Top Down vs. Step Up Therapy Biologics in IBD:

Treatment Algorithms

Top Down vs. Step Up TherapyTop Down vs. Step Up Therapy Biologics in IBD:Biologics in IBD:

Treatment AlgorithmsTreatment Algorithms

Stephen B. Hanauer, M.D.University of Chicago

Treatment Goals c.2008Treatment Goals c.2008Treatment Goals c.2008

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

• Induce and maintain response/remission• Prevent complications

– Disease Related– Therapy Related

• Improve quality of life• Limit surgery?

Current “Therapeutic Pyramids”Current Current ““Therapeutic PyramidsTherapeutic Pyramids””

BudesonideAntibiotics

5-ASA

MTXAZA/6-MP

Systemic Steroids

SurgeryInfliximab

Severe

Moderate

Mild

Systemic Corticosteroids

Infliximab

Aminosalicylates

Surgery Cyclosporine

Crohn’s Disease Ulcerative Colitis

Concept ObfuscatesInduction/Maintenance

Strategies

Conventional approach to Induction Therapy: step-up

Conventional approach to Induction Conventional approach to Induction Therapy: Therapy: stepstep--upup

Anti TNF-α

Systemic corticosteroids Aminosalicylates

Non-systemic corticosteroids

• Clinical approach to use “mildest” form of drug therapy to treat patients first

• Move to next step in non-responders

Dis

ease

sev

erity

Time

Natalizumab

Step-up management approachStepStep--up management approachup management approach

Advantages

• Patients attain remission with less toxic therapies

• Potentially more toxic therapies reserved for more severe or refractory disease

• Minimizes risk of adverse events

• Cost sparing (short-term?)

Disadvantages

• Patients have to “earn” most effective treatments

• Decrease in quality-of-life before patients obtain optimal therapy

• Likelihood of surgery is high

• Disease is not modified

IBDs are chronic, life-longIBDsIBDs are chronic, lifeare chronic, life--longlong

We cannot just look at the short-term induction therapy

LongLong--Term Therapy for IBD Term Therapy for IBD is Sequentialis Sequential

Induction Maintenance

Impact of Therapy will Depend on Degree of Structural Damage & Velocity of Progression Impact of Therapy will Depend on Degree of Impact of Therapy will Depend on Degree of Structural Damage & Velocity of ProgressionStructural Damage & Velocity of Progression

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

240228216204192180168156144132120108968472604836241200

20

40

60

80

100

Cum

ulat

ive

Prob

abili

ty (%

)

Patients at risk:Months

2002 552 229 95 37n=

Penetrating

StricturingInflammatory

High Potential Low Potential

Efficacy of AZA as Crohn’s Disease Maintenance Therapy

After Steroids in Adults*

Efficacy of AZA as Efficacy of AZA as CrohnCrohn’’ss Disease Disease Maintenance TherapyMaintenance Therapy

After Steroids in AdultsAfter Steroids in Adults*

Candy S, et al. Gut. 1995;37(4):674-678.

100

80

60

40

20

0

% P

atie

nts

Not

Fai

ling

Tria

l

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

Duration of Trial (months)

AZA 2.5 mg/kg per dPlacebo

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

p=0.001

42%

7%

Efficacy of 6-MP as Crohn’s Disease Maintenance Therapy

After Steroids in Steroid-naïve Children

Efficacy of 6Efficacy of 6--MP as CrohnMP as Crohn’’s Disease s Disease Maintenance TherapyMaintenance Therapy

After Steroids in SteroidAfter Steroids in Steroid--nanaïïve Childrenve Children

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

30

40

50

60

70

80

90

100

0 50 100 150 200 250 300 350 400 450 500 550 600

Days Since Remission Induction

% o

f Pat

ient

s in

Rem

issi

on

P<.007

91%

53%

N=55

6-MP

Control

At baseline, patients received prednisone plus either 6-MP or placebo. Steroids were tapered after induction of remission.

Three classes of anti-TNF:Fusion protein, antibodies and PEGylated Fab' fragment

Three classes of antiThree classes of anti--TNF:TNF:Fusion protein, Fusion protein, antibodies and PEGylated Fab' fragmentantibodies and PEGylated Fab' fragment

Coutesy of Stephen B. Hanauer, M.D.

Infliximab Adalimumab

IgG1 Fc

Fab

Etanercept

IgG1Fc

Receptor

Monoclonal antibody

Human

Human recombinant

receptor/Fc fusion protein

Chimeric

Fab′

Certolizumab pegol

PEG

PEGylated humanized

Fab′

fragment2 ×

20 kDa PEG

Clinical Trials with Anti-TNF Biologics in Refractory Crohn’s disease

Clinical Trials with AntiClinical Trials with Anti--TNF Biologics in TNF Biologics in Refractory CrohnRefractory Crohn’’s diseases disease

Drug

Placebo

Drug

Placebo

Drug

Placebo

Drug

Responder

ResponseMaintenance

Maintenance

Targan/InfliximabClassic I/Adalimumab

ACCENT I/InfliximabCHARM/AdalimumabPRECiSE 2/Certolizumab

CLASSIC II/AdalimumabPRECiSE1/Certolizumab

Comparing ACCENT I, CHARM, and PRECiSE 2 Results

Comparing ACCENT I, CHARM, and Comparing ACCENT I, CHARM, and PRECiSE 2 ResultsPRECiSE 2 Results

30.747.9

64.1

020406080

Week 6Response

Week 26Remission

OverallRemissionWeek 26

PRECiSE 2(certolizumab pegol)

ACCENT I*(infliximab)

CHARM**(adalimumab)

*5 mg/kg dose.**Maintenance trial with 80/40 mg induction dosing. Randomized responders = CR-70 at week 4. Week 26 remission among randomized responders on 40 mg every other week dosing.

2460

40

020406080

100

Week 4Response

Week 26Remission

OverallRemission

Week 26

22.839.0

58.5

020406080

Week 2Response

Week 30Remission

OverallRemission

Week 30

Patie

nts

(%)

Patie

nts

(%)

Patie

nts

(%)

Impact of Disease DurationImpact of Disease Duration

Clinical Remission at Weeks 26 by Disease Duration in adalimumab CHARM study

Clinical Remission at Weeks 26 by Disease Clinical Remission at Weeks 26 by Disease Duration in adalimumab CHARM studyDuration in adalimumab CHARM study

Schreiber S, et al. Gastroenterology 2007;132(4 Suppl 2):A-147

*p=0.002, **p<0.001, †p=0.014, ‡p=0.001 all vs placebo

Placebo All Adalimumab

1425

17

59*

40 41**

010203040506070

% o

f pat

ient

s

<2 years 2 to <5 years ≥5 years

N=23 N=39 N=36 N=57 N=111 N=233

Week 26 Remission with certolizumab by Duration Of Crohn’s Disease In PRECiSE 2

Week 26 Remission with certolizumabWeek 26 Remission with certolizumab by Duration Of Crohnby Duration Of Crohn’’s Disease In PRECiSE 2s Disease In PRECiSE 2

68%

55%47% 44%

37% 36%29%

24%

0%

20%

40%

60%

80%

100%

< 1 Year 1 - 2 Years 2 - 5 Years > 5 Years

Certolizumab Remission

Placebo Remission

Impact of Concomitant Impact of Concomitant ImmunomodulatorsImmunomodulators

ACCENT I: Comparable clinical outcomes with or without immunomodulators

ACCENT I: ACCENT I: Comparable clinical outcomes Comparable clinical outcomes with or without immunomodulatorswith or without immunomodulators

Lichtenstein et al, Gastroenterology 2007; 132: A-146 (No. 982)

6350 52

3753

41 3932

0

100

Week 30 Week 54 Week 30 Week 54

With concomitant IMM

Without concomitant IMM

Patients (%)

Response Remission

CHARM: Effect of concomitant adalimumab and immunosuppressive therapy on remission at

week 26 and 56

CHARM:CHARM: Effect of concomitant adalimumab Effect of concomitant adalimumab and immunosuppressive therapy on remission at and immunosuppressive therapy on remission at

week 26 and 56week 26 and 56

Colombel et al, Gastroenterology 2007; 132: 52

Patie

nts

in re

mis

sion

(%)

131 136 121 39 36 36 Without IMMWith IMM

Week 56Remission defined as CDAI <150

Placebo

Adalimumab 40 mg EOW, sc

Adalimumab 40 mg q-weekly, sc

12 13

37 3339

50

0

100

Continuous vs interrupted use of immunomodulators in the long-term efficacy

of infliximab (IFX): The IMID Trial

Continuous vs interrupted use of Continuous vs interrupted use of immunomodulators in the longimmunomodulators in the long--term efficacy term efficacy

of infliximab (IFX):of infliximab (IFX): The IMID TrialThe IMID Trial

Van Asche et al, Gastroenterology 2007; 132: A-103 (No. 734)

• 80 patients randomized to continue (+CON , n=40) or to interrupt (++DIS, n=40) immunomodulators (azathioprine or methotrexate) 6 months after the start of infliximab (5 mg/kg IV)

Median IFX levels, Week 8 to Week 104 combined

No need for early ‘rescue’ IFX: primary endpoint

p<0.005

0

1

10

100

Continued Discontinued

IFX trough levels (μg)Cumulative survival

0 20 40 60 80 100

0.0

0.2

0.4

0.6

0.8

1.0

Time (weeks)

Log Rank (Cox): 0735; Breslow: 0.906

Continued

Discontinued

Recent Anti-TNF Biologic TrialsRecent AntiRecent Anti--TNF Biologic TrialsTNF Biologic Trials

Step-up/Top-down (Steroid-naïve)

COMMITT(Steroid-induced, IS naive)

SONIC(Steroid-refractory, IS naïve)

Steroids Steroids IS

Infliximab + IS

Infliximab

Infliximab + MTX

Infliximab

Infliximab + AZA

AZA

Early Aggressive Biologic Therapy vs Conventional Management of Crohn’s Disease

Early Aggressive Biologic Therapy vs Early Aggressive Biologic Therapy vs Conventional Management of CrohnConventional Management of Crohn’’s Diseases Disease

D’Haens et al. Lancet 2008;371:660

Newly diagnosed, antimetabolite, anti-TNF, or steroid-naïve

CD patients (n=133)

Conventional therapy (n=66)

Early aggressive (n=67)+ IFX

+ AZA MTX

Steroids

Steroids

IFX (0,2,6 weeks) + AZA

+ (episodic) IFX

Steroids

Step-Up vs. Top-Down: ResultsStepStep--Up vs. TopUp vs. Top--Down: ResultsDown: Results

D'Haens G, et al. Lancet 2008;371:660-667

0

5

10

15

20

25

30

35

Perc

ent o

f Pat

ient

s020406080

6 Months 12 Months

% o

f Pat

ient

s

010203040

6 Months 12 Months

% o

f Pat

ient

s

CDAI < 150 & No Steroids

Steroid Use

Treatment Success* From Week 14 Through 2 YearsP = 0.03 P = 0.19

P < 0.001 P < 0.001

P < 0.001

0 0

Top Down

Step Up

60 41 61 50

3117

29

5

*Remission (CDAI < 150), discontinuation of steroids and infliximab, and no resection.

Step Up vs. Top Down: Complete Endoscopic Remission at 2 Years

Step Up vs. Top Down: Step Up vs. Top Down: Complete Endoscopic Remission at 2 YearsComplete Endoscopic Remission at 2 Years

D’Haens et al. Lancet 2008;371:660

(n=26)Early aggressive

(n=23)Conventional therapy

**p=0.003

Patie

nts

(%)

73

30

0

100

**

COMMITT: MTX plus IFX in CD (1)COMMITT: COMMITT: MTX plus IFX in CD (1)MTX plus IFX in CD (1)

Feagan B, et al. DDW 2008: #682C

– Patients with active CD on corticosteroids within last 6 weeks

– 1:1 randomization to • IFX + PBO (n=63)• IFX + MTX (n=63)

– Steroids withdrawn by Week 14 per protocol– IFX at 0, 2, and 6 weeks then maintenance q8W

• Primary analysis: time to treatment failure– CDAI <150, no prednisone by Week 14 and maintained

to Week 50– Relapse: CDAI increase of 70 points

COMMITT: MTX plus IFX in CD (2)COMMITT:COMMITT: MTX plus IFX in CD (2)MTX plus IFX in CD (2)

Feagan B, et al. DDW 2008: #682C

76.2

55.6

77.8

57.1

0

20

40

60

80

100

Week 14 Week 50

Patie

nts

in R

emis

sion

off

Ster

oids

(%)

MTX + IFX

PBO + IFX

p=0.83

p=0.63

• No difference in ITT analysis, duration of disease <2 years, by CDAI score

• No difference in infectious AEs (58.7% MTX vs 61.9% PBO)

SONICSONICSONIC

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

Induction + maintenance ofsteroid-free remission, mucosal healing,

IFX monotherapy vs IFX+AZA combination vs AZA monotherapy

in moderate-to-severe CD in patients with no prior exposure to biologic agents and immunosuppressants

Clinical remission without corticosteroids at week 26

Clinical remission Clinical remission without corticosteroids at week 26without corticosteroids at week 26

Sandborn et al., ACG 2008 annual meeting, abstract #29

Primary endpoint

31

44

57

0

20

40

60

80

100

Prop

ortio

n of

Pat

ient

s (%

)

AZA + placebo IFX + placebo IFX+ AZA

p<0.001

p=0.009 p=0.022

52/170 75/169 96/169

Mucosal healing at week 26Mucosal healing at week 26Mucosal healing at week 26

Sandborn et al., ACG 2008 annual meeting, abstract #29

17

30

44

0

20

40

60

80

100

Prop

ortio

n of

Pat

ient

s (%

)

AZA + placebo IFX + placebo IFX+ AZA

p<0.001

p=0.023 p=0.055

18/109 28/93 47/107

Secondary endpoint

COMMITT vs. SONICCOMMITT vs. SONICCOMMITT vs. SONIC

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

COMMITT

Steroid-induced patientsIS Naïve

Steroid-InducedForced steroid-taper by

week 14

SONIC

40% Steroid-dependent(refractory CDAI>250)

IS NaïveAd lib steroids to week 14

(↑↔↓) then taper

Yin & Yang of Concomitant Immunomodulators

Yin & Yang of Concomitant Yin & Yang of Concomitant ImmunomodulatorsImmunomodulators

• All biologics are immunogenic

• Antibodies (at least to infliximab)– Associated with

acute/delayed infusion reactions

– Shorter duration of response (with episodic therapy)

• Immunomodulators reduce immunogenicity across all trials

• Yet…• No difference in short- or

long-term responses to induction + maintenance therapy in refractory CD– ACCENT,CHARM, PREcISE

• No benefit with steroid- induction (COMMIT)

• Positive Benefit in steroid- dependent (SONIC)

• Increase long-term toxicity– Serious infections– Risk of neoplasia

Anti-TNF-α

RisksAntiAnti--TNFTNF--αα

RisksRisks

• Immunogenicity (all biologics)• Infliximab specific

– Infusion reactions • Class effect

– Drug-induced lupus– Injection site reactions (adalimumab, certolizumab pegol)– Non-Hodgkin’s lymphoma (including hepatosplenic

T-cell lymphoma in children on infliximab + azathioprine)– Serious infections (~3%)– Opportunistic infections (including tuberculosis,

histoplasmosis, coccidiomycosis)– Demyelination

When to Introduce Biologics?When to Introduce Biologics?

The “Tipping Point” may be Corticosteroids?

Challenges of Induction Maintenance 2009:Consider the Population

Challenges of Challenges of InductionInduction MaintenanceMaintenance 2009:2009:Consider the PopulationConsider the Population

Steroid-Naïve

Steroid-InductionThiopurine/MTX Maintenance (Markowitz)

Anti-TNF InductionThiopurine/MTX Maintenance

(Step-up/Top-Down)

Challenges of Challenges of InductionInduction MaintenanceMaintenance 2009:2009:Consider the PopulationConsider the Population

Steroid-DependentThiopurine/MTX Maintenance (Candy, Markowitz, Feagan)

FailureBiologic (ACCENT,CHARM,PREcISE)

Challenges of Challenges of InductionInduction MaintenanceMaintenance 2009:2009:Consider the PopulationConsider the Population

Steroid-RefractoryImmunosuppressive naïve

Anti-TNF + AZA induction & Maintenance (SONIC)

Steroid-RefractoryDespite Immunosuppressive

Anti-TNF induction& Maintenance

Stop Immunosuppressive

FailAssess Inflammation, Immunogenicity

Switch Anti-TNF or Natlizumab

Current and Future Therapeutic ParadigmsCurrent and Future Therapeutic ParadigmsCurrent and Future Therapeutic Paradigms

Current• Bottom-up approach• Conservative use of

immunomodulators• Goals

– Induce remission– Maintain remission– Prevent

complications– Optimize surgical

outcomes

Future• Early aggressive

approach• Earlier use of

immunomodulators• Additional goals

– Disease modification– Mucosal healing– Pharmacoeconomics

• Disease prevention!