1. 1 Benefit-Risk of Crohn’s Disease Therapeutics William Sandborn, MD Mayo Clinic and Mayo College of Medicine Rochester, MN, USA

2. 2 Back up slides shown

3. 3 CD303: Response and Remission at Month 6 Percent Response Remission P ≤ 0.001 N=40 N=32 P ≤ 0.001 P = 0.006 P = 0.016 N=171 N=168 CD303

4. 4 CD303: Response and Remission at Month 12 Percent Response Remission P ≤ 0.001 P = 0.006 P ≤ 0.001 P = 0.006 N=171 N=168 N=40 N=32 CD303

5. 5 CD307: Response by Varying CRP Cut-Point CRP Cutoff (mg/dl) Placebo Response (%) Natalizumab Response (%) P-value 2.87 (n=477) 3249<0.001 5 (n=415) 3251<0.001 10 (n=283) 2953<0.001 15 (n=235) 3052<0.001 20 (n=187) 2853<0.001 25 (n=147) 2356<0.001 50 (n=51) 13560.003 CD307

6. 6 CD301:  CRP - Response in patients with disease confined to the ileum Patients (%) Time (weeks)

7. 7 CD301: Week 10 Response by Baseline CRP ITT population - LOCF p<0.05 for all thresholds but CRP=9, 11 Patients in Response (%) C-Reactive Protein Baseline Threshold Level (mg/L)

8. 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

9. 9 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. 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

11. 11 Table 13 Efficacy of Natalizumab: Effect of Concomitant Immunosuppressants No Immunosuppressants at Baseline 1 Immunosuppressants at Baseline 1 n/N (%)NatalizumabPlacebop-valueNatalizumabPlacebop-value Induction (CD307) (ITT Population) 2 Response81/162 (50)49/153 (32)0.00143/97 (44)32/97 (33)0.106 Remission41/162 (25)25/153 (16)0.05227/97 (28)15/97 (15)0.039 Maintenance (CD303) (Efficacy Population) 3 Response58/106 (55)20/110 (18)<0.00132/62 (52)14/60 (23)0.002 Remission32/79 (41)12/77 (16)<0.00119/51 (37)6/43 (14)0.014 1.Patients on immunosuppressants at baseline had to be given a stable dose of immunosuppressants (azathioprine, 6-MP or methotrexate) during induction and maintenance 2. 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

12. 12 CD303: Response and Remission at Months 6 and 12 Tertiary Endpoints Patients (%) Response Remission P ≤ 0.001

13. 13 CD307: Response in Anti-TNF Failure Subgroups (Weeks 8 +12) Placebo n/n (%) Natalizumab n/n (%) OR ITT81/250 (32)124/259 (48)1.9 All TNF - F12/83 (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 Favors Placebo Favors Natalizumab 0.1 1 10 100 On immuno- suppressants No immuno- suppressants Unresponsive Intolerant TNF-F ITT Log Odds Ratio

14. 14 CD301:  CRP - Response for Patients with No response to initial TNF  therapy Patients (%) Time (weeks)