“Top Down” therapy is NOT the best strategy for treating Crohn’s Disease –

David G. Binion, M.D.

Co-Director, Inflammatory Bowel Disease CenterDirector, Translational Inflammatory Bowel Disease Research

Visiting Professor of MedicineDivision of Gastroenterology, Hepatology and Nutrition

University of Pittsburgh School of MedicineUPMC Presbyterian Hospital

Pittsburgh, PA, USA

Disclosure Grant Support

National Institutes of Health Crohn’s and Colitis Foundation of America Centocor Elan Biogen

Honoraria/consulting Centocor, Prometheus Laboratories, Abbott

laboratories, UCB Pharma, Salix Pharmaceuticals, Elan Biogen

Off label discussion of Drugs

Overview:

I. Evolution of Crohn’s disease (CD) therapy

II. New biologic agents for CD Anti-TNF-alpha agents Anti-IL-12/anti-IL23 Natalizumab

III. The “Top down vs step up” protocol for CD.

IV. Is “Top down” therapy a good idea for all CD patients? Heterogeneity of CD Disease modifying therapy in early CD

V. A rational approach for biologic therapy in IBD Who should be treated with biologics Risk/benefit assessment

I. Evolution of Crohn’s disease therapy

Crohn’s Disease: 1960’s historical perspective

Treatment limited to sulfasalazine and prednisone. No need for algorithm, because

limited options available

Biologic era in IBD management:Healing of refractory ulceration/fistula with Infliximab

van Dullemen HM et al. Gastroenterology. 1995;109:129.

Pretreatment 4 Weeks posttreatment

PretreatmentPretreatment 2 Weeks2 Weeks

10 Weeks10 Weeks 18 weeks18 weeks

Present DH, et al. N Engl J Med. 1999;340:1398–1405.

Drug therapy for Crohn’s disease - 2008

First line therapy

5-ASAbalsalazidebudesonideantibiotics(metronidazole,Cipro, rifaximin, amoxicillin,minocycline,tetracycline)

Immunomodulators/Second line therapy

corticosteroidsbudesonideazathioprine/6-MPmethotrexate

Biologic Therapy

infliximabadalimumabcertolizumab pegolnatalizumab

InvestigationalImmunomodulators

mycophenolate mofetilleflunamideFK 506thioguaninestem cell transplant

Biologics - in development

mesenchymal stem cellsabataceptthalidomideanti IL-12 (ABT-874)Trichuris suisprobiotic therapyvisilizumab (anti-CD3)Adacolumn (leukocytopharesis)golimumabfontalizumab

Nutritional therapy

elemental dietTPN

II. New biologic agents for IBD

Anti-TNF-alpha agents

Anti-IL-12/anti-IL23

Natalizumab

Molecular and cellular mechanisms in IBD

Sands BE. Inflammatory Bowel Dis.1997;3:95.

Nonspecific injuryand repair

NOROM

Proteases

PGE2

PAF

ThromboxaneLTB4

Growth factors Trefoil proteins

T-cellactivation

Pro-inflammatorycytokines

RestingMo

ActivatedMo

ActivatedPMN

Selectins

PMN

Integrins

Monocyte

MAdCAM-1

Lymphocyte

ICAM-1

Adhesionand recruitment

IL-8 IL-1IL-12/23

IFN-

TNF-

Th1 Th2 IL-10

IL-4

CD40CD40L

IL-2CD4+

T cell

NaiveT cell

B cell

CD4+ T cellsand T-helpersubsets

MHCClass II

B7

TCR

CD4CD28

CTLA4

Molecular and cellular mechanisms in IBD

Sands BE. Inflammatory Bowel Dis.1997;3:95.

Nonspecific injuryand repair

NOROM

Proteases

PGE2

PAF

ThromboxaneLTB4

Growth factors Trefoil proteins

T-cellactivation

Pro-inflammatorycytokines

RestingMo

ActivatedMo

ActivatedPMN

Selectins

PMN

Integrins

Monocyte

MAdCAM-1

Lymphocyte

ICAM-1

Adhesionand recruitment

IL-8 IL-1IL-12/23

IFN-

TNF-

Th1 Th2 IL-10

IL-4

CD40CD40L

IL-2CD4+

T cell

NaiveT cell

B cell

CD4+ T cellsand T-helpersubsets

MHCClass II

B7

TCR

CD4CD28

CTLA4

Biologics Under Investigation in IBD

_ Anti-TNF Strategies– Chimeric antibodies

– “Humanized” antibodies

– “Fully human” antibodies

– Antibody fragments

– Antisense compound

– TNF-BP1

– Thalidomide

_ Cytokine strategies– Il-1ra (anakinra)– Antibodies to Il-4, Il-6, Il-8, Il-12, Il-15, Il-

16, Il-18, Il-23– Il-10, Il-11

_ Anti-cell adhesion molecules– Antibodies to ICAM-1, VCAM-1, VLA-4,

-4 (natalizumab), 47– Antisense compound to ICAM-1– Anti NF-B, anti-OX40, anti-ZAP

_ Other approaches– rhuGrowth hormone, KGF- (failed in UC

trial), rosiglitizone, PAF inhibitor, EGF, RDP, Nu-286 (Wnt agonist)

Chimeric monoclonal Chimeric monoclonal antibody (75% humanantibody (75% human

IgGIgG11 isotype) isotype)

InfliximabInfliximab

IgGIgG11

ConstructConstruct of Anti-TNF- of Anti-TNF-αα Biologic Agents Biologic AgentsConstructConstruct of Anti-TNF- of Anti-TNF-αα Biologic Agents Biologic Agents

Mouse Mouse HumanHumanPEG, polyethylene glycol.PEG, polyethylene glycol.

Humanized Fab’Humanized Fab’fragment (95% humanfragment (95% human

IgGIgG11 isotype) isotype)

Certolizumab PegolCertolizumab Pegol

PEGPEG

PEGPEG

VHVHVLVL

CCHH11

No FcNo Fc

Human recombinant Human recombinant antibody (100% humanantibody (100% human

IgGIgG11 isotype) isotype)

AdalimumabAdalimumab

IgGIgG11

Clinical Response and Remission with Infliximab

Targan SR, et al. N Engl J Med. 1997;337:1029-1035.

4%

16%

48%

81%

0

20

40

60

80

100

4-week ClinicalResponse

4-week ClinicalRemission

Placebo (n=25)

REMICADE 5 mg/kg(n=27)

P<0.001

P<0.001

% P

ati

ents

ACCENT I: Maintenance Infliximab for CD in Randomized Responders (N = 335)

Hanauer SB, et al. Lancet. 2002;359:1541–1549.

Week 30

Week 54

% o

f P

atie

nts

% o

f P

atie

nts

Placebo

Infliximab10 mg/kg

Infliximab

5 mg/kg

Clinical Remission

60

40

20

0

Clinical Response

60

40

20

0

p < 0.0001

p = 0.0002

60

40

20

0

p < 0.0001

p = 0.0001

p = NS

p = NS

26

4760

15

3646

p = 0.002

p = 0.003

60

40

20

0

p < 0.0001

p = 0.007

p = NS

p = NS

25

3945

14

2838

CLASSIC I: Results at Week 4

* p < 0.05 vs placebo; †p = 0.001 vs placebo; ‡p = 0.007 vs placebo.Clinical remission = CDAI < 150; Clinical response = 70 or 100 is a ≥ 70 or ≥ 100 point decrease in CDAI from baseline.Hanauer S, et al. Gastroenterology. 2006;130:323–33.

Placebo Adalimumab 40/20

Adalimumab 80/40 Adalimumab 160/80

18

24

36

12

5459

37 3440

50

% o

f P

atie

nts

*

*

25

0

10

20

30

40

50

60

70

59

Clinical Remission

Clinical Response

70

Clinical Response

100

*‡

†

CHARM: Clinical Remission of CD Over Time With Adalimumab

Randomized Responders (n = 499)

* *

* **

* * * *

*

**

* * * * **

†

% o

f P

atie

nts

Weeks

47

40

41

36

1712

*p < 0.001 vs placebo; †p = 0.005 vs placebo.EOW = every other week; remission = CDAI < 150.Colombel JF, et al. DDW 2006, Abstract 686d.

0

10

20

30

40

50

60

0 10 20 30 40 50 60

Placebo Adalimumab 40 mg EOW Adalimumab 40 mg weekly

26 56

Placebo q 4 wk (N = 212)

Certolizumab pegol 400 mg q 4 wk (N = 216)

*

*

0

20

40

60

80

Clinical Response (decrease in CDAI ≥ 100

points)

Clinical Remission(CDAI < 150 points)

% o

f P

atie

nts

*p < 0.001 vs placebo.Schreiber S, et al. Gut. 2005;54(Suppl VII):A82.

36

63

29

48

PRECiSE 2: Clinical Response and Remission at Week 26 in Patients With CD

Randomized Responders (N = 428)

Overview of Results of Long-Term Anti-TNF Trials

Response† Remission Response‡ Remission Response‡ Remission

Remission = CDAI score < 150† Decrease in CDAI score of 70 points and 25%‡ Decrease in CDAI score of 100 points

27.0

51.0

21.0

39.0

Pat

ien

ts (

%)

Hanauer SB et al. Lancet. 2002;359:1541–1549.Colombel J et al. Gastroenterology. 2006;131:950.Schreiber S et al. Gut. 2005;54(Suppl VII):A82.

Week 26–30

26.0

52.0

17.0

40.0

62.8

36.2

47.9

28.6

Infliximab 5 mg/kg

ACCENT 1 n = 113

CHARMn = 172

PRECiSE 2 n = 215

Adalimumab 40 mg EOW Certolizumab pegol 400 mg every 4 weeks

Placebo Placebo Placebo

*P = .0002; **P = .003; ***P < .001

*

**

***

***

***

***

0

20

40

60

80

100

Natalizumab as Maintenance Therapy for Crohn’s Disease: ENACT-2 Trial

Sandborn WJ et al. N Engl J Med. 2005;353:19121925.

Natalizumab 300 mg

Placebo

Pat

ien

ts (

%)

Response≥ 70-point decrease

in CDAI

RemissionCDAI ≤ 150

PP < .05 < .05 PP < .05 < .05 PP < .05 < .05 PP < .05 < .05

Mean CDAI Scores Over 24 Months of Continuous Treatment With Natalizumab

Panaccione R, et al. Am J Gastroenterol. 2006;101(Suppl 2):S450. Abstract 1152.

Mea

n C

DA

I S

core

350

300

250

200

150

100

50

0

All patients (n = 87)Prior exposure to anti-TNF (n = 22)Prior failure of anti-TNF (n = 11)

291.5298.2301.5

90.079.589.5

72.157.864.5

71.964.094.6

Months

OLEBaseline

ENACT-2

Baseline

ENACT-1

Baseline

2724211812963

Summary: Anti-TNF-Summary: Anti-TNF-αα Therapy in IBD Therapy in IBD

_ Effective therapy for Effective therapy for induction and remission of induction and remission of active CD and fistulizing active CD and fistulizing CD (infliximab) CD (infliximab)

_ In the current management In the current management paradigm, reserved for paradigm, reserved for patients with more severe patients with more severe diseasedisease

_ Mucosal healing with long-Mucosal healing with long-term therapy (infliximab)term therapy (infliximab)

_ Safety issuesSafety issues– InfectionsInfections– Reactivation of latent TBReactivation of latent TB– Possible lymphoma riskPossible lymphoma risk– Hepatosplenic T-cell lymphoma Hepatosplenic T-cell lymphoma

in young patients on infliximab in young patients on infliximab plus concomittant azathioprine (n plus concomittant azathioprine (n = 8)= 8)

_ ImmunogenicityImmunogenicity– Infliximab:Infliximab: Infusion reactions Infusion reactions

contributing to loss of responsecontributing to loss of response– Other anti-TNF-Other anti-TNF-αα agents: agents:

Immunogenicity occurs; Immunogenicity occurs; significance is uncertainsignificance is uncertain

Patients With CD Who Developed HSTCL While Receiving Infliximab and Immunomodulators

_ 8 cases of HSTCL have been reported in CD patients receiving infliximab plus azathioprine or 6-mercaptopurine

– AZA or 6-MP use for 3 to 7 years prior to starting IFX

_ 7 males; 1 female_ Age range: 12 to 31 years_ Duration of CD: 2 to 8 years_ T-cell receptor type at presentation: 3 αβ; 5 γδ_ HSTCL occurred at varying times after IFX exposure--

– 5 years after 1 dose of IFX 5 mg/kg (1 case)– 2-3 years after 1-3 doses of IFX 5 mg/kg (3 cases)– 2-5 years after 10-20 doses of IFX 5-10 mg/kg (4 cases)

_ Outcome: 6 patients died; 1 responded to chemo; 1 starting chemo

_ Incidence – approximately 1 in 1000

HSTCL = Hepatosplenic T-cell lymphoma.Thayu M, et al. J Pediatr Gastroenterol Nutr. 2005;40:220–222; Centocor press release, May 2006.

Natalizumab: Safety_ Most common AEs (≥ 10% of patients) were headache,

nausea, and nasopharyngitis_ 8–14% of patients discontinued treatment due to AEs_ 6 cases of progressive multifocal leukoencephalopathy

(PML) have been reported – 35,000 patients treated to date

_ Patients in all clinical trials have been re-evaluated for PML2,3

– 89% of eligible clinical trial patients participated (N = 3389)– No additional, confirmed cases of PML were identified in > 3000 patients– PML was excluded in all but 1 patient, where repeat MRI and CSF were

not available– Estimated risk of PML in this population:

• < 1 per 1000 patients (0.1%; 95% CI: 0.2–2.8 per 1000)3

• Incidence in CD: 1 in 1275• Incidence in MS: 2 in 2248• In outpatient use < 1 in 3 - 6000 patients

1. Sandborn WJ, et al. N Engl J Med. 2005;353:1912–1915; 2. Sandborn WJ, et al. DDW 2006, Abstract 492;3. Yousry T A, et al. N Engl J Med. 2006; 354:924–933.

III. Step-up vs Top-down Approach

D’Haens GR, et al. Lancet 2008. 371: 660-7.

New Approaches to Therapeutic Intervention in Crohn’s Disease?

The “Step-up” vs “Top-down” Trial

Corticosteroids

Corticosteroids

Corticosteroids

+ (episodic) IFX

IFX +

AZA

+ AZA/MTX

+ IFX

AZA, azathioprine; IFX, infliximab; MTX, methotrexate.AZA, azathioprine; IFX, infliximab; MTX, methotrexate.

Assessment of Top-Down Versus Step-Up Strategies in CD

• Newly diagnosed CD of < 4 years’ duration (N = 129)

• Naive to immunomodulators and biologics

Step-up (n = 64)

Steroids

+ IFX

+ AZA MTX

Steroids

Steroids

Top-down(n = 65)IFX (Wk 0, 2, 6)

+ AZA

IFX + AZA

+ (episodic) IFX

Steroids

CDAI < 150 Points AND No Steroids AND No Surgery

Weeks

% o

f P

atie

nts

Step-upTop-down

*

0

20

40

60

80

100

0 20 40 60 80 100

Co-primary endpoints6 & 12 months

†*

* P < 0.01; † P < 0.05D’Haens GR, et al. Lancet 2008. 371: 660-7.

Top-Down Versus Step-Up TrialClinical Results at 2 Years

D’Haens GR, et al. Lancet 2008. 371: 660-7.

Reduction and Disappearance of Ulcers

% o

f P

atie

nts

88

71

47

30

p < 0.001

p < 0.001

0

20

40

60

80

100

Reduction Disappearance

Step-upTop-down

Patients Receiving Immunosuppressants

Weeks

% o

f P

atie

nts

Patients Receiving Infliximab

0

50

100

0 20 40 60 80 100

Step-upTop-down

0

50

100

% o

f P

atie

nts

80%

20%

What does mucosal healing in Crohn’s disease mean clinically?

Endoscopic Healing and Reduced Hospitalizations and Surgeries: Infliximab maintenance for Crohn’s disease

0%

8%

0

10

20

30

40

50

Hospitalization Surgery

Patients with no healing(n=74)

Rat

e o

f H

osp

ital

izat

ion

s an

d S

urg

erie

s (%

)

0%

Patients with healing at 1 visit (10 or 54 wk) (n=16)

Patients with healing at both 10 and 54 wks

Rutgeerts P et al. Gastroenterology. 2002;123(suppl):43.M2138.

25%

46%

0%(34*) (4*) (6*)

*Number per 100 patients

Infliximab: ACCENT IInfliximab: ACCENT I

Weighing the Value of Top-Down Therapy

• Maintenance of Maintenance of remissionremission

• Improved function and Improved function and QOLQOL

• Early promotion of Early promotion of mucosal healing to mucosal healing to prevent complicationsprevent complications

• Side effectsSide effects

• CostCost

• Majority of patients may Majority of patients may not require more potent not require more potent treatments initiallytreatments initially

• Under-treatment of Under-treatment of most severe patients most severe patients with episodic strategy?with episodic strategy?

Benefits Disadvantages

Lichtenstein GR, et al. Inflamm Bowel Dis. 2004;10:S2–S10.Caprilli R, et al. Digestive Liver Dis. 2005;37:973–979.

IV. Is “Top-down” treatment a good idea for managing all patients with

Crohn’s disease?

Natural History of Crohn’s disease

Heterogeneity of Crohn’s disease. Severe CD phenotypes.

1998 - Tale of 2 boys

Patient -1 12 year old boy

with weight loss and diarrhea

Diagnosis – Crohn’s disease of ileum and colon

Treated with steroids + immune modifiers

Patient -2 13 year old boy

with weight loss and diarrhea

Diagnosis – Crohn’s disease of ileum and colon

Treated with steroids + immune modifiers

With permission, S Kugathasan MD

2003 - Tale of 2 boysPatient -1 He had been in clinical

remission for first 2 years Relapse required a short

course of steroids Normal growth and timely

puberty He has been in remission

since then Repeat colonoscopy – all

lesions were healed.

Patient -2 Became steroid dependent; no

response to most meds. Allergic to biologic therapy retreatment following episodic dosing.

1st surgery in 6 months Recurrence of Crohn’s Delayed puberty Stunted growth More steroids, tube feeding Bowel perforation needed 2nd

surgery Further hospitalization and TPN 3rd surgery for ‘ostomy’ Doing OK, hoping to get his

bowel reconnected in futureWith permission, S Kugathasan MD

Probability of Surgery for Crohn’s Disease

Years After Diagnosis

Patients (%)

1 Surgery

2Surgeries

≥ 3Surgeries

NoSurgery

5 37 7 5 51

10 39 11 12 39

15 34 14 22 30

Munkholm P et al. Gastroenterology. 1993;105:1716–1723.

severemoderate mild

Probability of Surgery for Crohn’s Disease

Years After Diagnosis

Patients (%)

1 Surgery

2Surgeries

≥ 3Surgeries

NoSurgery

5 37 7 5 51

10 39 11 12 39

15 34 14 22 30

Munkholm P et al. Gastroenterology. 1993;105:1716–1723.

Can we predict these subgroups at the time of diagnosis?

Must we wait to have multiple surgeries to define severe disease?

Estimate of Work Capacity: 10 Years Following Diagnosis

Fully capable Partially capable IncapableYears

% P

atie

nts

Binder V et al. Gut. 1985;26:146.

0

20

40

60

80

100

0 1 2 3 4 5 6 7 8 9 10

30% of CD ptswith disability

Heterogeneity of Crohn’s disease

Predictability of the postoperative course of Crohn's disease.

Rutgeerts P, Geboes K, Vantrappen G, Beyls J, Kerremans R, Hiele M.

Gastroenterology. 1990;99:956-963

Rutgeerts Endoscopic Scoring System – neoterminal ileum

I,1 I,3

I,4

Actuarial analysis of symptomatic recurrence in patients stratified according to severity of endoscopic lesions

Rutgeerts P, et al. Gastroenterology. 1990;99:956-963

Actuarial analysis of symptomatic recurrence in patients stratified according to severity of endoscopic lesions

Severe Crohn’ssubgroup – rapidpost-operativesymptomaticrecurrence

Rationale for disease modifying therapy in Crohn’s disease.

What can our pediatric gastroenterology colleagues teach

us about Crohn’s disease?

Early disease –Inflammation

Late disease –Tissue remodelingTime

Efficacy of AZA as Maintenance Therapy

in Patients with Active CD*

Duration of Trial (months)

* Remission induced by prednisolone tapered over 12 wk Candy S, et al. Gut. 1995;37:674.

80

60

40

20

0

% P

atie

nts

No

t Fa

iling

Tri

al

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

AZA 2.5 mg/kg/d (n=33)

Placebo (n=30)

100

P=0.001

BiologicTherapypatients

Duration of Remission With 6-MP in Children With Newly Diagnosed CD

1.00

0.75

0.50

0.25

0.000 100 200 300 400 500 600

Days from Start of Remission

Fra

ctio

n i

n R

emis

sio

n

6-MP

Controls

P < .007

Markowitz J et al. Gastroenterology. 2000;119:895.

REACH: Response and Remission Rates to Infliximab in Pediatric Patients With Moderate-to-Severe CD

88

64

33

59 56

24

0

20

40

60

80

100

Week 10 Week 54 q8 Week 54 q12

Response Remission

% o

f P

atie

nts

n = 99 n = 66 n = 29n = 33 n = 17 n = 12

p = 0.002p < 0.001

*

Clinical Remission Clinical Response

Hanauer SB, et al. Lancet. 2002;359:1541–1549.

ACCENT IWeek 54

Placebo

Infliximab 5 mg/kg

60

40

20

0

p = 0.0001

15

36

60

40

20

0

p = 0.007

14

28

Changes in PCDAI Score Following Infliximab Infusion

(10 Weeks)

0

20

40

60

80

100

PC

DA

I S

core

0 2 4 6 8 10 12

Weeks Following Infliximab Infusion

Kugathasan S et al. Am J Gastroenterol. 2000;95:3189.

94% responserate

Mucosal and histologic healing after infliximab in Early CD

0 8 16 24 32 40 56

Duration of Response Following Initial Infliximab Infusion: Early vs. Late CD

% P

atie

nts

Wit

ho

ut

Rel

apse

640

25

50

75

Late CD (n=8)

Early CD (n=6)

48

Weeks Following Infliximab Infusion

100

Kugathasan S et al. Am J Gastroenterol. 2000;95:3189.

PRECiSE 2: Week 26 Clinical Response or Remission by Duration of Crohn’s Disease

*P < 0.01; †P < 0.05; ‡P < 0.001 vs placebo.Sandborn WJ, et al. Am J Gastroenterol. 2006;101(Suppl 2):S394. Abstract 1109.

Placebo

Certolizumab

68

55

4744

37 3629

24

< 1 1 to < 2 2 to < 5 ≥ 5

90

75

6257

37

50

3633

0

20

40

60

80

100

< 1 1 to < 2 2 to < 5

Pat

ien

ts (

%)

≥ 5

Duration of Crohn’s Disease (years)

Response Remission

*

††

‡

‡

n = 54 42 100 229 54 42 100 229

Biologic induction for all Crohn’s disease patients implies episodic dosing for those who will require

longterm maintenance.

Why is episodic dosing of biologic therapy problematic in IBD?

Maintenance Treatment

Serum Concentrations of Infliximab:All Randomized Patients

Antibodies to Infliximab Through Week 54

• 14% of patients were antibody to infliximab (+)

0

2

4

6

8

10

12

14

16

18

20

nu

mb

er

of

pa

tie

nts

0 10 20 30 40 50 60 70 80 90 100 110 120 130

number of weeks between 1st and 2nd infusions of infliximab

Outcome of 86 infliximab second infusions

Acute systemic reaction

Delayed systemic reaction

Kugathasan S et al. Am J Gastroenterol. 2002; 97: 1408-14.

Analysis of longterm infliximab performance in Crohn’s disease

2nd Analysis: Last maintenance infusion

Past Episodic group

Scheduled group

Both groups received ≥ 24 months maintenance

start

infliximab

last

infliximab

Mean 40 months

Mean 50

months

Fewer patients hospitalized & undergoing surgery on SCHEDULED infliximab

Before infliximab Therapy

% o

f P

atie

nts

Past Episodic (n=24)Scheduled (n=28)p =NS p =NS

46 46

6158

0

10

20

30

40

50

60

70

Hospitalization Surgery

At last infliximab infusion

p < 0.001 p < 0.001

67

21

7

67

Hospitalization Surgery

Fewer TOTAL hospitalizations & surgeries on scheduled infliximab

Before Infliximab Therapy

Nu

mb

er

of

Ev

en

ts

Past Episodic (n=24)Scheduled (n=28)p =NS p =NS

1714

55 55

0

10

20

30

40

50

60

Hospitalization Surgery

At last infliximab infusion

7

p < 0.001 p < 0.001

32

2

28

Hospitalization Surgery

110 surgeriesin 52 pts

Durability of infliximab in Crohn’s disease

50% of CD patients have discontinued infliximab by 6 years of maintenance therapy (n = 153)

Gonzaga J et al. Gastroenterology 2008; 134: A665.

V. A rational approach for biologic therapy in Crohn’s disease

Crohn’s disease - medical management algorithm:No partial obstruction or abscess detected

Moderate

AZA/6MP/MTX to induce/maintain remission

AZA/6MP/MTX maintenance

Corticosteroid taper

breakthrough

SevereMild

5-ASA,Budesonideor antibiotics

Inadequate response toAZA/6MP/MTX

infliximab, adalimumab,certolizumab, natalizumabmaintenance

No

Yes

unable to taperCorticosteroids

Surgical patients

Corticosteroid-Free Clinical Remission at Week 26

SONIC

Primary Endpoint

30.6

44.4

56.8

0

20

40

60

80

100

Pro

po

rtio

n o

f P

atie

nts

(%

)

AZA + placebo IFX + placebo IFX+ AZA

p<0.001

p=0.009 p=0.022

52/170 75/169 96/169

Sandborn, WJ et al. ACG 2008.

Mucosal Healing at Week 26

SONIC

16.5

30.1

43.9

0

20

40

60

80

100

Pro

po

rtio

n o

f P

atie

nts

(%

)

AZA + placebo IFX + placebo IFX+ AZA

p<0.001

p=0.023 p=0.055

18/109 28/93 47/107

Sandborn, WJ et al. ACG 2008.

Duration of Remission With 6-MP in Children With Newly Diagnosed CD

1.00

0.75

0.50

0.25

0.000 100 200 300 400 500 600

Days from Start of Remission

Fra

ctio

n i

n R

emis

sio

n

6-MP

Controls

P < .007

Markowitz J et al. Gastroenterology. 2000;119:895.

Summary and conclusions - I

Multiple biologic agents targeting TNF-, IL-12/23 and 4 integrin are being developed for Crohn’s disease.

Rapid, effective therapy to induce remission has long-term benefit, specifically for mucosal healing in CD.

Precedent for disease modifying therapy exists with pediatric CD patients.

Summary and conclusions - II

Antibody based biologic therapy for CD is not flexible. Re-starting therapy is associated with immunogenicity, allergy and diminished efficacy.

Rapid identification of the high risk subgroup of patients (approximately 25% of CD) who will ultimately require biologic therapy for long-term maintenance of remission remains the ultimate goal.

Risk-benefit assessment will favor use of biologic agents in the severe Crohn’s disease subgroups.