1. CES-1 InterSePT International Suicide Prevention Trial InterSePT Study Design Efficacy and Safety Results Rocco Zaninelli, MD Executive Director Clinical Research and Development Novartis Pharmaceuticals Corporation C

2. CES-2 InterSePT: Overview of Presentation  Study title and objective  Study design  Statistical methods  Results  Examination of referral process  Conclusions from InterSePT C

3. CES-3 International Suicide Prevention Trial (InterSePT): Objective A prospective, randomized, international, parallel-group comparison of Clozaril ® /Leponex ® versus Zyprexa ® in the reduction of suicidality in patients with schizophrenia or schizoaffective disorder who are at risk for suicide  Open-label study  Specific assessments were blinded C

4. CES-4 Study Design C

5. CES-5 RANDOMIZATIONRANDOMIZATION Clozaril ® Zyprexa ® Study Schematic 2-wk intervals §Transition from previous medication ends at Week 4. C CSR pp 26, 32 200 to 900 mg/day 5 to 20 mg/day W 104 W 26W 4 Baseline Starting dose during transition § 12.5 mg BID 5 mg OD 1-wk intervals

6. CES-6 Patient Selection Criteria Patients with schizophrenia or schizoaffective disorder at high risk for suicide as documented by at least 1 of the following:  Suicide attempt within last 3 years  Hospitalization to prevent suicide in last 3 years  Moderate to severe suicidal ideation with depressive symptoms within 1 week of baseline  Moderate to severe suicidal ideation and self-harm command hallucinations within 1 week of baseline C

7. CES-7 Choice of Comparison Medication  Use of placebo unethical and inappropriate  Use of typical antipsychotic not considered current standard of care  Zyprexa ® – Atypical antipsychotic; pharmacologically similar to Clozaril ®§ – Lower rate of suicidality-related adverse events versus Risperdal ®|| – Effective in psychosis and generally well tolerated – Available in most countries interested in conducting InterSePT C § Bymaster et al, 1996. || Tran et al, 1996; Beasley et al, 1997.

8. CES-8 Rationale for Open-Label Design Blinding would be compromised by  White blood cell count monitoring with Clozaril ®  Different adverse event profiles C

9. CES-9 Type 1 event or Type 2 event Primary Efficacy Endpoint C

10. CES-10 Type 1 Event Definition  A significant suicide attempt or hospitalization due to imminent suicide risk (including increased level of surveillance) as determined by the blinded Suicide Monitoring Board (SMB) C

11. CES-11 Suicide Attempt Definition  Actions committed by a patient either with willful intent or as a response to internal compulsions or disordered thinking that put himself/herself at high risk for death C

12. CES-12 Type 2 Event Definition  Worsening of suicidality as measured by a CGI-SS-BP score of 6 or 7 (“much worse” or “very much worse”) C OR   An implicit worsening of severity of suicidality as indicated by the occurrence of a suicide attempt or hospitalization to prevent suicide (Type 1 event)

13. CES-13 Secondary Efficacy Assessments  Clinical Global Impression of Severity of Suicidality—Blinded Psychiatrist (CGI-SS-BP)  InterSePT Scale for Suicidal Thinking by Blinded Psychiatrist (ISST-BP) §  Positive and Negative Syndrome Scale (PANSS) ||  Calgary Depression Scale (CDS) ¶  Covi Anxiety Scale (Covi) # C § Lindenmayer et al, in press; || Kay et al, 1988. ¶ Addington et al, 1993; # Lipman, 1982.

14. CES-14Database SMBmembers Medical Monitor Data Flow: Determination of Suicide Attempt/Hospitalization to Prevent Suicide CPatient Blinded data Site

15. CES-15 Independent Suicide Monitoring Board (SMB) K. Ranga Rama Krishnan, MB, ChB Professor of Psychiatry and Behavioral Sciences Duke University Medical Center C

16. CES-16 SMB: Members  International experts in psychiatry and suicidology – Ranga Krishnan, MB.ChB (USA)—Chair – Isaac Sakinofsky, MD (Canada) – Hannele Heila, MD (Finland)  Not affiliated with investigative sites  Membership remained constant throughout the trial and each member participated in all meetings C

17. CES-17 SMB: Role  Blinded review of relevant data to determine whether a Type 1 event occurred – All deaths: to determine if cause was suicide – Potential suicide attempts: to determine their potential lethality (ie, true/serious attempts) – Hospitalizations related to suicidal behavior: to determine if caused by imminent risk of suicide C

18. CES-18 SMB: Material Used in Determination of Type 1 Events  Suicide attempt form  Rescue intervention form  Calgary Depression Scale  ISST  Clinical reports  History of suicidal behavior C

19. CES-19 SMB: Cases Reviewed for Determination of Type 1 Events  Potential events reviewed577  SMB-determined Type 1 events483 – Suicide attempts111 – Hospitalizations to prevent suicide372 C

20. CES-20 Suicide Monitoring Board: Summary  Members were independent of any of the sites  Blinded review of every potential Type 1 event  Classification of each event based on a pre-defined process  Determinations of Type 1 events were unanimous C

21. CES-21 Statistical Methods C

22. CES-22 Primary Efficacy Analysis  Time-to-event analysis based on the WLW method § – Used to analyze time-to-multiple-event data – Allows combination of different types of events  For InterSePT, used first Type 1 and first Type 2 event (stratified by country grouping)  WLW method established for revised primary endpoint by protocol amendment §Wei, Lin, and Weissfeld. 1989. C

23. CES-23 Supportive Analyses  Cox’s proportional hazards analysis – Explanatory variables included drug treatment, number of suicide attempts, current substance/alcohol abuse, country grouping, gender, and age groups  Kaplan-Meier estimates of cumulative probabilities  Analysis of clinical variables based on last-observation-carried-forward (LOCF) C

24. CES-24 Sample Size  Statistical assumptions – Randomization ratio 1:1 – Log-rank test with alpha = 5% (2-sided) – Power: 80% – Estimated 45% of Clozaril ® and 55% of Zyprexa ® patients with at least 1 Type 1 event by the end of 2 years – Total of 381 events (762 patients) – Allowing for 15% dropout rate, ~ 900 patients to be randomized C Protocol p. 48

25. CES-25 InterSePT Results Characteristics of Study Population C

26. CES-26 InterSePT Study Centers and Dates 67 centers 11 countries First patient first visitMarch 19, 1998 Last patient last visitFebruary 14, 2001 Database lockJune 9, 2001 3 CSR p. 17 C

27. CES-27 Patient Disposition Patients, n (%) Disposition Clozaril ® Zyprexa ® Screened 1,065 total Randomized (ITT)490(100) 490(100) Treated479(97.8)477(97.3) Completed298(60.8) 302(61.6) Discontinued192(39.2)188(38.4) Complete 1º efficacy data73(14.9) 88(18.0) “True” dropouts119(24.2)100(20.4) CSR table 7-1 C

28. CES-28 Demographics at Baseline Age, yr18 - 32168(34.3)178(36.3) 33 - 44216(44.1)204(41.6)  45106(21.6)108(22.0) Mean age at onset, yr 24.9 ± 8.6 24.4 ± 8.3 Male301(61.4)301(61.4) Race Caucasian356(72.7)337(68.8) Black 65(13.3) 86(17.6) Oriental 6(1.2) 7(1.4) Other 63(12.9) 60(12.2) C Patients, n (%) Clozaril ® Zyprexa ® Demographic parameterN = 490N = 490 Patients, n (%) Clozaril ® Zyprexa ® Demographic parameterN = 490N = 490 CSR T7.4 ITT population.

29. CES-29 Diagnosis and History of Treatment Resistance Diagnosis Schizophrenia300(61.2)309(63.1) Schizoaffective disorder190(38.8)181(36.9) Treatment resistant135(27.6)128(26.1) C Patients, n (%) Clozaril ® Zyprexa ® N = 490N = 490 Patients, n (%) Clozaril ® Zyprexa ® N = 490N = 490 CSR T7.4

30. CES-30 Clinical Characteristics at Baseline Mean ± SD Characteristics Clozaril ® Zyprexa ® CGI-SS-BP § 2.2 ± 1.02.2 ± 1.0 ISST-BP7.4 ± 5.77.3 ± 5.7 Lifetime suicide attempts3.6 ± 7.53.2 ± 4.5 Lifetime hospitalizations3.7 ± 7.73.2 ± 4.8 to prevent suicide PANSS-T84.8 ± 21.1 82.6 ± 20.9 CDS9.8 ± 5.99.9 ± 5.9 Covi Anxiety Scale3.8 ± 2.73.9 ± 2.7 CSR table 7-1 C §2 = Mildly suicidal; 3 = Moderately suicidal.

31. CES-31 Study Discontinuations Patients, n (%) Clozaril ® Zyprexa ® Discontinued forN = 490N = 490 Withdrawn consent 50 (10.2) 49 (10.0) Adverse event41 (8.4)33 (6.7) Lost to follow-up33 (6.7)39 (8.0) Protocol violation29 (5.9)20 (4.1) Administrative reasons23 (4.7)27 (5.5) Death 8 (1.6) 5 (1.0) Unsatisfactory effect on psychosis 5 (1.0) 9 (1.8) Abnormal lab value 2 (0.4) 0 (0.0) Abnormal procedure result 1 (0.2) 0 (0.0) Unsatisfactory effect on suicide risk 0 (0.0) 6 (1.2) Total (380, 39%)192 (39.2)188 (38.4) C CSR T7-1

32. CES-32 Study Medication: Total Daily Dose Clozaril ® Zyprexa ® N = 477N = 477 Mean ± SD274 ± 15517 ± 6 Median26217 Range13 - 7253 - 41 C

33. CES-33 InterSePT Results Efficacy Results Primary Endpoint C

34. CES-34 Patients Experiencing SMB-Determined Type 1 Events: Suicide Attempts and Hospitalizations CSR Table 9-5 C

35. CES-35 Distribution of Patients by Number of Suicide Attempts or Hospitalizations to Prevent Suicide

36. CES-36 Patients Experiencing Type 2 Events: Worsening of Suicidality, Suicide Attempt, Hospitalization to Prevent Suicide CSR Table 9-5 C 120 161 ® ®

37. CES-37 Results of WLW and Cox’s Analyses Hazard ratio 95% CI P value WLW.031 Cox’s proportional hazard analysis § Type 1 0.74 0.57, 0.96.021 Type 20.76 0.60, 0.97.026 Hazard ratio 95% CI P value WLW.031 Cox’s proportional hazard analysis § Type 1 0.74 0.57, 0.96.021 Type 20.76 0.60, 0.97.026 CSR Table 9-1 § Protocol specified full model. C

38. CES-38 Kaplan-Meier Estimates of Cumulative Probabilities of a Type 1 or Type 2 Event 32% 24% C 37% 28% Clozaril ® Zyprexa ® Type 1Type 2

39. CES-39 Cox’s Analyses of Type 1 Events by Subgroups 0.300.370.450.550.670.8211.221.49 Non-treatment resistant Treatment resistant Schizophrenia Schizoaffective Female Male North America Rest of World Age 18 - 32 Non-White White 33 - 44 > 44 Hazard ratio (95% CI) <------------- favoring Clozaril ® -------------- favoring Zyprexa ® -->

40. CES-40 InterSePT Results Efficacy Results Secondary Efficacy Assessments C

41. CES-41 Change in Severity of Suicidality CGI-SS-BP at Week 104 C CSR Table 9.3-17 < < < P =.280

42. CES-42 LS Mean Change From Baseline ISST-BP, PANSS-T, CDS and Covi at Week 104 C CSR Table 9-10 P =.359 P =.399 P =.578 P =.767

43. CES-43 LS Mean Daily Dose (mg) of Concomitant Psychotropic Medications Least square mean (± SE) MedicationsClozaril ® Zyprexa ® P value Antipsychotics § 2.1 ± 0.3 3.8 ± 0.3<.001 Antidepressants || 16.7 ± 1.120.7 ± 1.0.001 Sedatives/ 6.3 ± 0.610.1 ± 0.6<.001 anxiolytics ¶ Mood stabilizers # 487.3 ± 43.2620.6 ± 39.9.011 § Haloperidol, || fluoxetine, ¶ diazepam, # carbamazepine equivalents. C

44. CES-44 Safety C

45. CES-45 Incidence of Adverse Events and Serious Adverse Events Patients, n (%) Clozaril ® Zyprexa ® N = 479 N = 477P value AEs443(92.5)450(94.3).297 SAEs231(48.2)235(49.3).796 PTT 10.1-1 No cases of agranulocytosis, myocarditis, or cardiomyopathy in the Clozaril group 1 case of cardiomyopathy in the Zyprexa group C

46. CES-46 Clozaril ® Zyprexa ® Adverse event N = 479N = 477 Salivary hypersecretion229 (47.8)28 (5.9)<.0001 White blood cell decrease28 (5.8) 4 (0.8)<.0001 Constipation120 (25.1)46 (9.6)<.0001 Weakness36 (7.5)11 (2.3)<.001 Postural hypotension21 (4.4) 1 (0.2)<.0001 Convulsions12 (2.5) 2 (0.4).012 Clozaril ® Adverse Events of Interest Patients, n (%) P value § C § Fisher’s exact test. PTT 10.1-2

47. CES-47 Clozaril ® Zyprexa ® Adverse event N = 479N = 477 Weight increased150 (31.1)265 (55.6)<.0001 Dry mouth26 (5.4)43 (9.0).034 Diabetes mellitus NOS16 (3.3)21 (4.4) NS Asthma 5 (1.0)19 (4.0).004 Laceration 2 (0.4)19 (4.0)<.001 Epistaxis0 5 (1.0).031 Zyprexa ® Adverse Events of Interest Patients, n (%) C Statistically significant differences between groups. NOS = Not otherwise specified § Fisher’s exact test. PTT 10.1-2 P value §

48. CES-48 Clozaril ® Zyprexa ® Adverse event N = 479N = 477 Depression137 (28.6)173 (36.3).013 Suicidal ideation125 (26.1)153 (32.1).046 Suicide attempt37 (7.7) 66 (13.8).002 Drug abuse 4 (0.8)14 (2.9).018 Tension 3 (0.6)11 (2.3).034 Mood disorder0 8 (1.7).004 Insomnia 96 (20.0)155 (32.5)<.0001 Akathisia21 (4.4)39 (8.2).016 Somnolence220 (45.9)118 (24.7)<.0001 Dizziness129 (26.9) 59 (12.4)<.0001 Dysarthria23 (4.8) 2 (0.4)<.0001 Syncope15 (3.1) 5 (1.0).039 Neuropsychiatric Adverse Events Patients, n (%) P value § § Fisher’s exact test. C PTT 10.1-2

49. CES-49 Cause of deathClozaril ® Zyprexa ® Suicide5 (+1)3 (+1) Cardiac arrhythmia21 Coronary artery disease1 Myocardial infarction1 Cardio-respiratory arrest 2 Stroke 1 Pulmonary embolism1 Car accident1 Lymphoma1 Carcinoma1 Total139 Deaths Patients, n C PTT 10.1-2

50. CES-50 Examination of the Process of Referral of Potential Type 1 Events to the SMB

51. CES-51Database SMBmembers Medical Monitor InterSePT Design: Potential Bias in Referrals to SMB CPatient Blinded data Site PI

52. CES-52 Method to Review the Process of Referral of Potential Type 1 Events to SMB  Assumption: referral bias limited to all cases not referred to SMB (N = 701)  Search term dictionary developed based on AE terms and Query and Comment databases  Search term dictionary applied to each case  CRFs from term-matched cases were reviewed: – Whether PI was queried regarding occurrence of suicidal behavior – PI’s response – Whether AE was potentially related to suicidal behavior

53. CES-53 Review of Referral Process: Summary of Findings 5Number of cases with occurrence of potential suicidal behavior 279 Number of cases with at least one search-term match 701Total number of non-referred cases These results indicate that, although the PIs were unblinded, they acted without bias (3 Clozaril, 2 Zyprexa)

54. CES-54 Conclusions From InterSePT (1)  During InterSePT, treatment with Clozaril ® compared with Zyprexa ® was associated with a 26% reduction of risk for suicide attempts and hospitalizations to prevent suicide.  For all subgroups examined, there was a high degree of consistency in the reduction of risk for suicidal behavior in the Clozaril group compared to the Zyprexa group. C

55. CES-55 Conclusions From InterSePT (2)  The reduction of risk in the Clozaril group appears not to be attributable to a greater effect on psychotic or depressive symptoms or to greater use of concomitant psychotropic medications.  Adverse event profiles for both study drugs were generally consistent with previous experience and current product labeling.  The open-label design was not associated with biased assessments by the PIs. C

56. CES-56 Overall Conclusion The results of InterSePT show that Clozaril ® is effective and safe in reducing the risk of emergent suicidal behavior in patients with schizophrenia or schizoaffective disorder. C