CBR-1

Benefit/Risk Assessment for Use of Clozaril in the Treatment of Emergent

Suicidal Behavior

John M. Kane, MD

Chairman, Department of PsychiatryThe Zucker Hillside Hospital

The North Shore–Long Island Jewish Health System

Professor of Psychiatry, Neurology and NeuroscienceAlbert Einstein College of Medicine

C

CBR-2

Benefit and Risk for Treatment of Suicidal Behavior

BenefitsBenefits

RisksRisks

Reduction of Suicidal Behavior

Treatment Intervention

CBR-3

Clozaril®

Clinical Uses

First approved in 1969 for treatment of schizophrenia

Plays unique role in management of treatment-resistant and partially-responsive patients

Increased interest in other clinical uses eg, substance abuse, smoking cessation, movement disorders, aggression, suicidal behavior

CBR-4

The Burden of Suicidal Behavior

Untreated suicidal behavior leads to increased Morbidity and mortality Hospitalizations (psychiatric or medical) Emergency room visits Interventions to prevent suicide attempts

– Concomitant medication– Increased surveillance

Family burden Societal costs

CBR-5

InterSePT as Basis for Benefit/Risk Assessment of Clozaril®

Well-designed, prospective, randomized study

Endpoints are objectively determined by blinded SMB

Compares 2 atypical antipsychotics

Long-term (2 years) efficacy and safety assessments

Procedures designed to maximize patient safety

C

CBR-6

Results of WLW and Cox’s Analyses

Hazardratio 95% CI

P value

WLW .031

Cox’s proportional hazard analysis§

Type 1|| 0.74 0.57, 0.96 .021

Hazardratio 95% CI

P value

WLW .031

Cox’s proportional hazard analysis§

Type 1|| 0.74 0.57, 0.96 .021

CS

R T

ab

le 9

-1

§Protocol specified full model.||Suicide attempts or hospitalizations to prevent suicide.

CBR-7

0.0

0.1

0.2

0.3

0.4

0.5

0 2 4 6 8 10 12 14 16 18 20 22 24

Time, months

Cu

mu

lati

ve p

rob

abili

ty

Kaplan-Meier Estimates of Cumulative Probabilities of a Suicide Attempt or Hospitalization to Prevent Suicide

32%

24%

C

Clozaril®

Zyprexa®P = .0195

CBR-8

Clinically Meaningful Outcomes

CS

R T

ab

le 9

-5C

34

82

137125

55

107

173

153

0

20

40

60

80

100

120

140

160

180

Suicide attempts Hospitalizations Depression Suicidal ideation

Nu

mb

er

of

pa

tie

nts

Clozaril® Zyprexa®

§Fisher’s exact test.

P < .008§

P < .026§

P < .013§

P < .046§

(adverse events) (adverse events)

CBR-9CBR-9

CBR-10

Clinical Risks of Intervention

Agranulocytosis– Current estimated incidence in US is 0.3%

during first year of treatment– Well-established risk management system

Myocarditis– Current rate in US is 5 per 100,000 patient years

Seizures– Incidence 3%

Weight gain and disturbances in glucose regulation

CBR-11

InterSePT Risk Experience With Clozaril®

Adverse event profile generally consistent with previous clinical experience

No cases of agranulocytosis, myocarditis, or cardiomyopathy were observed in the Clozaril-treated group

Convulsions: 2.5% (N = 12)

C

CBR-12

InterSePT Benefit Experience

Significantly lower risk of suicidal behavior relative to Zyprexa® (P = .03)

26% reduction in risk of suicide attempts or hospitalizations to prevent suicide for Clozaril® relative to Zyprexa

C

CBR-13

Number Needed to Treat (NNT) to Prevent a Suicide Attempt

Clozaril® has a 2-year NNT of 13

– If 13 at-risk patients were treated with Clozaril instead of Zyprexa®, we would prevent 1 suicide attempt or 1 hospitalization to prevent suicide

8

CBR-14

Benefit Risk CalculationRisk in 2 years

for every1,000 patients

on Clozaril®

Risks Agranulocytosis 3.5

Myocarditis < 1

Benefits Number of patients for whom one suicide attempt, suicide, or hospitalization related to suicide, was prevented compared to treatment with Zyprexa®

77

CBR-15

Conclusions

Suicidal behavior in patients with schizophrenia or schizoaffective disorder represents an important unmet medical need

InterSePT demonstrates the efficacy of Clozaril® in reducing suicidal behavior in comparison with Zyprexa®

Use of Clozaril for the proposed indication poses no additional safety risk

Clozaril should be an available treatment option for patients with suicidal behavior

C