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

2 Back up slides shown

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

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

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

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

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 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 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

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) /97 (44)32/97 (33)0.106 Remission41/162 (25)25/153 (16) /97 (28)15/97 (15)0.039 Maintenance (CD303) (Efficacy Population) 3 Response58/106 (55)20/110 (18)< /62 (52)14/60 (23)0.002 Remission32/79 (41)12/77 (16)< /51 (37)6/43 (14) 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 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 CD303: Response and Remission at Months 6 and 12 Tertiary Endpoints Patients (%) Response Remission P ≤ 0.001

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 On immuno- suppressants No immuno- suppressants Unresponsive Intolerant TNF-F ITT Log Odds Ratio

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