Step Up versus Top Down Therapy for IBD

Gary R. Lichtenstein, MDProfessor of Medicine

Director, Center for IBDUniversity of PA School of Medicine

Hospital of the University of PA Philadelphia, PA

Current “Therapeutic Pyramid” for Crohn's disease

Severe

Moderate

MildAdapted from: Hanauer et al, Am J Gastroenterol 2001; 96: 635

BudesonideAntibiotics

5-ASA

MTXAZA / 6-MP

Systemic steroids

Surgeryanti-TNF-α

Rationale for early use of biological therapies in Crohn’s disease

• Target important mediators of inflammatory response i.e., greater specificity than existing therapies

• Useful for active disease and for maintenanceof remission

• Highly effective for management of fistulae

• Potential to alter the long-term course (disease modification)

Rutgeerts et al, Gastroenterology 2004; 126: 1593

Top down vs step up strategyWhat are the long-term considerations?

Long-Term Evolution of Crohn's Disease is Structural Damage

Cosnes et al, Inflamm Bowel Dis 2002; 8: 244

24022821620419218016815614413212010896847260483624120

0

20

40

60

80

100

Cumulative probability (%)

Patients at risk: Months2002 552 229 95 37n=

Penetrating

StricturingInflammatory

Role of Glucocorticoids inMild-to-Moderate Disease

• Effective induction agents, but do not modify disease

• Prednisolone* High clinical response rates (92%), but only about

one third of patients have mucosal healing No correlation between clinical activity index and

endoscopic assessment

• Limited maintenance efficacy Only about one third of patients have prolonged

response 1 year after first course

• Long-term toxicity; potential for dependency• Budesonide allows longer therapy but has not

changed long-term outcomes*Modigliani R et al. Gastroenterology. 1990;98:811818.Reviewed in Rutgeerts P et al. Rev Gastroenterol Disord. 2004;4(suppl 3):S3S9.

Predictors of Disabling Disease:Requirement for Steroids Is Turning Point

Beaugerie L et al. Gastroenterology. 2006;130:650–656.

5-year clinical course after diagnosis

VariableNondisabling, %

(n = 166)Disabling, %

(n = 957) P value

Age at onset < 40 years ≥ 40 years

77.122.9

87.712.3

.0004

Location of disease Small bowel only Small bowel + colon Colon only

44.625.929.5

32.839.427.8

.002

Smoking status Smoker Ex or nonsmoker

50.349.7

57.442.6

.09

Perianal lesions at diagnosis Yes No

17.582.5

26.43.6

.01

Required steroids for first flare Yes No

37.362.7

65.234.8

.0001

Cumulative incidence of surgical resection over 1 yr in Crohn's disease pts starting corticosteroids

Faubion et al, Gastroenterology 2001; 121: 255

38% of patients required surgery within 12 mos.

n=77n=77 Days

Cumulative probability (%)

30 60 90 182 3650

100

80

60

40

20

Efficacy of AZA as Crohn’s Disease Maintenance Therapy After Steroids*

80

60

40

20

0

Patients not failing trial (%)

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15Duration of trial (months)

AZA 2.5 mg/kg per day

Placebo

*Remission induced by prednisolone tapered over 12 wks Inclusion: Patients were not steroid dependent

Candy et al, Gut 1995; 37: 674

42%

7%

n=63 patients with active disease

p=0.001

100

Treatment with azathioprine is 35% (42–7%) more effective in maintaining remission

Feagan et al, N Engl J Med 2000; 342: 1627

Methotrexate maintenance after steroids in Crohn’s disease

• Multi-center, randomized, controlled trial

• 76 steroid-dependent patients

• In remission following methotrexate 25 mg IM x 16 weeks

• Randomized to 15 mg IM or placebo x 40 weeks

Weeks since randomization

100

90

80

70

60

50

40

30

Remission (%)

MethotrexatePlacebo

n=40

n=36

0 4 8 12 16 20 24 28 32 36 40

65%

39%

65% of 39% responders = 26% overall

p=0.04

Do immunosuppressives change the course of Crohn’s disease?

Cosnes et al, Gut 2005; 54: 237

No change in operative rates

Patients operated on (%)

Months after diagnosis

78–82 (n=34)

p=0.81

50

40

30

20

10

00 12 24 36 48 60

93–97 (n=176)

83–87 (n=46)

88–92 (n=102)

98–02 (n=102)

ACCENT I: Maintenance of clinical response in week 2 responders

Hanauer et al, Lancet 2002; 359: 1541

+++p<0.001, 10 mg q-8wks vs single infusion ++p=0.001, 5 mg q-8wks vs single infusion

***p<0.001, 10 mg q-8wks vs single infusion **p=0.002, 5 mg q-8wks vs single infusion

***

Single infusion

Infliximab 5 mg/kg q-8wks

Infliximab 10 mg/kg q-8wks

110 113 112 110 113 112

+++

++**

2717

5143

5953

Week 30 Week 54

Patients who maintained response (%)

0

100

n=

Step-Up and Top-Down Therapy for Crohn’s Disease

Anti TNF

AZA/MTX

Steroids

5-ASA/SPS

Anti TNF

AZA/MTX

Steroids

Combination

Step-up therapy

Top-downtherapy

Lichtenstein GR et al. Inflamm Bowel Dis. 2004;10:S2–S10.

Step-Up vs Top-Down:Study Design

D’Haens G et al Lancet 2008;371:660-667

133 Crohn’s patients, CDAI > 220Diagnosed < 4 years ago

Never treated with glucocorticoids (GCs), immunomodulators, or infliximab (IFX)

Step up Top down

Budesonide 9 mg/dayor

Prednisone 40 mg/day

IFX at weeks 0, 2, and 6+

AZA 2–2.5 mg/kg/day

AZA if repeated need for GCs, dependency

IFX for immunosuppression failure

Repeat IFX for relapse

GCs for failure to respond to IFX

Management of Recent-Onset CD: A controlled, randomized trial comparing

step up and top down therapy

Newly diagnosed* Crohn’s disease (n=130)

Step up (n=65)

Steroids

Top down (n=65)

IFX (0/2/6) + AZA

+ IFX

+ AZA MTX

Steroids

Steroids

IFX + AZA

+ (episodic) IFX

Steroids

*within 4 yearsD’Haens G et al Lancet 2008;371:660-667

Management of Recent Onset Crohn’s Disease

Top down(n=65)

Step up(n=65)

0

100

6 months 12 months n=20

75

48

77

64

75

21

n=14

Remission with steroid withdrawal

Endoscopic healing (at 2 years)

Patients (%)p=0.006 p=0.15 p=0.002

D’Haens G et al Lancet 2008;371:660-667

Endoscopy before treatment

Infliximab: Endoscopic HealingInfliximab: Endoscopic Healing

Rutgeerts P, et al Gastro Endoscopy 2006

Endoscopy after treatment at weeks 0, 2 & 6

Infliximab: Endoscopic HealingInfliximab: Endoscopic Healing

Week 10 ResultsWeek 10 Results

Rutgeerts P, et al Gastro Endoscopy 2006

Step-Up vs Top-Down Trial: Relapse Rate

Weeks following randomization

P = .018

Top down

Su

bje

cts

no

t fa

ilin

g (

%)

0

20

40

60

80

100

14

Year 1

14

Step up

Year 2

20 26 32 38 44 50 56 62 68 74 80 86 92 98 104

D’Haens G et al Lancet 2008;371:660-667

Top Down vs. Step Up Secondary Endpoint: Mean Number of Days of Steroid Use

0.545.6

70.2

79.7

0

10

20

30

40

50

60

70

80

90

Year 1 Total (Years 1 + 2)

Days

Top Down Step Up

*Preliminary data

D’Haens G et al Lancet 2008;371:660-667

0

10

20

30

40

50

60

70

80

90

100

1-8 9-16 17-24 25-32 33-40 41-48 49-56 57-64 65-72 73-80 81-88 89-96 97-104

Week

% o

f P

atie

nts

Top Down Step Up

†Numbers for the top down group indicate patients who required episodic IFX

Top Down vs. Step Up Secondary Endpoint: Proportion of Patients

Receiving Infliximab

*Preliminary data D’Haens G et al Lancet 2008;371:660-667

PRECiSE 1

Certolizumab Pegol Study Designs

CZP 400 mg sc (Wk. 0, 2, 4 then Q4W to week 24)

Placebo (Wk 0,2,4 the Q4W to week 24)

Doses

Weeks 0 2 4 6 8 12 16 20 24 26(6&26)

Co-primary endpoint Co-primary

endpoint

Responders(CDAI ↓ ≥100 pts)

Nonresponders Discontinue

CZP 400 mg sc Q4W to week 24

Placebo Q4W to week 24

PRECiSE 2

Doses

Weeks 0 2 4 6 8 12 16 20 24 26

Open Label

(CZP 400 mg)

Primary endpoint

CDAI 220-450

Stratified for:• CRP <10 mg/L or 10 mg/L• Baseline IS and steroids

Schreiber S, et al. NEJM 2007Sandborn WJ, et al. NEJM 2007

Sandborn et al, NEJM 2007

Certolizumab pegol 3 inj, placebo maintenance, SC

Certolizumab pegol 3 inj, 400 mg q-4weekly, SC

Early intervention with biologics enhances efficacy: PRECiSE 2

***p<0.001**p<0.01*p<0.05

Any <1 1–<2 2–<5 ≥5

Response(≥100 pt

DecreaseCDAI)

n= 210 215 35 19 22 20 55 45 98 131

Patients (%)

36.2

***62.8

**89.5

*62.2 ***

57.3

37.150

75

36.4 32.7

CD duration (yr)

0

100

Remission (CDAI ≤150)

Patients (%)

Any <1 1–<2 2–<5 ≥5n= 210 215 35 19 22 20 55 45 98 131

28.6

***47.9

*68.4

46.7 ***44.3

37.1 36.4

55

29.123.5

CD duration (yr)

0

100

Week 26

Placebo (n=170) Placebo

Baselin

e / Week 0

N=

854*

Week 4

n=

778

Week 56

‡

40 mg eow Open-label

40 mg eow (n=172)

40 mg ew (n=157)

Flare / Nonresponse

40 mg ew Open-label

Week 26

‡ 40 mg eow

40 mg ew

Week 240 mg

80 mg

Open label Randomized, double-blind, placebo-controlled

Week 4 stratified

by CR-70 response†

Week 12

CHARM: Study Design

*Previous anti-TNF: 49.6%†CDAI decrease ≥ 70 points from baseline ‡Two co-primary endpoints: Clinical remission (CDAI <150) at Weeks 26 and 56 in Week 4 CR-70 responders vs placebo

Flare / Nonresponse

Colombel JF, et al. Gastroenterol. 2007;132:52–65

Screening period

14 days

CHARM: Adalimumab in early Crohn’s disease

Adalimumab 40 mg q-weekly SC (n=157)

Placebo (n=170)

Adalimimab 40 mg EOW SC (n=172)

Week 26

Patients in remission CDAI <150 (%)

17 2514

56

35 37 454564

0

100

<2 years 2 to <5 years ≥5 years

* *

* *

Patients in remission CDAI <150 (%)

17 11 11

52

35 33 385250

0

100

<2 years 2 to <5 years ≥5 years

*

* ***

Week 56

Disease duration

Disease duration

Schreiber et al, Gastroenterology 2007; 132: A147 (Abstract 985)

*p<0.05

Preliminary Data

Patient PopulationSONIC

• Subjects 21 years of age or older with:– Moderate-to-Severe Crohn’s disease (CD)

• CDAI 220 and 450

– No prior exposure to biologic agents or immunomodulators

– Normal TPMT

Sandborn, WJ et al. ACG 2008.Preliminary Data

Study DesignSONIC

Week 0*

Week 2

Week 6

Week 14

Week 22

Week 30

Visits

Week 46

Week 38

Week 54

•••

• Infusions

Primary Endpoint (Corticosteroid-free Remission at Week 26)

Secondary Endpoint (Week 50)

• • •

Randomization of patients

Mai

nE

xte

ns

ion

Week 26*

Week 50

Azathioprine 2.5 mg/kg + placeboinfusions

Infliximab 5 mg/kg+ placebo capsules

Infliximab 5 mg/kg+ Azathioprine

2.5 mg/kg

• • •

• • •

* Endoscopy performed at Weeks 0 & 26

•••

• • •

• • •

Week 10

Week 18

Week 42

•••

Sandborn, WJ et al. ACG 2008.Preliminary Data

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

29

Sandborn, WJ et al. ACG 2008.Preliminary Data

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

30

Sandborn, WJ et al. ACG 2008.Preliminary Data

Corticosteroid-Free Clinical Remission Through Week 26

SONIC

*p<0.05 IFX+AZA vs AZA+PBO, IFX+PBO vs AZA+PBO

†p<0.05 IFX+AZA vs IFX+PBO

0

20

40

60

80

100

0 2 4 6 8 10 12 14 16 18 20 22 24 26

Week

AZA + placebo IFX + placebo IFX + AZA

Pro

po

rtio

n o

f P

atie

nts

(%

)

**

** *

*

* *

†

31

Sandborn, WJ et al. ACG 2008.Preliminary Data

Anti-TNF-α is most effective therapy

to date, so why not use first?

Hospitalization accounts for >50% of healthcare costs in Crohn's disease*

Feagan et al, Am J Gastroenterol 2000; 95: 1955

Inpatient (57%)

Outpatient (24%)

MD Office (8%)

Medications (4%)

Emergency Room (2%)

Home Care (3%)

SNF (2%)

Other (1%)

In-patient

*Data from patients with a CD-related medical claim (10/94–09/95) included in a

1994 integrated claims databasen=607

Influence of anti-TNF-α (infliximab) on resources in Crohn's disease: UK study

• 1093 fewer bed days • Fewer investigations

(OR 0.39; 95% CI 0.29–0.52)• Out-patient (OP) visits unchanged

(standard follow-up)

Jewell et al, Gastroenterology 2004; 126: S1218Jewell et al, Data submitted for publication

• Number of abdominal operations halved

• 33 fewer examinations under anesthesia (EUA) (OR 0.34; 95% CI 0.20–0.59)

OperationsHospitalization

0

400

800

1200

1600

Bed days OP visits Investigations

6-mo pre IFX treatment 6-mo post IFX treatment

0

10

20

30

40

50

60

EUA Operations

n=205

Rates of Hospitalization and Surgery:The ACCENT I Trial

7.4

2.63.1

0

2

4

6

8

10

Pat

ien

ts w

ith

h

osp

ital

izat

ion

(%

)

Pat

ien

ts w

ith

in

tra-

abd

om

inal

su

rger

y (%

)

Episodic 5 mg/kg scheduled 10 mg/kg scheduled(n = 188) (n = 192) (n = 193)

P = .04

P = .07

P = .047

P = .023

Rutgeerts P et al. Gastroenterology. 2004;126:402413.

Rates of Hospitalizations and Surgeries:The ACCENT II Trial

Pro

po

rtio

n o

f p

atie

nts

h

osp

ital

ized

(%

)

Week 14 respondersn = 195

Nu

mb

er o

f su

rger

y/p

roce

du

res

per

100

pat

ien

ts P < .01 P < .05

Infliximab 5 mg/kg Placebo

Randomizedn = 282

Week 14 responders n = 195

Randomizedn = 282

Lichtenstein GR et al. Gastroenterology. 2005;128:862-869.

TREAT™ Registry Data: Safety of infliximab (IFX) and other Crohn’s

disease therapies

• Only prednisone and narcotics associated with increased risk of mortality and serious infections

• Continuous + intermittent IFX-treated patients have similar rates of mortality as patients not treated with IFX

Lichtenstein GR et al, Gastroenterology 2007; 132: A-178 (No. S1124)

***p≤0.001

Incidence per 100 patient-years

Rate within 3 monthsof IFX infusion

Rate outside 3 monthsof IFX infusion

IFX-treated

Non-IFX treated

Serious infections Malignancy Lymphomas

RR 1.77CI 1.27–2.46

RR 0.74CI 0.49–1.12

RR 1.08CI 0.22–2.992

0

0.67

1.19

0.390.53

0.04 0.05

***

Preliminary Data

Current and future therapeutic paradigms in Crohn's disease

Goals induce remission maintain remission prevent complications optimize surgical outcomes improve quality-of-life

Current* Step up approach Conservative use of immunomodulators

Additional goals disease modification mucosal healing pharmacoeconomics disease prevention improve quality-of-life

Future Top down approach Earlier use of immunomodulators

*Hanauer et al, Am J Gastroenterol 2001; 96: 635Preliminary Data

Learnings from RA / BEST trial

BEST Study: Early rheumatoid arthritis

• Multicenter randomized controlled trial comparing 4 treatment strategies

No progression in Total Sharp Score

Group 1 Group 2 Group 3 Group 4

100

80

60

40

20

0

Goekoop-Ruiterman et al, Arthritis Rheum 2005; 52: 3381

Clinical and radiographic outcomes were assessed at baseline, 3 months, 1 year

508 patients randomized to 1 of 4 treatment strategies

Patients (%)

Sequential monotherapy

Step-up combination therapy

Initial combination therapy with taperedhigh dose prednisone

Initial combination therapy with infliximab

Have We Truly Evolved ?

Vermiere et al, Aliment Pharmacol Ther 2006; 25: 3

Response

Continue Tx and observe

Response

Taper & stop Tx Observation

Relapse within 1yr?

Steroids + AZA or MTX

No response

AZA or MTX? Surgery

Relapse

Anti-TNF-No response

No response

Colonic(± small intestine) Small intestine

Smoking cessationSulfasalazine ± antibiotics

Smoking cessationBudesonide / corticosteroids

Patient Mild presentation Inflammatory disease No perianal disease No extraintestinal manifestations Non-smoking

Management plan: Low risk of progression

Adapted from Vermiere et al, Aliment Pharmacol Ther 2006; 25: 3

Patient Young age at onset (<18 yr) Non-inflammatory disease behavior Extensive disease (small/large bowel) Early steroid need Extraintestinal manifestations Active smoker

Response

Taper and stop steroids and continue immunosuppressants

Smoking cessationBudesonide / corticosteroids + AZA or MTX

No response

Anti-TNF-

Response

Maintenance

No response

Switch anti-TNF-

Surgery

Management plan: Intermittent to High Risk of Progression

Summary

• Preliminary studies have provided some evidence that reversing the treatment paradigm from a "step up" to a "top down" approach may positively alter the natural history of CD

• Evidence suggests that early use of biologic therapy is effective in improving quality-of-life and helping patients to achieve and maintain remission

Current Management Recommendation for

patients with Crohn’s Disease

• Top-down approach is preferred

– Less clinical relapse

– Less Steroid use

– Better mucosal healing

– Fewer • hospitalizations • Surgeries

– Likely to have fewer strictures

Current Management Recommendation for

patients with Crohn’s Disease

• Top-down approach is not preferred

– Overtreatment of approximately 30% of patients

– Uncertain safety difference

– ? More or less benefit if given as routine maintenance

STEP UP

TOP DOWN