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