Future Clinical Trials: Unanswered Questions in the Care of IBD Patients

William J. Sandborn, MD Chief, Division of Gastroenterology Director, UCSD IBD Center

Unanswered Questions

Step down Test Versus No Test Mucosal healing Prevention of postoperative recurrence Anti-TNF versus vedolizumab

Step Down

Withdrawal of AZA in 80 PatientsWith CD Treated With Scheduled IFX Maintenance:

Clinical Outcomes

No need to discontinue IFX

Pro

po

rtio

n o

f P

atie

nts

0.0

0.2

0.4

0.6

0.8

1.0

Log rank (Cox): P=0.735

0 8 16 24 32 40 48 56 64 72 80 88 96

Weeks

No need for early rescue IFX

Pro

po

rtio

n o

f P

atie

nts

0.0

0.2

0.4

0.6

0.8

1.0

Log rank (Cox): P=0.374

0 8 16 24 32 40 48 56 64 72 80 88 96Weeks

104

ContinuedDiscontinued

Reprinted from Gastroenterology 134(7), Van Assche G, et al. Withdrawal of immunosuppression in Crohn's disease treated with scheduled infliximab maintenance: a

randomized trial, 1861-1868. Copyright 2008, with permission from the AGA Institute.

***

Withdrawal of AZA in CD Patients Treated With Scheduled IFX Maintenance: Serum CRP and IFX Concentrations Over Time

8

11

910

CR

P (

mg

/L)

6

0

2

4

7

1

3

5

0 8 16 24 32 40 48 56 64 72 80 88 96 104

Weeks[I

FX

] μ

g/m

L 6

0

2

4

7

1

3

5

0 8 16 24 32 40 48 56 64 72 80 88 96 104

Weeks

DiscontinuedContinued

ContinuedDiscontinued

P=.15

P=.11

P=.051P=.048

P=.0046P=.028

P=.043

P=.19

Con 40 39 32 31 28 27 22 22 20 20 19 18 17 16Dis 40 38 33 28 25 22 20 20 18 18 18 18 18 18N=

10

1

Tro

ug

h IF

X (

μg

/mL

)

Con Dis

2.87

1.65

P<.0001

20

0

CR

P (

mg

/L)

Con Dis

1.62.8

P<.005

15

10

5

**

CRP, C-reactive protein

Reprinted from Gastroenterology 134(7), Van Assche G, et al. Withdrawal of immunosuppression in Crohn's disease treated with scheduled infliximab maintenance: a

randomized trial, 1861-1868. Copyright 2008, with permission from the AGA Institute.

STORI Trial Patients with Crohn's disease who were treated for at least 1 year with

scheduled infliximab and an antimetabolite and had been in corticosteroid-free remission for at least 6 months

Assessed the risk of relapse after discontinuation of infliximab in patients on combined maintenance therapy with immunosuppressors and to identify the risk factors for relapse

Results: After 1 year of infliximab discontinuation, the relapse rate was 44% Patients who relapsed were successfully retreated with infliximab Of the 40 evaluable responses to retreatment at 4 weeks, 37 were in

remission

Reprinted from Gastroenterology 141(1), Louis E, et al. Maintenance of remission among patients with Crohn's disease

on antimetabolite therapy after infliximab therapy is stopped, 63-70. Copyright 2012, with permission from the AGA Institute.

PredictiveFactor

Hazard Ratio

P Value

CDEIS >0hsCRP ≥5 mg/LHemoglobin ≤14.5 g/dLInfliximab trough levels ≥2 μg/mL

2.33.26.02.5

0.04<0.001<0.001

0.02

CDEIS, Crohn’s Disease Endoscopic Index of Severity; usCRP, ultrasensitive C-reactive protein

Test Versus No Test

Factors Affecting the Pharmacokinetics of Monoclonal Antibodies

IMPACT on PK Presence of ADAs Decreases serum [mAbs]

Three fold-increased clearanceWorse clinical outcomes

Concomitant use of IS Reduces formationIncreases serum [mAbs]

Decreases mAbs clearanceBetter clinical outcomes

High Baseline [TNF-α] May decrease [mAbs] by increasing clearance

Low Albumin Increases clearanceWorse clinical outcomes

High Baseline CRP Increases clearance

Body size High BMI may increase clearance

Gender Males have higher clearance

Ordas I, Feagan B, Mould D, Sandborn WJ. Clin Pharmacol Ther 2012

ACT 1+2: Proportions of Patients with Ulcerative Colitis Achieving Efficacy Endpoints by Serum Infliximab

Concentrations

Pro

po

rtio

n o

f p

atie

nts

(%

)

<21.3 <0.11≥21.3 –< 33.0

≥0.11-<2.4

≥33.0 –< 47.9

≥2.4-<6.8> 47.9 > 6.8

Reinisch W, et al., Digestive Disease Week 2012; Abstract # 566

Afif W, Sandborn WJ. Am J Gastroenterol 2010;105:1133-9.

Clinical Outcomes of Patients with Detectable Antibodies to Infliximab or Sub-therapeutic Infliximab Concentrations

Response to testComplete/partial response (%)

P value

Detectable HACA Increase infliximab 1/6 (17) P<0.004

Change anti-TNF 11/12 (92)

Subtherapeutic concentration

Increase infliximab 25/29 (86) P<0.016

Change anti-TNF 2/6 (33)

Elevating Infliximab Concentration from Sub-Therapeutic Levels is Effective in Regaining Response

in HACA (-) Patients

Treatment Algorithm in IBD Patients With Clinical Symptoms

(Infliximab and HACA Concentrations)

Positive HACA

Change to another anti-TNF agent

Change to non-anti-TNF agent

persistent disease

Increase infliximab dose or

frequency

Change to non-

anti-TNF agent

Change to different anti-TNF

agent

Change to different anti-TNF

agent

Subtherapeutic IFX concentration

Therapeutic IFX concentration

Active disease on endoscopy/radiology?

Change to different anti-TNF

agent

Investigate alternate etiologies

yes no

Afif W, et al. Am J Gastroenterol 2010;105:1133-9.

Mucosal Healing

MUCOSAL HEALING AND TIME TO COLECTOMY IN INFLIXIMAB-TREATED PATIENTS

1 = MILD 2 = MODERATE 3 = SEVERE0 = NORMAL

Colombel JF, et al. Gastroenterology. 2011.

Association Between Week 8 Mayo Endoscopy Sub-score and and Corticosteroid-Free Symptomatic Remission at Week 30 During Anti-TNF Antibody

Therapy

Week 8 Mayo endoscopy sub-score

Corticosteroid-free

symptomatic remission, %

P value

0 46 < 0.001

1 34

2 11

3 6.5

Colombel JF, et al. Gastroenterology 2011

Working Definition of Deep Remission

Overall, aiming for deep remission (DR) is managing disease beyond symptom control

– In patients with no bowel damage or disability, DR is resolution of one or more objective measures of inflammation (endoscopy, markers, imaging) AND resolution of symptoms

• To prevent damage and disability

– In patients with existing bowel damage and disability, DR is resolution of one or more objective measures of inflammation (endoscopy, markers, imaging) AND improvement of symptoms if possible

• To prevent further damage and disability, and reverse damage if possible

Development of the Crohn’s Disease Digestive Damage Score, the Le´mann Score

Benjamin Pariente, Jacques Cosnes, Silvio Danese, William J Sandborn, Maı¨te´ Lewin, Joel G Fletcher, Yehuda Chowers, Geert D’Haens, Brian G Feagan, Toshifumi Hibi, Daniel W Hommes, E. Jan Irvine, Michael A. Kamm, Edward V Loftus, Edouard Louis, Pierre Michetti, Pia Munkholm, Tom Oresland, Julian Pane´s, Laurent Peyrin-Biroulet, Walter Reinisch, Bruce E Sands, Juergen Schoelmerich, Stefan Schreiber, Herbert Tilg, Simon Travis, Gert van Assche, Maurizio Vecchi, Jean-Yves Mary, Jean-Fre´de´ric Colombel, Marc Le´mann

Pariente B et al. Inflamm Bowel Dis. 2011;17(6):1415.

Peyrin-Biroulet L et al. GUT. 2011.

Inflammatory Activity and Progression of Damage in a Theoretical Patient with CD

Pariente B et al. Inflamm Bowel Dis. 2011;17(6):1415.

Inflam

mato

ry activity (C

DA

I, CD

EIS

, CR

P)

Surgery

Stricture

Stricture

Fistula/abscess

Diseaseonset

Dig

esti

ve d

amag

e

Diagnosis Earlydisease

CDAI, Crohn’s Disease Activity Index; CDEIS, Crohn’s disease endoscopic index of severityCRP; c-reactive protein

EXTEND: patients with Crohn’s disease who achieved deep remission* with adalimumab at Week 12 and

hospitalization rates

Colombel JF, Sandborn WJ, et al. Gut 2010;59(Suppl 3):A80: OP371 at UEGW 2010

All-cause hospitalizationthrough Week 52

CD-related hospitalizationthrough Week 52

17

0

5

10

15

20

0/11 9/53All

ho

spit

aliz

atio

n (

%)

9

0

5

20

0/11 5/53

CD

-rel

ated

ho

spit

aliz

atio

n (

%)

Deepremission*

(Week 12)

Non-deepremission*

(Week 12)

Deepremission*

(Week 12)

Non-deepremission*

(Week 12)

10

15

* Deep remission defined as clinical remission (CDAI <150) and complete mucosal healing in EXTENDCD: Crohn’s disease; CDAI: Crohn’s disease activity index

Prevention Of Postoperative Recurrence

Crohn’s Disease: Recurrence After Surgery

Rutgeerts P, et al. Gastroenterology. 1990;99(4):956

Survival withoutsurgery

Survival withoutlaboratory recurrence

Survival withoutsymptoms

Survival withoutendoscopic lesions

20

40

80

100

0

60

Yr

Pat

ient

s (%

)

0 1 2 3 4 5 6 7 8

(%)

P=.0006P=.0009

P=.67

P=.05

Crohn’s disease patients with surgical resection of the ileum with an ileocolonic anastomosis

0

67

8090

39

54

815

0

20

40

60

80

100

Endoscopicremission

Absence of CD on colonoscopy

Clinicalremission

Clinicalrecurrence

Placebo

Infliximab 5 mg/kg

Regueiro M, et al. Gastroenterology 2009

Infliximab for Prevention of Postoperative Recurrence in Crohn’s Disease

N=23; within 4 wk of surgery, patients received study drug at 0, 2, 6 wk then Q 8 wk for 1 yr

15

Anti-TNF Versus Vedolizumab

Infliximab Induction and Maintenance Therapy in Patients with Ulcerative Colitis:

Clinical Response

†P.002 vs placebo‡P<.001 vs placebo

3730

20

69

5246

62

5144

0

10

20

30

40

50

60

70

80

8 Weeks 30 Weeks 54 Weeks

% o

f P

atie

nts

Placebo IFX 5 mg/kg IFX 10 mg/kg

‡‡

‡ †

‡

29 26

65

47

69

60

0

10

20

30

40

50

60

70

80

8 Weeks 30 Weeks

% o

f P

atie

nts

Placebo IFX 5 mg/kg IFX 10 mg/kg

‡

‡

‡

ACT 1 ACT 2

‡‡

Rutgeerts P. N Engl J Med. 2005;353:2462.

Infliximab Induction and Maintenance Therapy in Patients with Ulcerative Colitis:

Clinical Remission

†P.003 vs placebo‡P<.001 vs placebo

6

11

34

2628

36

0

5

10

15

20

25

30

35

40

8 Weeks 30 Weeks%

of

Pat

ien

ts

Placebo IFX 5 mg/kg IFX 10 mg/kg

15 16 17

39

34 3532

3734

0

5

10

15

20

25

30

35

40

45

8 Weeks 30 Weeks 54 Weeks

% o

f P

atie

nts

Placebo IFX 5 mg/kg IFX 10 mg/kg

‡ ‡‡

† †

‡

‡

‡

ACT 1 ACT 2

‡‡

Rutgeerts P. N Engl J Med. 2005;353:2462.

Infliximab Induction and Maintenance Therapy in Patients with Ulcerative Colitis:

Mucosal Healing

Mucosal healing = endoscopic subscore of 0 or 1

34

2518

62

5046

59

49 47

0

10

20

30

40

50

60

70

8 Weeks 30 Weeks 54 Weeks

% o

f P

atie

nts

Placebo IFX 5 mg/kg IFX 10 mg/kg

‡

31 30

60

46

6257

0

10

20

30

40

50

60

70

8 Weeks 30 Weeks

% o

f P

atie

nts

Placebo IFX 5 mg/kg IFX 10 mg/kg

ACT 1 ACT 2

†

‡ ‡‡‡

‡ ‡ ‡ ‡

†P.009 vs placebo‡P<.001 vs placebo Rutgeerts P. N Engl J Med. 2005;353:2462.

Vedolizumab (Anti-Alpha 4 Beta 7 Integrin) For Moderately-to-Severely Active Ulcerative Colitis: Results at Week 6 in 374

PatientsP<0.001

P=0.0009

P=0.0012

Feagan B. DDW 2012 Late Breaking Abstract

Vedolizumab (Anti- 47 Integrin) For Maintenace of Response in Moderately-to-Severely Active Ulcerative Colitis: Results at

Week 52 in 373 Patients

Feagan B. ACG 2012 Abstract

Comparative Effectiveness Trials Already Completed But Results Not Fully

Implemented By Clinicians

Mesalamine not effective for Crohn’s disease SONIC and UC Success – azathioprine < infliximab <

combination therapy Early use of azathioprine + steroids not more effective than

a tapering course of steroids

Conclusions

Comparative effectiveness studies are needed to better guide future clinical practice