Immunosuppressive Medications and IBD: Now and What’s Next

Stephen B. Hanauer, MD

University of Chicago

Indications for Immunosuppressives in IBD

• Crohn’s Disease– Steroid-Sparing (Maintenance)– Maintenance after Biologics

• Reduction of Immunogenicity

– Post-Surgical Maintenance

• Ulcerative Colitis– Steroid-Sparing

Anti TNF-α therapiesSurgery

Systemic corticosteroids AminosalicylatesN

on-systemic corticosteroids

Conventional approach to Induction Therapy: step-up

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

• Move to next step in non-responders

Dis

eas

e s

eve

rity

Time

Step-up 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-long

We cannot just look at the short-term induction therapy

Long-Term Therapy for IBD is Sequential

InductionMaintenance

Maintenance Therapy is Dictated by Induction Therapy

Induction Maintenance

Aminosalicylate Aminosalicylate

Maintenance Therapy is Dictated by Induction Therapy

Induction Maintenance

CorticosteroidAminosalicylate (UC)ThiopurineMethotrexate (CD)

Maintenance Therapy is Dictated by Induction Therapy

Induction Maintenance

Cylcosporine Thiopurine

Maintenance Therapy is Dictated by Induction Therapy

Induction Maintenance

Anti-TNFThiopurine (Steroid-Naïve)Anti-TNF (Steroid-Refractory)

Maintenance Therapy is Dictated by Induction Therapy

Induction Maintenance

Natalizumab Natalizumab

“Natural History” of Disease Behavior in CD

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

24022821620419218016815614413212010896847260483624120

0

10

20

30

40

50

60

70

80

90

100

Cum

ulat

ive

Pro

babi

lity

(%)

Patients at risk:Months

2002 552 229 95 37N =

Penetrating

StricturingInflammatory

Progression Toward Surgery

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

Progression

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

24022821620419218016815614413212010896847260483624120

0

10

20

30

40

50

60

70

80

90

100

Cum

ulat

ive

Pro

babi

lity

(%)

Patients at risk:Months

2002 552 229 95 37N =

Penetrating

StricturingInflammatory

High Potential Low Potential

Difference between Early & Late Intervention with

Immunosuppressants

60% exposed to IS therapy

No Change in Surgery Rates

Efficacy of AZA as Crohn’s Disease Maintenance Therapy

After Steroids in Adults*

100

80

60

40

20

0

% P

atie

nts

No

t F

aili

ng

Tri

al

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 d

Placebo

*Remission induced by prednisolone tapered over 12 wk

Inclusion: Patients were not steroid dependent

p=0.001

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

42%

7%

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

After Steroids in Steroid-naïve Children

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 P

ati

en

ts i

n R

em

iss

ion

P<.007

91%

53%

N=55At baseline, patients received prednisone plus either 6-MP or placebo. Steroids were tapered after induction of remission. Markowitz J et al. Gastroenterology. 2000;119:895.

6-MP

Control

Dosing Considerations with Thiopurines

AZATHIOPRINE/6-MERCAPTOPURINE

Azathioprine 6-mercaptopurine Thioinosinic 6-thioguanine (AZA) (6-MP) acid (6-TG)

6-methyl-mercaptopurine (6-MMP)

6-thiouric acid

TPMTHPRT IMDPH

GMPS

XO

Distribution of Thiopurine Methyltransferase Enzyme Activity in the Population

12

Weinshilboum.Weinshilboum. Am J Hum Genet Am J Hum Genet. 1980. 1980

88

66

44

22

00

% of Subjects/0.5 units of Activity% of Subjects/0.5 units of Activity

00 55 1010 1515 2020

Erythrocyte TPMT Activity (UErythrocyte TPMT Activity (UmLmL-1-1))

TPMTTPMTHH

TPMTTPMTHH1010

TPMTTPMTLL

TPMTTPMTHH

TPMTTPMTLL

TPMTTPMTLL

Early Evidence with Allopurinol

6-MP 6-TG

6-MMP

6-thiouric

HEPATOXICITY

↑↑ACTIVITY

INACTIVE

X0

HPRT,IMDPH,GMPS

Sparrow & Hanauer DDW 2005

CONTROVERSIES REGARDING THERAPEUTIC DRUG MONITORING

• No Prospective Data

• Time Course to AZA/6-MP Activity > 8-12 weeks– Sandborn I.V. Loading trial

• Mechanisms of Action of 6-MP?

• Relationship of 6-MMP to Bone Marrow – Also of 6-Thioguanine to Bone Marrow

• Cost Effectiveness vs. Clinical Monitoring with WBC

Indications for Therapeutic Monitoring

• Primary Dosing Regimens– Aim for target levels– Expensive

• Assessment of Non-Responders or Elevated Transaminases

– Consistent with current practices– May be more cost-effective

• Assessment of Adherence– Pediatrics

SUMMARY

• Pharmacogenitic Considerations are Important for IBD Therapeutics

• Therapeutic Drug Monitoring May Offer Improvements If:– Prospectively Demonstrated– Superior Safety and Efficacy to Clinical and

Routine Laboratory Monitoring

Optimizing Dose of ThiopurinesConsider Pharmacology & TPMT

Status

• TPMT Homozygotes– Start very low (e.g. 25 mg, 2-3 times/week)

• TPMT Heterozygotes– Start low dose (~1 mg/kg)

• TPMT Normal– Start 2.5 mg/kg

• TPMT High (abnormal LFTs, ↑6MMP)– Consider reducing dose & adding allopurinol

Feagan B, et al. N Engl J Med 2000.

Methotrexate Maintenance after Steroids in Crohn’s Disease

• Multicenter, 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

% R

emis

s ion

Methotrexate

Placebo

n=40

n=36

0 4 8 12 16 20 24 28 32 36 40

100

90

80

70

60

50

40

30

65%

39%

65% of 45% responders=30% overall

Yin & Yang of Concomitant Immunomodulators

• 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

• Increase toxicity– Serious infections– Risk of neoplasia

50

37

1.9

43

3.3

41

32

5.3

48

4.6

0

20

40

60

45

34

7.2

55

36

3.9

4536

5.1

53

27

5.8

0

20

40

60

ACT I 54 wk Response

ACT I 54 wk Remission

ACT I 54 wk Hosp

ACT II 30 wk Response

ACT II 30 wk Remission

ACT II 30 wk Hosp

ACCENT I 54 wk

Response

ACCENT I 54 wk

Remission

ACCENT I 54 wk Hosp

ACCENT II 54 wk

Response

ACCENT II 54 wk

Response

Do Concomitant Immune-modulators Improve Efficacy of Infliximab in CD and UC?

IMM + IMM -

All p-values = NS

% p

atie

nts

% p

atie

nts

Lichtenstein GR, et al. DDW 2007. #982

Crohn’s disease

Ulcerative colitis

Patients in remission (%)

131 136 121 39 36 36

Without IMMWith IMM

Week 56

Remission defined as CDAI <150

CHARM: Concomitant adalimumab and immunosuppressive therapy DO NOT

impact on remission at week 56

Placebo

Adalimumab 40 mg EOW, sc

Adalimumab 40 mg

q-weekly, sc

12 13

3733

39

50

0

100

Colombel et al, Gastroenterology 2007; 132: 52

Certolizumab pegol q-4w 400 mg, sc

Certolizumab pegol (3 injections) + placebo

Schreiber et al, N Engl J Med 2007; 357: 239

With IMM Without IMM

(n=86) (n=87) (n=124) (n=128)

*** ***

3339

61 64

0

100

Patients (%)

***p<0.001 CR100

PRECiSE 2: Concomitant certolizmab pegol and immunosuppressive therapy DO NOT impact on Clinical response at

week 26

- IMM - IMM+ IMM + IMM

Month 6 Month 12

P≤0.009 for all comparisons with placebo

ENACT-2 Concomitant immunosuppressive DO NOT impact on

Remission at 6 or 12 Months PlaceboPlacebo

NatalizumabNatalizumab

(111) (106) (60) (62) (111) (106) (60) (62)

Sandborn W, Colombel J-F, Enns R, et al. Presented at: DDW 2006; May 20-25, 2006; Los Angeles, CA.

31

21

54 53

30

23

5860

0

10

20

30

40

50

60

70

Per

cen

t

COMMITT: MTX plus IFX in CD (1)

Methods:• Randomized, double blind, PBO-controlled trial

– Patients with active CD on corticosteroids within last 6 weeks

– 1:1 randomization to • IFX + PBO (n=63)• IFX + MTX (dose escalation: 10 mg,10 mg, 20 mg, 25 mg) (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

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

COMMITT: MTX plus IFX in CD (2)

76.2

55.6

77.8

57.1

0

20

40

60

80

100

Week 14 Week 50

Pat

ien

ts i

n R

emis

sio

n o

ff S

tero

ids

(%)

MTX + IFX

PBO + IFXp=0.83

p=0.63

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

• 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)

What about stopping Immunomodulators?

Discontinued IMM (n=40)

Continued IMM (n=40)

Patients treated with AZA, 6-MP, or MTX

plus IFX 5 mg/kg and in clinical remission for

≥6 months

Week 104

Percentage of patients requiring a change in

IFX dosing or who discontinued IFX

IMID: Impact of Concomitant Immunosuppression on the Outcome of

Maintenance Infliximab Therapy

6-MP=6-mercaptopurine; AZA=azathioprine; IFX=infliximab; IMM=immunomodulator therapy with AZA, 6-MP, or MTX; MTX=methotrexate

Van Assche G, Paintaud G, Magdelaine C, et al. Gastroenterology. 2007;132:A-103. [Abstract #734]

Randomization(N=80)

IMID: Impact of Concomitant Immunosuppression on the Outcome of Maintenance Infliximab

Therapy

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

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

Risks Associated With Long-term Use of Immunosuppressants (AZA/6-MP)1,2

• Overall toxicity 15%

• Pancreatitis 3.3%

• Bone marrow depression (leukopenia) 2-5%

• Allergic reactions 2%

• Drug hepatitis 0.3%

• Infectious complications 7.4%

• Malignant neoplasm 3.1%

• Opportunistic infections

• Lymphoma

– Associated with ≥fourfold increase in risk of EBV (+) lymphoma and prior treatment with AZA/6-MP

– 1 additional lymphoma will occur every 300 to 4,500 years after therapy with AZA or 6-MP, depending on patient age

– Consistent with RA reports

0

2

4

6

8

10

12

1985-1992 1993-2000

EBV (-)/AZA (+)

EBV (-)/AZA (-)

EBV (+)/AZA (+)

EBV (+)/AZA (-)

Lag time observed between AZA/6-MP treatment and lymphoma development (median, 3.5 years)

1. Present DH, Meltzer SJ, Krumholz MP, et al. Ann Intern Med. 1989;111:641-649. 2. Dayharsh GA, Loftus EV Jr, Sandborn WJ, et al. Gastroenterology. 2002;122:72-77.

Lymphoma Occurrence in IBD Patients Increasedin the 8-year Period After Introduction of AZA and 6-MP

EBV=Epstein-Barr virus

Pa

tie

nts

(%

)

Ex: from Risk Factors for Opportunistic Infections in IBD A Case-Control Study of 100 Patients (1998-2003)

Odds Ratio (95% CI)

P value

Any medication (5-ASA, AZA/6MP, Steroids, MTX, Infliximab)

3.50 (1.98-6.08) <0.0001

5-ASA 0.98 (0.61-1.56) 0.94

Corticosteroids 3.35 (1.82-6.16) <0.0001

AZA/6MP 3.07 (1.72-5.48) 0.0001

MTX 4.00 (0.36-4.11) 0.26

Infliximab 4.43(1.15-17.09)

0.03

One medication 2.65 (1.45-4.82) 0.0014

Two medications 9.66(3.31–28.19)

<0.0001Toruner M, et al. Gastroenterol. 2008.

Opportunistic infections and anti-TNF therapies :

Infliximab + Azathioprine in Patients WithActive Steroid Dependent Crohn’s Disease

• 115 pts active CD (CDAI >150) despite treatment with prednisone 10 mg/d for 6 mo

• Stratified for pre-study use of AZA/ 6-MP for > 6 mo, or no prior AZA/6-MP

• All treated with AZA 2 to 3 mg/kg or 6-MP 1 to 1.5 mg/kg

• Randomized to infliximab 5 mg/kg or placebo at 0, 2, 6 weeks

• Steroids systematically tapered• Primary endpoint: % clinical remission &

off steroids at Week 24

• No difference in outcome for AZA/6-MP treated and naive patients

3829

22

75

57

40

0

10

20

30

40

50

60

70

80

Week 12 Week 24 Week 52%

Rem

issi

on O

ff S

tero

ids

Placebo Infliximab

P<0.001

P=0.003

Lemann. Gastroenterology. 2006

P=0.04

Conventional Treatment of UC: Immunomodulators

• Immunomodulators are effective for maintenance of remission, but not induction

• Blinded, controlled clinical trial data are limited compared to CD

AZA Withdrawal in Patients With UC Who Required AZA to Achieve

RemissionRelapse Rates at 52 Weeks

59

36

0

10

20

30

40

50

60

70

% o

f P

ati

en

ts

Placebo AZA (mean dose 100 mg)

P=.04

Randomized controlled trial of patients who had been receiving AZA for 6 months Hawthorne AB et al. BMJ. 1992;305:20.

N=79

Treatment Success* After 6 Months

19

53

0

10

20

30

40

50

60

% o

f P

ati

en

ts

5-ASA 3.2 g/d (in 3 divided doses) AZA 2 mg/kg per day

AZA vs 5-ASA for Steroid-Dependent, Active UC

Ardizzone S et al. Gut. 2006;55:47.

P=.006

*Defined as clinical remission (Powell-Tuck Index Score of 0) and endoscopic remission (Baron Index Score 1) plus steroid discontinuationPatients treated with concurrent tapering dose of steroids

† 0.8 g at breakfast and lunch and 1.6 g at dinner

N=72†

Conventional Treatment: CsA

• CsA is effective for induction of remission in severe UC

• CsA has demonstrated little efficacy for maintenance of remission

• Use is limited due to significant safety concerns

Intravenous CsA: Severe Active Steroid-Refractory

UC

141313

6

0

5

10

15

20

LichtigerScore at Week

0

LichtigerScore at Week

2

Lic

hti

ger

Sco

re (

0 to

21)

Placebo CsA 4 mg/kg

N=20*Lichtiger score <10 points for 2 consecutive days

P<.001

0

82

0

10

20

30

40

50

60

70

80

90

Clinical Response at Week 2

% o

f P

atie

nts

Placebo CsA 4 mg/kg

*

Lichtiger S et al. N Engl J Med. 1994;330:1841.

CsA Use in Acute UC: Long-Term Experience

Campbell S et al. Eur J Gastroenterol Hepatol. 2005;17:79.

Oxford 1996 to 200376 patients with

severe UC

56 respondersto CsA

65%

90%

42%

66%

58%

40%

0%

20%

40%

60%

80%

100%

0 6 12 18 24 30 36 42 48 54 60 66

Months Since Initiation of Cyclosporin

CSA + 6MP/aza* (n=27)

CSA alone (n=15)

All Patients (n=42)

Avoidance of Colectomy with Azathioprine After CYSA Induction

Cohen, Stein, Hanauer. Am J Gastroenterol 1999;94(6):1587-1592

Pro

bab

ilit

y of

Avo

idin

g C

olec

tom

y

Cyclosporine as a “Bridge” to Azathioprine Maintenance in UC

Study No. CYA Initial Sustained SustainedDose Response Response Response

on AZA no AZA

Fernandez 13 4 mg/kg IV 12/13 7/8 1/4

Ramkrishna 6 1-2 mg/kg IV 5/6 4/5 0/1

Cohen 42 4 mg/kg IV 36/42 20/25 6/11

Rowe 36 2.5 mg/kg IV 26/36 7/19 5/7

Stack 22 4 mg/kg IV 20/22 7/10 5/10 ____ ___ ___

99/119(83%) 45/67(67%) 17/33(51%)

Cyclosporine Use in Acute Ulcerative Colitis: Long-Term Experience

Year 1 2 3 4 5 6 7

Percent without colectomy

67 57 48 41 31 16 12

Percent in remission

41 35 25 18 12 8 6

142 patients with severe acute UC treated with IV CyA118 (83%) responded44 patients (31%) were on AZA, 74 (52%) were started de novoAt 1 year, 23/44 (52%) of patients on AZA required colectomy compared with 12/74 (16%) starting AZA

Moskowitz. Gastroenterology 2005 Abstract

Should Biologics be used Earlier in IBD?

• Anti-TNF is more efficacious than conventional therapies

• Anti-TNFs are safer than conventional therapies (Corticosteroids)

• May be more cost-effective (over time) than conventional therapies

• Conventional Therapies Induce/Maintain Remissions in majority of patients

• Majority of patients do not need cost/toxicity risks of biologics

• Long-term safety experience in children & pregnancy

• Can we transition back to conventional immune modulators as in RA?

When to Introduce Biologics?

The “Tipping Point” may be Corticosteroids?

Challenges of InductionMaintenance 2008:

Consider the PopulationSteroid-Naïve

Steroid-InductionThiopurine/MTX Maintenance

Anti-TNF InductionThiopurine/MTX Maintenance

Challenges of InductionMaintenance 2008:

Consider the Population

Steroid-Dependent

Thiopurine/MTX Maintenance

Failure

Biologic

Challenges of InductionMaintenance 2008:

Consider the Population

Steroid-RefractoryImmunosuppressive

naïveAnti-TNF induction

Thiopurine/MTX Maintenance?

Steroid-RefractoryDespite

ImmunosuppressiveAnti-TNF induction &

MaintenanceStop Immunosuppressive

FailAnti-TNF + Switch

FailSwitch or Natalizumab

SummaryImmunosuppressives in IBD

• Most Effective as Maintenance Therapies– After Steroids– After Biologics– After Cyclosporine (UC)

• Early Aggressive Therapy is most effective• Optimal Dosing for Thiopurines Remains to be

Established– Consider Pharmacogenomics

• Role for Methotrexate Continues to Evolve• Cyclosporine for Severe/Fulminant UC• Monotherapy with Biologics appears effective

and safe