosteroid-free ClinicalRemission and Mucosal Healing at Week 26
Colombel JF et al N Engl J Med 2010;362:1383-95.
Colombel JF, et al. J Crohn’s Colitis 2010;4:S11
Deep remission defined as clinical remission (Crohn’s Disease Activity Index [CDAI] <150) and mucosal healing (absence of mucosal ulceration)
0
5
10
15
20
25
Patie
nts
with
dee
p re
mis
sion
(%)
Week 12
6/61 10/62
9.8
16.1p=0.34
12/620/61
19.4p<0.001
Week 52
Adalimumab, induction-only (placebo)Adalimumab, every other week
EXTEND: Deep Remission with Adalimumab
Patients achieving deepremission are more likelyto have IBDQ remission
(p<0.05)
1 Logistic regression adjusted baseline IBDQ score IBDQ remission = IBDQ≥170
IBDQ remission at week 5264
26
0
25
50
75
Deep remission(Wk 12)
Non-deep remission1
(Wk 12)
Wee
k 52
IBD
Q re
mis
sion
(%)
7/11 14/53
Colombel JF, et al. UEGW 2010, Barcelona, Spain, October 23-27:OP371
Deep Remission at Week 12 is Associated with Better Quality of Life at Week 52
EXTEND
1.0
0.9
0.8
0.6
0.7
0.5
0 1 2 3 4 5 6 7 8 9 10
Years since 1-year visit
Prop
ortio
n of
pati
ents
no
t res
ecte
d
HR = 0.42 (0.20-0.89) p=0.027
16.9%
31.0%
MH
No MH
1.00
0.96
0.94
0.86
0.90
0 1 2 3 4 5 6 7 8 9 10
Years since 1-year visit
Prop
ortio
n of
pati
ents
no
t col
ecto
mis
ed
HR = 0.34 (0.14-0.86) p=0.02
3.4%
9.7%
MH
No MH
ULCERATIVE COLITIS CROHN’S DISEASE
Soldberg IC, et al. Scand J Gastroenterol 2009
Mucosal Healing after 1 Year and Risk of Surgery
Lichtenstein GR, et al. Gastroenterology 2005
N=96
P<0.05 P<0.05
N=99N=139N=143
* Surgery major enough to categorise a patient as a treatment failure in the trial, excluding drainage of abscesses, seton placement and stricture dilation.
Infliximab Scheduled Therapy Results in Fewer Surgical Procedures
Adalimumab: Reduction in Hospitalisation Risk
78% reduction in Crohn’s-related hospitalisation at 3 monthsThe difference was apparent 2 weeks after randomisation57% relative risk reduction at 12 months
Feagan BG, et al. Gastroenterology 2007;
Croh
n’s-
rela
ted
hosp
italis
ation
risk
(%)
Days since randomisation
0
10
20
30
0 50 100 150 200 250 300 350
Week 2
Placebo
Adalimumab
n=499; CHARM
Log-rank test: risk was significantly different (p<0.01)
Clinical Practice Experience:Leuven CD Real-Life Data
1Schnitzler F, et al. Gut. 2009;58:492-500; 2Ferrante M, et al. J Crohn’s Colitis. 2008;2:219-225.
CD Cohort: 63.4% With Sustained Clinical Benefit
Median Follow-up 55 Months1
63.4%
Biologic plausibility, pipeline
Do all patient equally benefit from available biologics
Goals of therapy
Do biologics change the course and natural history of CD
Problems and pitfalls in biologics therapy for CD
Adult age and virtually any disease duration
Clinical activity (symptoms scoring)
SOP responsive/refractor
y
Concomitant treatment
Clinical trial patients
DO BIOLOGIS IMPACT ON THE NATURAL HISTORY OF CROHN’S DISEASE ?
Early disease
Chronic uncomplicated disease course
Complicated disease
T
TH1TH17 TH1
TH1
TH1TH17
TH17
MMP
Ulcer/fistulaIFN-
IL-12
IL-2
3 T-bet
TH1
TH1
TH1
TH1
↓apo
ptos
is
TH1TH1TH1TH1
TH1
TH1
TH1
TH1
TH1
TH1
TH1
TNF- TIMP
↑collagendeposition
Fibrosis
IL-17
IL-8
Blood vessel
TH1
Scartissue
TH2TH2
TH2
IL-4
IL-5
IL-13
Immune cells: key players of the IBD-associated tissue damage
Treg
CD103+
TSLP,TGF-,
RA
TH1
TIMP
Treg
CD103+
TH1
TLRsMHC-1/2B7
IL-15
IL-8TLRsNOD2mTNF
TLRs CD40
Dendritic cell
Macrophage
T0
T17T2
T2T2
T1
T1
T1
T1T1 T1T1T1 T1 T1T1T1 T1 T1T1
T17 T17
T cells
Th1Th1
Th2Th2
CD4+
Th0
CD4 -
CD8 -
Naive T cell
IL-2
IL-17
IL-22
IL-6
IL-10
TGF-
IL-13
IL-4
IL-5
IFN-
IL-2
IL-12
IFN-
STAT4
IL-23
CD4+/CD25+
FOXP3IL-18
Th17Th17
Star wars
APC
Th1
Th17IL1β,IL6,IL23
IL12
IL17AIL17F
IFNγTNFαIL21
TNFα IL1βIL6IL18
Th1/Th17 IFNγIL17
EARLY CD LATE CD
?
Zorzi F et al FISMAD 2011
COMBINING EX VIVO DATA WITH CLINICAL EVIDENCE
Infliximab prevents Crohn’s disease recurrence after ileal resection
Regueiro M et al GASTROENTEROLOGY 2009;136:441–450
10/1110
Grade 0-1 Grade 2-4
1/112/13
1011/13
INFLIXIMAB PLACEBO
Endoscopic score after 1 year of resection
INFLIXIMAB PLACEBO
Range 15-54%
Gisbert JP and Panes J. Am J Gastroenterol 2009
Maintenance of Remission Among Patients With Crohn’s Disease on Antimetabolite Therapy After Infliximab Therapy Is Stopped
52 relapses in 115 patients Median (±SE) follow up 21 1 mo
LOUIS E et al GASTROENTEROLOGY 2012;142:63–70
TREAT Registry: Serious InfectionsLogistic Regression Data (Multivariate)
Odds Ratio 95% CI
Age (years) 1.01 0.99-1.03
Female 1.24 0.81-1.90
Moderate or severe CD 2.11 1.10-4.05*
Current use of infliximab 1.40 0.95-2.07
Current use of 6MP/AZA/MTX 0.88 0.61- 1.27
Current use of corticosteroids 2.21 1.46- 3.34*
Current use of narcotic analgesics
2.38 1.56- 3.63*
*P < .05
Lichtenstein GR, et al. Clin Gastroenterol Hepatol. 2006
Advanced Age Is an Independent Risk Factor for Severe Infections and Mortality in Patients Given Anti–Tumor Necrosis
Factor Therapy for Inflammatory Bowel Disease
Feagan BG et al. Am J Gastroenterol. 2000;95:1955.
5%0
10
20
30
40
50
60
70
80
90
100
0 10 20 30 40 50 60 70 80 90 100
% All Patients
% C
ost
12%20%
31%
41%
50%
60%
70%
80%90%
100%
A Minority of patients Account for the Majority of Costs
Cost Distribution for Crohn’s Disease
Yanai H and Hanauer SB. Am J Gastroenterol 2011
Brand name Cover Release Site AsacolEudragit S pH>7 Colon ± terminal ileum
Salofalk Eudragit-L pH>6 Colon + ileumMesasal Eudragit-L pH>6 Colon + ileumPentasa Ethylcellulose Time and Colon + ileum+ jejunum pH-dependent Mesavancol MMX pH Colon
Oral Intravenous Topical (suppository, foam, enema)
Prednisolone Hydrocortisone Hydrocortisone Prednisone Metyl-prednisolone Prednisolone metasulfobenzoato Budesonide Budesonide Beclomethasone Beclomethasonediproprionate dipropionate
Drugs Drugs Corticosteroids
5-ASA
AZAAZA
6-MP6-MP
6-TG6-TG
Biological agents
Immunomodulators
There is no validated definition of Mucosal Healing (MH) in CD patients
The “ideal„ definition of MH could be complete endoscopic healing of all inflammatory and ulcerative lesions of the gut mucosa in CD
No endoscopic indices have validated a cut-off value for MH
Pineton de Chambrun G et al. Nat Rev Gastroenterol Hepatol 2010Armuzzi A et al. JCC 2012
Mucosal Healing in CD
Clinical Practice Experience:Leuven CD and UC Real-Life Data
UC Cohort: 68% With Sustained Clinical Response
Median Follow-up 33.4 Months2
68%
CD Cohort: 63.4% With Sustained Clinical Benefit
Median Follow-up 55 Months1
63.4%
1Schnitzler F, et al. Gut. 2009;58:492-500; 2Ferrante M, et al. J Crohn’s Colitis. 2008;2:219-225.
Any adult age and virtually any disease duration
Clinical trial patients
Panaccione R, et al. J Crohn’s Colitis 2009;3:S69-70Panaccione R, et al. J Crohn’s Colitis 2009;3:S69-70
Pts randomised to ADA, in remission (CDAI<150) at week 56 of CHARM, and enrolled in OLE ITT (n=145). LOCF: last observation carried forward; NRI: non-responder imputation. 467 patients enrolled in the open-label extension (ADHERE)
All adalimumab, NRI
All adalimumab, LOCF
Week 56CHARM
Week 24ADHERE
Week 48ADHERE
Week 60ADHERE
Week 108ADHERE
Patie
nts
with
rem
issi
on (%
)
77 7264
85 84 8378 81
0
20
40
60
80
100
111/145 105/145 93/145123/145 122/145 120/145113/145 118/145145 145
CHARM / ADHERE: Remission Sustained through 3 Years
Open label extension (OLE)CHARMbaseline
6 mo 12 mo 24 mo 36 mo
100 100
D’Haens G, et al. Lancet 2008
Colombel JF et al NEJM 2010
Discontinuation of Infliximab in Patients in Stable Remission on Combination Therapy
(Azathioprine Maintained)
# at risk : 115 102 79 63 51 47 39 27 20 12 9
79±4%
56±5%
50±5%
Louis E et al. Gastroenterology ,2009;136(Suppl 1):A-146, Gastroenterology epub 2011.
52 relapses in 115 patients Median (±SE) follow up 21 1 mo
NATURAL HISTORY OF CROHN’S DISEASEA decades long history
Early disease
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