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Benefit-Risk of Crohn’s Disease Therapeutics

William Sandborn, MDMayo Clinic and

Mayo College of MedicineRochester, MN, USA

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Back up slides shown

3CD303: Response and Remission at Month 6

37

30 30

18

67

56 55

47

0

10

20

30

40

50

60

70

80

Overall TNF-F Overall TNF-F

Placebo

Natalizumab

Pe

rce

nt

Response Remission

P ≤ 0.001

N=40 N=32 N=40 N=32

P ≤ 0.001

P = 0.006

P = 0.016

N=171 N=168 N=171 N=168

CD303

4CD303: Response and Remissionat Month 12

2420 22

18

59

5055

47

0

10

20

30

40

50

60

70

80

Overall TNF-F Overall TNF-F

Placebo

Natalizumab

Pe

rce

nt

Response Remission

P ≤ 0.001 P = 0.006 P ≤ 0.001

P = 0.006

N=171 N=168 N=171 N=168N=40 N=32 N=40 N=32

CD303

5CD307: Response by Varying CRP Cut-Point

CRP Cutoff (mg/dl)

Placebo Response (%)

Natalizumab Response (%)

P-value

2.87 (n=477) 32 49 <0.001

5 (n=415) 32 51 <0.001

10 (n=283) 29 53 <0.001

15 (n=235) 30 52 <0.001

20 (n=187) 28 53 <0.001

25 (n=147) 23 56 <0.001

50 (n=51) 13 56 0.003

CD307

6CD301: CRP - Response in patients with disease

confined to the ileum

2730

33

37

50 50

39

44

5351 52

56

20

25

30

35

40

45

50

55

60

2 4 6 8 10 12

Placebo (n=30)

Natalizumab (n=135)

Pa

tie

nts

(%

)

Time (weeks)

7CD301: Week 10 Response by Baseline CRP

ITT population - LOCF

35

40

45

50

55

60

65

0 5 10 15 20 25 30

NatalizumabPlacebo

p<0.05 for all thresholds but CRP=9, 11

Pa

tient

s in

Res

pon

se (

%)

C-Reactive Protein Baseline Threshold Level (mg/L)

8

Pulmonary Aspergillosis 75-year-old male with Crohn’s disease had received

10 infusions of natalizumab

– Concomitant NSAID use and high-dose steroids in tapering regimen

Perforated duodenal ulcer, severe GI hemorrhage, and peritonitis 1 month following last dose of natalizumab

Spent several weeks in hospital, including ICU

– CT of lungs showed bilateral infiltrates

– Sputum culture revealed Aspergillus sp

Patient developed multi-organ failure and died 3 months after last dose of natalizumab

CD301 / 303 / 351

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Pneumocystis carinii Pneumonia 69-year-old male with Crohn’s disease had received 34

infusions of natalizumab

History of cirrhosis due to nonalcoholic steatohepatitis with varices, portal hypertension, splenomegaly, and ascites

– Developed hepatic encephalopathy 1 month after last dose of natalizumab

– Natalizumab stopped; patient treated and recovered

Hospitalized 1 month later with hepatic encephalopathy, acute renal failure, and anemia

– Treated in ICU, intubated, and transfused

– Sputum culture revealed PCP

– Developed multi-organ failure and died

CD301 / 303 / 351

10

Burkholderia cepacia Pneumonia 62-year-old woman with CD, type II DM, HT, and

tobacco use– Received 3 infusions of natalizumab

– Developed non-productive cough with dyspnea

– Cardiomegaly, hydrothorax, pulmonary vessel congestion with atelectasis

• Diagnosed and treated as CHF

– Bronchoscopic lavage revealed Burkholderia cepacia

• Treated with antibiotics

11Table 13 Efficacy of Natalizumab: Effect of

Concomitant Immunosuppressants

No Immunosuppressants at Baseline1

Immunosuppressants at Baseline1

n/N (%) Natalizumab Placebo p-value Natalizumab Placebo p-value

Induction (CD307) (ITT Population)2

Response 81/162 (50) 49/153 (32) 0.001 43/97 (44) 32/97 (33) 0.106

Remission 41/162 (25) 25/153 (16) 0.052 27/97 (28) 15/97 (15) 0.039

Maintenance (CD303) (Efficacy Population)3

Response 58/106 (55) 20/110 (18) <0.001 32/62 (52) 14/60 (23) 0.002

Remission 32/79 (41) 12/77 (16) <0.001 19/51 (37) 6/43 (14) 0.0141.Patients on immunosuppressants at baseline had to be given a stable dose of immunosuppressants (azathioprine, 6-MP or methotrexate) during induction and maintenance2. Proportion of patients in response (or remission) at both Weeks 8 and 12 3. Proportion of patients in response (or remission) at Month 3 who maintained response (or remission) through 12 additional months of therapy to Month 15.p-values are from logistic regression Source: CD307, Tables 37 and 38; CD303, Section 15.2, Tables 2.16c and 2.17c

12CD303: Response and Remission at Months 6 and 12Tertiary Endpoints

37

24

30

22

67

5955 55

0

10

20

30

40

50

60

70

80

Month 6 Month 12 Month 6 Month 12

Placebo (n=170) Natalizumab (n=168)

Pa

tie

nts

(%

)Response Remission

P ≤ 0.001P ≤ 0.001P ≤ 0.001P ≤ 0.001

13CD307: Response in Anti-TNF Failure Subgroups

(Weeks 8 +12)

Placebon/n (%)

Natalizumabn/n (%)

OR

ITT 81/250 (32) 124/259 (48) 1.9

All TNF - F 12/83 (14) 34/89 (38) 3.7

Intolerant 4/38 (11) 16/36 (44) 6.7

Unresponsive 8/45 (18) 18/53 (34) 2.4

w/o immuno-suppressants

7/51 (14) 22/54 (41) 4.5

with immuno-

suppressants

5/32 (16) 12/35 (34) 2.8

FavorsPlacebo

Favors Natalizumab

0.1 1 10 100

On immuno-suppressants

No immuno-suppressants

Unresponsive

Intolerant

TNF-F

ITT

Log Odds Ratio

14CD301: CRP - Response for Patients with

No response to initial TNF therapy

8

15 15

23 23

15

26

3840

48

38

49

0

5

10

15

20

25

30

35

40

45

50

2 4 6 8 10 12

Placebo (n=13)

Natalizumab (n=55)

Pa

tie

nts

(%

)

Time (weeks)