Efficacy of Natalizumab in Crohns Disease

1
Efficacy of Natalizumab in Crohns Disease

• Stephen Jones, MBBS
• Director, Clinical Development

2
Natalizumab for the Treatment of Crohns Disease

• Mechanism of action of natalizumab
• Treatment objectives for Crohns disease, and the
  clinical trial tools used to evaluate them
• Efficacy of natalizumab in the Phase III clinical
  development program
• Induction of response (CD301, CD307)
• Maintenance of response (CD303)
• Summary of Efficacy

3
Integrins Mediate Leukocyte Adhesion During
Inflammation
VCAM
4
Natalizumab Inhibits the Trafficking of
Leukocytes into Inflamed Tissues
5
Crohns Disease Treatment Objectives

• Induce response and remission
• Maintain response and remission
• Reduce steroid use
• Improve quality of life

6
Outcomes Measured inCD Clinical Trials

• Crohns Disease Activity Index (CDAI)
• Primarily based on
• Subject completed diary, recording bowel
  activity, abdominal pain and general well-being
• Physician assessment including weight and
  hematocrit
• Score range 0-600
• Moderate-to-severely active 220-450
• Clinical response 70 point reduction in CDAI
  from baseline value
• Clinical remission lt 150 on CDAI

7
Additional Outcomes Measured inCD Clinical Trials

• Inflammatory Bowel Disease Questionnaire (IBDQ)
• Disease-specific quality of life questionnaire
• Total scale score ranges from 32 (worst) to 224
  (best)
• A score of 170 equates to clinical remission
• Short Form 36 (SF-36)
• General quality of life questionnaire
• Steroid sparing
• Proportion of patients discontinuing steroids at
  a particular time-point
• C-Reactive Protein (CRP)
• Objective marker of inflammation
• Change over time

8
Clinical Development Program in CD
Phase 2 Program
CD202 Induction Study
CD201 Pilot Study
Phase 3 Program
CD301 Induction Study 12 weeks(905 subjects)
CD303 Maintenance Study 12 months (428 subjects)
CD307 Induction Study 12 weeks (509 subjects)
CD351 Open-label 2-year safety study (1100
subjects in total)
9

• Induction of response/remission in patients with
  moderately to severely active Crohns disease

CD301
10
CD301 Study Design
905 patients with moderate to severely active
Crohns disease (CDAI  220 to  450)
905 patients with moderate to severely active
Crohns disease (CDAI ? 220 to ? 450)
41 Natalizumab (N724) Placebo (N181)
41 Natalizumab (N724) Placebo (N181)
WEEK
0
4
8
-2
12
20
10
6
2
R
R
R
R
R
R
Screening Phase (1-2 Wks)
Follow-up Phase (8 Wks) or entry in CD303
Treatment Phase (12 Wks)
R Patient Randomization
11
CD301 Patient Disposition
12
CD301 Baseline Characteristics
13
CD301 Response ( 70 Reduction in CDAI)Primary
Outcome Week 10
70
Placebo (N181)
65
300 mg (N724)
61
P0.051
58
60
57
56
53
55
51
51
50
49
Patients ()
50
45
45
40
40
33
35
30
Week 2
Week 4
Week 6
Week 8
Week 10
Week 12
14
CD301 Response for Patients with Elevated
Baseline CRP Post Hoc Analysis
P0.007
Patients ()
15
CD307

• Induction of response/remission in patients with
  moderately to severely active CD and elevated CRP

16
CD307 Study Design
509 patients with moderate to severely active CD
(CDAI  220 to  450) and elevated serum CRP (gt
2.87 mg/L)
11 Natalizumab (N259) Placebo (N250)
12
12
0
4
8
-2
0
4
8
-2
0
4
8
-2
0
4
8
-2
0
4
8
-2
-2
20
0
4
8
WEEK
R
R
R
R
R
R
Follow-up Phase (8 Wks)
Screening Phase (1-2 Wks)
Treatment Phase (12 Wks)
R Patient Randomization
R Patient Randomization
R Patient Randomization
R Patient Randomization
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CD307 Objectives and Endpoints

• Primary endpoint response ( 70 point reduction
  in CDAI from baseline) at weeks 812
• Secondary endpoints
• Remission (lt150) at weeks 812
• Response at week 12
• Remission at week 12

18
CD307 Patient Disposition
19
CD307 Baseline Characteristics
20
CD307 Response ( 70 Point Reduction in
CDAI)Primary Outcome (Weeks 8 12)
70
Placebo (n250)
Natalizumab (n259)
60
60
56
Plt0.001
51
48
50
44
40
40
37
Patients ()
32
30
20
10
0
Week 4
Week 12
Weeks 8 12
Week 8
21
CD307 Remission (CDAI lt150)Secondary Outcome
(Weeks 8 12)
45
Placebo (n250)
38
40
Natalizumab (n259)
35
32
P0.002
30
26
25
24
25
Patients ()
21
20
16
16
15
10
5
0
Week 4
Week 8
Week 12
Weeks 8 12
22
CD307 Median CRP Over Time
16
14.2
13.5
14
12
12.7
10
8
Median CRP
6
6.5
Placebo
4
Natalizumab
2
0
Week 0
Week 4
Week 8
Week 12
23
CD307 ITT vs CD301 Elevated CRP
PopulationConsistent Induction of Response At
Weeks 8 12
P0.002
Plt0.001
Patients ()
N250
N259
N134
N526
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CD307 Response (Weeks 812) Patients Failed
Other CD Therapies vs ITT
Natalizumab
Placebo
Plt0.001
P0.003
P0.007
Plt0.001
N168 N187
N172 N182
N250
N259
N83 N89
IMM Immunosuppressants
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Summary of Induction of Response/Remission

• Induced response/remission in patients with
  objective evidence of inflammation
• Induced response/remission consistently across
  subgroups of patients who failed other therapies
• Steroids
• Immunosuppressants
• TNF-? inhibitors
• Natalizumab is an effective treatment for
  patients with moderately to severely active
  Crohns disease

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CD303

• Maintenance of clinical response/remission

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CD301/CD303 Study Flow Chart
CD301 Moderately to severely active disease (CDAI
220, 450) Treatment Phase (3 months)
CD303 Responders with mildly active disease (70
pt ? CDAI lt220, 150) OR remission (lt150)
11 Natalizumab 300 mg Placebo
Wk10
12
0R
1
11
2
3
4
5
6
7
8
9
10
MONTH
CD303
R Randomization
Treatment Phase (12 months)
28
CD303 Patient Disposition
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CD303 Primary Outcome

• Primary outcome proportion () of patients who
  did not lose response (CDAI 220 and increase in
  CDAI 70) and no rescue at any assessment
  through month 6
• Contingent Primary proportion () of patients
  maintaining remission (CDAI lt 150) at any
  assessment through month 6

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CD303 Sustained ClinicalResponse at Every
Assessment
100
P lt 0.001
80
61
54
60
Patients ()
40
28
20
Natalizumab (n168)
20
Placebo (n170)
Primary endpoint
0
0
1
2
3
4
5
6
7
8
9
10
11
12
?
Time (months)
Start CD303
31
CD303 Sustained Clinical Remission at Every
Assessment
100
80
P lt 0.001
60
Patients ()
44
39
40
26
15
Natalizumab (n130)
20
Placebo (n120)
Contingent primary endpoint
0
0
1
2
3
4
5
6
7
8
9
10
11
12
?
Time (months)
Start CD303
32
CD303 Mean Total IBDQ Score Over Time
200
190
Plt0.001
182
180
Remission
170
160
Mean Total IBDQ Score
150
140
Natalizumab Responders
130
Natalizumab
Placebo
124
120
-3
0
3
6
9
12
Baseline CD301
Start CD303
Time (months)
Irvine EJ, Gastroenterology. 1994.
33
CD303 Steroid Withdrawal

• Study CD303 was also designed to investigate
• Ability of natalizumab maintenance treatment to
  eliminate oral steroid use
• Number of subjects with a steroid-free remission
• Subjects followed a protocol-defined steroid
  withdrawal algorithm at Week 10 of CD301 and
  continued during CD303

34
CD303 Proportion of Subjects Withdrawn from
Steroids Month 6 and Month 12
Steroid Elimination
Steroid Free Remission
Plt0.001
P0.014
Patients ()
35
CD303 Secondary Endpoints
36
CD303 Response and RemissionWithout Concomitant
Immunosuppressants
Response
Remission
Placebo n111
Natalizumab n106
Month 12
Month 12
Month 6
Month 6
37
CD303 Anti-TNF-? Failure Population
Response
Remission
Patients ()
38
Summary Efficacy of Natalizumab for Crohns
disease

• Induction
• Demonstrated efficacy for response and remission
  in patients with an objective marker of
  inflammation
• Demonstrated efficacy in patients who failed
  therapy with corticosteroids, with
  immunosuppressants and patients who failed
  therapy with an anti-TNF-a inhibitor
• Maintenance
• Demonstrated sustained response and remission
  with maintenance treatment
• Significant QoL improvements are maintained with
  natalizumab
• Significant steroid-sparing effect
• Concomitant immunosuppressants were not required
  to maintain long-term efficacy