Top down vs Step-up Approach. David G. Binion, M.D

1
Emergence of New Biologic Agents in IBDTop
down vs Step-up Approach.
David G. Binion, M.D.
Director, IBD Center Division of Gastroenterology
Hepatology Professor of Medicine Medical
College of Wisconsin Milwaukee, WI, USA

2
Disclosure

• Grant Support
• National Institutes of Health
• Crohns and Colitis Foundation of America
• Proctor Gamble Pharmaceuticals
• Speakers Bureau
• Centocor
• Honoraria
• Prometheus Laboratories, Abbott laboratories,
  AstraZeneca, UCB Pharma, Proctor Gamble, Salix
  Pharmaceuticals, Axcan Pharma
• Off label discussion of Drugs

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Overview

• I. New Biologic Agents for IBD
• Anti-TNF-alpha agents
• Anti-IL-12/anti-IL23
• Natalizumab
• II. The Top down vs step up protocol for
  Crohns disease (CD).
• III. Is Top down therapy a good idea for all CD
  patients?
• Heterogeneity of CD.
• Disease modifying therapy in early CD
• IV. A rational approach for biologic therapy in
  IBD
• Who should be treated with biologics
• Risk/benefit assessment

5
I. New biologic agents for IBD

• Anti-TNF-alpha agents
• Anti-IL-12/anti-IL23
• Natalizumab

6
Molecular and cellular mechanisms in IBD
T-cell activation
TCR CD4 CD28 CTLA4
Nonspecific injury and repair
MHC Class II
PAF
NO
B7
PGE2
ROM
Proteases
Thromboxane
LTB4
Growth factors Trefoil proteins
Resting Mo
Naive T cell
Activated PMN
Pro-inflammatory cytokines
IL-2
CD4 T cell
Selectins
B cell
Activated Mo
CD40L
PMN
TNF-
CD40
CD4 T cells and T-helper subsets
IL-12/23
IL-4
IL-8
Integrins
IL-1
ICAM-1
Monocyte
Adhesion and recruitment
IFN-
MAdCAM-1
Th1
Th2
IL-10
Lymphocyte
Sands BE. Inflammatory Bowel Dis.1997395.
7
Molecular and cellular mechanisms in IBD
T-cell activation
TCR CD4 CD28 CTLA4
Nonspecific injury and repair
MHC Class II
PAF
NO
B7
PGE2
ROM
Proteases
Thromboxane
LTB4
Growth factors Trefoil proteins
Resting Mo
Naive T cell
Activated PMN
Pro-inflammatory cytokines
IL-2
CD4 T cell
Selectins
B cell
Activated Mo
CD40L
PMN
TNF-
CD40
CD4 T cells and T-helper subsets
IL-12/23
IL-4
IL-8
Integrins
IL-1
ICAM-1
Monocyte
Adhesion and recruitment
IFN-
MAdCAM-1
Th1
Th2
IL-10
Lymphocyte
Sands BE. Inflammatory Bowel Dis.1997395.
8
Biologics Under Investigation in IBD

• 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), ?4?7
• 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)

• Anti-TNF Strategies
• Chimeric antibodies
• Humanized antibodies
• Fully human antibodies
• Antibody fragments
• Antisense compound
• TNF-BP1
• Thalidomide

9
Crohns Disease 1960s historical perspective
10
Biologic era in IBD managementHealing of
refractory ulceration/fistula with Infliximab
van Dullemen HM et al. Gastroenterology.
1995109129.
Present DH, et al. N Engl J Med.
199934013981405.
11
Construct of Anti-TNF-a Biologic Agents
12
Clinical Response and Remission with Infliximab
Plt0.001
Plt0.001
Patients
Targan SR, et al. N Engl J Med.
19973371029-1035.
13
ACCENT I Maintenance Infliximab for CD in
Randomized Responders (N 335)
Clinical Remission
p 0.002
60
p 0.003
40
Week 30
45
39
20
25
Placebo
Infliximab 5 mg/kg
0
Infliximab10 mg/kg
Week 54
38
28
14
Hanauer SB, et al. Lancet. 200235915411549.
14
CLASSIC I Results at Week 4

70


59
59

60
54
50
50

40
37
40
36
34
of Patients
30
24
25
18
20
12
10
0
Clinical Remission
Clinical Response ?70
Clinical Response ?100
p lt 0.05 vs placebo p 0.001 vs placebo p
0.007 vs placebo. Clinical remission CDAI lt
150 Clinical response ?70 or ?100 is a 70 or
100 point decrease in CDAI from
baseline.Hanauer S, et al. Gastroenterology.
200613032333.
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CHARM Clinical Remission of CD Over Time With
AdalimumabRandomized Responders (n 499)
Placebo
Adalimumab 40 mg EOW
Adalimumab 40 mg weekly

60



47
41

50









40





40
of Patients
30
36
20
17
10
12
0
56
26
0
10
20
30
40
50
60
Weeks
p lt 0.001 vs placebo p 0.005 vs placebo.EOW
every other week remission CDAI lt
150.Colombel JF, et al. DDW 2006, Abstract 686d.
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PRECiSE 2 Clinical Response and Remission at
Week 26 in Patients With CD Randomized
Responders (N 428)
Placebo q 4 wk (N 212)
Certolizumab pegol 400 mg q 4 wk (N 216)
80

60

63
48
of Patients
40
36
29
20
0
Clinical Response (decrease in CDAI 100
points)
Clinical Remission (CDAI lt 150 points)
p lt 0.001 vs placebo.Schreiber S, et al. Gut.
200554(Suppl VII)A82.
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Overview of Results of Long-Term Anti-TNF Trials
Week 2630
ACCENT 1 n 113
CHARM n 172
PRECiSE 2 n 215
100
Certolizumab pegol 400 mg every 4 weeks
Infliximab 5 mg/kg
Adalimumab 40 mg EOW
80
Placebo
Placebo
Placebo

62.8


60
52.0
51.0

47.9
Patients ()


40.0
39.0
36.2
40
28.6
27.0
26.0
21.0
17.0
20
0
Response Remission Response
Remission Response Remission
Remission CDAI score lt 150 Decrease in CDAI
score of ? 70 points and ? 25 Decrease in CDAI
score of ? 100 points
Hanauer SB et al. Lancet. 200235915411549. Col
ombel J et al. Gastroenterology.
2006131950. Schreiber S et al. Gut.
200554(Suppl VII)A82.
P .0002 P .003 P lt .001
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Infliximab therapy for UC
ACT 1
Rutgeerts P et al. N Engl J Med.
2005353(23)2462-2476.
19
Anti-IL-12 (ABT-874) in Active Crohns Disease
Patients With Clinical Response(Decrease in CDAI
?100)
Patients With Clinical Remission (CDAI lt150)
P0.032
P0.033
70
70
75
60
P0.066
69
60
50
P0.066
50
50
40
40
Percentage of Subjects
Percentage of Subjects
38
30
30
20
20
25
10
10
13
0
0
0
0
Week 7
Week 19
Week 7
Week 19
Placebo
3 mg/kg
Placebo
3 mg/kg
Mannon PJ et al. N Engl J Med. 20042512069?2079.
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Adhesion and Recruitment
Mucosal and Inflammatory Zip Codes
Chemokines
Leukocyte
VCAM-1
VascularEndothelium
MAdCAM-1
21
Construct of Natalizumab
Natalizumab Humanized mAb against
a4-integrins Human IgG4 framework with CDRs
grafted from murine antibodies
22
Natalizumab as Maintenance Therapy for Crohns
Disease ENACT-2 Trial
Response 70-point decrease in CDAI
RemissionCDAI 150
Natalizumab 300 mg Placebo
Patients ()
P lt .05
P lt .05
P lt .05
P lt .05
Sandborn WJ et al. N Engl J Med.
20053531912?1925.
23
Mean CDAI Scores Over 24 Months of Continuous
Treatment With Natalizumab
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)
Mean CDAI Score
27
24
21
18
12
9
6
3
OLEBaseline
ENACT-2Baseline
ENACT-1Baseline
Months
Panaccione R, et al. Am J Gastroenterol.
2006101(Suppl 2)S450. Abstract 1152.
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Summary Anti-TNF-a Therapy in IBD

• Effective therapy for induction and remission of
  active CD and fistulizing CD (infliximab)
• In the current management paradigm, reserved for
  patients with more severe disease
• Mucosal healing with long-term therapy
  (infliximab)

• Safety issues
• Infections
• Reactivation of latent TB
• Possible lymphoma risk
• Hepatosplenic T-cell lymphoma in young patients
  on infliximab plus concomittant azathioprine (n
  8)
• Immunogenicity
• Infliximab Infusion reactions contributing to
  loss of response
• Other anti-TNF-a agents Immunogenicity occurs
  significance is uncertain

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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 aß 5 ?d
• 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.
200540220222 Centocor press release, May
2006.
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Natalizumab Safety

• Most common AEs ( 10 of patients) were
  headache, nausea, and nasopharyngitis
• 814 of patients discontinued treatment due to
  AEs
• 3 cases of progressive multifocal
  leukoencephalopathy (PML) have been reported
• 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 gt 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 0.22.8 per
  1000)3
• Incidence in CD 1 in 1275
• Incidence in MS 2 in 2248

1. Sandborn WJ, et al. N Engl J Med.
200535319121915 2. Sandborn WJ, et al. DDW
2006, Abstract 4923. Yousry T A, et al. N Engl
J Med. 2006 354924933.
28
II. Step-up vs Top-down Approach
Hommes D, Baert F, van Assche G, et al.
Gastroenterology. 2006130(suppl 2)A108-A109.
29
New Approaches to Therapeutic Intervention in
Crohns Disease?The Step-up vs Top-down
Trial
IFX AZA
IFX
AZA/MTX
(episodic) IFX
Corticosteroids
Corticosteroids
Corticosteroids
AZA, azathioprine IFX, infliximab MTX,
methotrexate.
30
Assessment of Top-Down Versus Step-Up Strategies
in CD
CDAI lt 150 Points AND No Steroids AND No Surgery

• Newly diagnosed CD of lt 4 years duration (N
  129)
• Naive to immunomodulators and biologics

IFX AZA
(episodic) IFX


Top-down(n 65) IFX (Wk 0, 2, 6) AZA
Steroids
of Patients
Co-primary endpoints6 12 months
Weeks
P lt 0.01 P lt 0.05
Hommes D, et al. DDW 2006, Abstract 749.
31
Top-Down Versus Step-Up TrialClinical Results at
2 Years
Reduction and Disappearance of Ulcers
Step-up
Top-down
100
Patients Receiving Infliximab
p lt 0.001
100
88
of Patients
50
p lt 0.001
80
71
0
60
100
of Patients
47
40
30
of Patients
50
Patients Receiving Immunosuppressants
20
0
0
0
20
40
60
80
100
Reduction
Disappearance
Weeks
Hommes D, et al. DDW 2006, Abstract 749. DHaens
GR, et al. DDW 2006. Abstract 764.
32
What does mucosal healing in Crohns disease mean
clinically?
33
Endoscopic Healing and Reduced Hospitalizations
and Surgeries Infliximab maintenance for Crohns
disease
Infliximab ACCENT I
Patients with no healing (n74)
50
46
Patients with healing at 1 visit (10 or 54
wk) (n16)
40
Patients with healing at both 10 and 54 wks
30
Rate of Hospitalizations and Surgeries ()
25
20
8
10
(4)
(34)
(6)
0
0
0
0
Hospitalization
Surgery
Rutgeerts P et al. Gastroenterology.
2002123(suppl)43.M2138.
Number per 100 patients
34
Weighing the Value of Top-Down Therapy
Benefits
Disadvantages

• Maintenance of remission
• Improved function and QOL
• Early promotion of mucosal healing to prevent
  complications

• Side effects
• Cost
• Majority of patients may not require more potent
  treatments initially
• Under-treatment of most severe patients with
  episodic strategy?

Lichtenstein GR, et al. Inflamm Bowel Dis.
200410S2S10.Caprilli R, et al. Digestive
Liver Dis. 200537973979.
35
III. Is Top-down treatment a good idea for
managing all patients with Crohns disease?
36
Natural History of IBD

• Heterogeneity of Crohns disease.
• Severe CD phenotypes.

37
1998 - Tale of 2 boys

• Patient -2
• 13 year old boy with weight loss and diarrhea
• Diagnosis Crohns disease of ileum and colon
• Treated with steroids immune modifiers

• Patient -1
• 12 year old boy with weight loss and diarrhea
• Diagnosis Crohns disease of ileum and colon
• Treated with steroids immune modifiers

With permission, S Kugathasan MD
38
2003 - Tale of 2 boys

• Patient -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 Crohns
• 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
  future

With permission, S Kugathasan MD
39
Probability of Surgery for Crohns Disease
Munkholm P et al. Gastroenterology.
199310517161723.
40
Probability of Surgery for Crohns Disease
Can we predict these subgroups at the time of
diagnosis?
Must we wait to have multiple surgeries to
define severe disease?
Munkholm P et al. Gastroenterology.
199310517161723.
41
Predictability of the postoperative course of
Crohn's disease.

• Rutgeerts P, Geboes K, Vantrappen G, Beyls J,
  Kerremans R, Hiele M.
• Gastroenterology. 199099956-963

42
Rutgeerts Endoscopic Scoring System neoterminal
ileum
I,3
I,1
I,4
43
Actuarial analysis of symptomatic recurrence in
patients stratified according to severity of
endoscopic lesions
Rutgeerts P, et al. Gastroenterology.
199099956-963
44
Actuarial analysis of symptomatic recurrence in
patients stratified according to severity of
endoscopic lesions
45
Rationale for disease modifying therapy in IBD.
What can our pediatric gastroenterology
colleagues teach us about IBD?
46
Early disease Inflammation
Late disease Tissue remodeling
Time
47
Efficacy of AZA as Maintenance Therapyin
Patients with Active CD
100
AZA 2.5 mg/kg/d (n33) Placebo (n30)
80
60
Patients Not Failing Trial
40
P0.001
20
0
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Duration of Trial (months)
Remission induced by prednisolone tapered over
12 wk
Candy S, et al. Gut. 199537674.
48
Duration of Remission With 6-MP in Children With
Newly Diagnosed CD
1.00 0.75 0.50 0.25 0.00
6-MP Controls
Fraction in Remission
0 100 200 300 400 500 600
P lt .007
Days from Start of Remission
Markowitz J et al. Gastroenterology. 2000119895.
49
REACH Response and Remission Rates to Infliximab
in Pediatric Patients With Moderate-to-Severe CD
Clinical Response
Clinical Remission
ACCENT I Week 54
60
60
p 0.0001
p 0.007
40
40
Placebo
36
Infliximab 5 mg/kg
28
20
20
15
14
0
0
Hanauer SB, et al. Lancet. 200235915411549.
50
Changes in PCDAI Score Following Infliximab
Infusion (10 Weeks)
100
94 response rate
80
60
PCDAI Score
40
20
0
0
2
4
6
8
10
12
Weeks Following Infliximab Infusion
Kugathasan S et al. Am J Gastroenterol.
2000953189.
51
Mucosal and histologic healing after infliximab
in Early CD
52
Duration of Response Following Initial Infliximab
Infusion Early vs. Late CD
Early CD (n6)
100
Late CD (n8)
75
Patients Without Relapse
50
25
0
0
8
16
24
32
40
56
64
48
Weeks Following Infliximab Infusion
Kugathasan S et al. Am J Gastroenterol.
2000953189.
53
PRECiSE 2 Week 26 Clinical Response or Remission
by Duration of Crohns Disease
Response
Remission
100

90
Certolizumab

Placebo
80
75

68

62
57
60
55

50
47
Patients ()
44
37
37
36
36
40
33
29
24
20
0
lt 1
1 to lt 2
2 to lt 5
5
lt 1
1 to lt 2
2 to lt 5
5
n 54 42 100
229 54
42 100 229
Duration of Crohns Disease (years)
P lt 0.01 P lt 0.05 P lt 0.001 vs
placebo.Sandborn WJ, et al. Am J Gastroenterol.
2006101(Suppl 2)S394. Abstract 1109.
54
Biologic induction for all IBD patients implies
episodic dosing for those who will require
longterm maintenance.
Why is episodic dosing of biologic therapy
problematic in IBD?
55
Serum Concentrations of InfliximabAll
Randomized Patients
Maintenance Treatment
56
Antibodies to Infliximab Through Week 54

• 14 of patients were antibody to infliximab ()

57
Outcome of 86 infliximab second infusions
20
Acute systemic reaction
18
16
Delayed systemic reaction
14
12
number of patients
10
8
6
4
2
0
0
10
20
30
40
50
60
70
80
90
100
110
120
130
number of weeks between 1st and 2nd infusions of
infliximab
Kugathasan S et al. Am J Gastroenterol. 2002 97
1408-14.
58
Analysis of longterm infliximab performance in
Crohns disease

• 2nd Analysis Last maintenance infusion

Both groups received 24 months maintenance
Mean 40 months
Mean 50 months
start infliximab
last infliximab
59
Fewer patients hospitalized undergoing surgery
on SCHEDULED infliximab
Past Episodic (n24)
Scheduled (n28)
p NS
p NS
70
61
58
60
46
46
50
of Patients
40
30
20
10
0
Hospitalization
Surgery
Before infliximab Therapy
60
Fewer TOTAL hospitalizations surgeries on
scheduled infliximab

Past Episodic (n24)
Scheduled (n28)
p NS
p NS
60
55
55
50
40
Number of Events
30
17
20
14
10
0
Hospitalization
Surgery
Before Infliximab Therapy
61
IV. A rational approach for biologic therapy in
IBD
62
Crohns disease - medical management
algorithm No partial obstruction or abscess
detected
Moderate
Severe
Mild
5-ASA, Budesonide or antibiotics
unable to taper Corticosteroids
Corticosteroid taper
AZA/6MP/MTX to induce/ maintain remission
No
Inadequate response to AZA/6MP/MTX
Yes
breakthrough
Infliximab or adalimumab maintenance
AZA/6MP/MTX maintenance
Surgical patients
63
Summary and conclusions - I

• Multiple biologic agents targeting TNF-?,
  IL-12/23 and ?4 integrin are being developed for
  IBD.
• 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.

64
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 IBD subgroup.

65

• Acknowledgments
• MCW IBD Center
• Mazen Issa, M.D.
• Dawn B. Beaulieu, M.D.
• Jasmohan Bajaj, M.D., M.S.
• Kia Saeian, M.D., M.S.
• Ashwin N. Ananthakrishnan, M.D., M.P.H.
• Lydia Rosenbaum
• Josh F. Knox, P.A.-C.
• Sue Skaros, P.A.-C.
• Sarah Lundeen, A.P.N.P.
• Sheila Thierfelder, C.C.R.C.
• Jeanne Emmons, R.N.
• Victoria Nelson
• Heather Brandenburg
• Gary Sudakoff, M.D.
• Hitoshi Ogawa, M.D., Ph.D.

University of Maryland Raymond K. Cross ,
M.D. Crohns and Colitis Foundation of
America National Institutes of Heath
NIDDK Digestive Disease Center MCW Proctor
Gamble Pharmaceuticals
66
Estimate of Work Capacity10 Years Following IBD
Diagnosis
Patients
Years
Binder V et al. Gut. 198526146.
67
Rates of early adverse reactions in patients with
autoimmune hepatitis and Crohns disease
p 0.008
29
5
ADVERSE REACTIONS NO ADVERSE REACTIONS
AUTOIMMUNE HEPATITIS
CROHNS DISEASE
JS Bajaj et al. Am J Gastroenterol 2005 100
1121-5.
68
ACCENT II Cumulative Number of Surgeries Over
Time in Responders
Infliximab 5 mg/kg maintenance (n 96)
Placebo maintenance (n 99)
125
100
75
Cumulative Number of Surgeries Procedures
50
25
Randomization
0
0
2
6
14
22
30
38
46
54
Weeks
Lichtenstein GR, et al. Gastroenterology.
2005128862869.
69
Natalizumab as Induction Therapy for Crohns
Disease ENACT-1 Trial
P .051
Natalizumab (n 724)
Natalizumab (n 724)
56
49
Patients with remission ()
Patients with response ()
Placebo (n 181)
Placebo (n 181)
Primary endpoint
Week
Week
Sandborn WJ et al. N Engl J Med.
20053531912?1925.
70
Anti-Interleukin 12 (ABT-874) in Active Crohns
Disease
Response( 100-point decrease in CDAI)
Remission(CDAI 150)
Placebo (n 8) 1 mg/kg (n 15) 3 mg/kg (n
16) Treatment period
Patients ()
Patients ()
Week
Week
Mannon PJ et al. N Engl J Med. 20042512069?2079.