SS- 1

1
Use of Clozaril and Zyprexa as Concomitant
Medication (Simultaneous Use)

• 69 Clozaril patients used Olanzapine as
  concomitant medication
• 17 Zyprexa patients used Clozapine as concomitant
  medication
• WLW analysis results after excluding above
  patients (P .021)

Clozaril Zyprexa N 421 N 473 Type
1 80 135 Type 2 95 154
2
Suicide History at Baseline
8
CSR ABA 451-Clozaril

• Patients, n ()
• Clozaril Zyprexa N 490 N 490

Suicide history Lifetime attempts, n
490
489 0 77 (15.7) 86 (17.6) 1 124 (25.3) 99 (20.2)
2 - 3 154 (31.4) 157 (32.0) 4 -
5 60 (12.2) 75 (15.3) gt 5 75 (15.3) 72 (14.7) Mi
ssing 0 (0.0) 1 (0.2) Mean 3.6 (7.5) 3.2 (4.5) M
edian
2 2 Range
0 - 120 0 - 50
Treatment resistance determined by clinical
assessment.
3
Number and Percent of Type 1 or Type 2 Events by
Diagnosis Subgroup
19
Clozaril Clozaril Clozaril Clozaril Zyprexa Zyprexa Zyprexa Zyprexa
Events n/N K-M () K-M () n/N n/N K-M ()
Schizophrenia Schizophrenia Schizophrenia Schizophrenia Schizophrenia Schizophrenia Schizophrenia Schizophrenia Schizophrenia
Type 1 51/300 17.0 17.0 19.5 19.5 82/309 26.5 29.3
Type 2 67/300 22.3 22.3 25.9 25.9 98/309 31.7 35.1
Schizoaffective Schizoaffective Schizoaffective Schizoaffective Schizoaffective Schizoaffective Schizoaffective Schizoaffective Schizoaffective
Type 1 51/190 26.8 26.8 31.0 31.0 59/181 32.6 37.2
Type 2 53/190 27.8 27.8 32.1 32.1 63/181 34.8 39.5
Kaplan-Meier estimates of cumulative
probability of event at Week 104.
4
Retrieved Dropout Patients With Type 1 Events
22
Events, () Events, ()
Clozaril N 61 Zyprexa N 60
No Type 1 event 41 (67.2) 35 (58.3)
Type 1 event 20 (32.8) 25 (41.7)
12 Clozaril and 3 Zyprexa patients had Type 1
events after discontinuation.
5
WLW and Coxs Analyses of Type 1 and Type 2
Events Excluding Followup Data After
Discontinuations
Hazard ratio 95 CI P value
WLW .006
Coxs proportional hazard analysis Coxs proportional hazard analysis
Type 1 0.66 0.51, 0.87 .003
Type 2 0.70 0.55, 0.90 .005
6
Influence of Change in Blinded PsychiatristNumber
() of Patients With Worsening in CGI-SS-BP of
Type 2 Event
19
Clozaril Zyprexa
Worsening CGI-SS-BP, score 6 or 7 (with a change in BP) 13 8
Change in a BP occurred after Type 2 event 7 5
Change in BP before Type 2 event 6 3
7
Agreement Between SMB and Blinded Psychiatrist
With Regard to Occurrence of Type 1 Events
19

• Concordance 90.5 (84 all)
• 2 possible explanations for discrepancies
• BP evaluation of Type 1 event was not subject to
  challenge. All SMB determinations required
  consensus of all 3 SMB members
• SMB reviewed all PEP (n 577) whereas BP
  assessed on average 8 - 9 PEPs (range (0 - 42)
  less variability in reviewing PEP by SMB could be
  expected
• Primary endpoint, patients first SMB-determined
  Type 1 event, prospectively defined and agreed
  upon with FDA
• High degree of agreement between SMB and BPs
  regarding this endpoint confirms validity of
  endpoint for demonstrating efficacy in patients
  at risk for suicidal behavior

8
Coxs Analyses of Patients With Type 1 Events as
Determined by SMB and BP
19
Hazard ratio 95 CI P value
SMB 0.74 0.57, 0.96 .021
BP 0.86 0.67, 1.11 .236
Both SMB and BP agreed 0.84 0.64, 1.10 .195
9
Number of Patients with Score of 6 or 7 on
CGI-SS-BP (Type 2 Event)

• Clozaril 38
• Zyprexa 42
• CGI-SS-BP not assessed after discontinuation

10
Clozaril Zyprexa
Schizoaffective N 190 N 181
Baseline mean 81.9 80.5
Mean change from baseline -20.4 -19.9
P value lt .001 lt .001
Schizophrenia N 300 N 309
Baseline mean 86.7 83.8
Mean change from baseline -21.3 -18.1
P value lt .001 lt .001