1. Alan Breier, M.D. Leader, Zyprexa Product Team Lilly Research Fellow Professor of Psychiatry, Indiana University School of Medicine Adjunct Associate of Psychiatry, University of Maryland School of Medicine Lilly Research Laboratories A Division of Eli Lilly and Company

2. Alzheimer's Disease Major Public Health Priority 4.5 million US citizens affected - numbers dramatically rising with aging population Massive human suffering - patients and families $80-$100 billion per year in total treatment costs - $213,000 per family treatment costs >50% have psychosis and/or behavioral disturbances - major precipitant for institutional care Neuroleptics commonly used off-label - currently insufficient FDA direction to prescribers - high rate of adverse events, e.g., EPS, TD, excessive sedation

3. Antipsychotic Drug Use in the Elderly (>65 yrs.) US Experience (1998-1999) Dementias14.7 30% Depression10.4 21% Schizophrenia 8.8 18% Bipolar 4.7 9% Other11.2 22% Total50.0100% Source: IMS: Medical MIDAS Moving Annual Total Q399 Days of Therapy (in millions)

4. Challenges Urgent need to establish clear guidelines for drug approval - each month: 20,000 new AD cases $5.7 billion in treatment costs Strike the correct balance between appropriate clinical nosology and accelerating drug development - 3-4 years for new registration trials and approval - Data from existing controlled trials could expedite approval and appropriate labeling

5. Psychosis Associated with Alzheimer's Disease Support for a Distinct Indication Clinical features (symptoms, course) are specific to AD Clinical presentation is readily recognized by clinicians and operationally defined by validated rating instruments May represent a distinct AD subgroup Antipsychotic drug response may be specific to AD

6. Psychosis Associated with Alzheimer's Disease Essential Diagnostic Criteria Diagnosis of dementia of the Alzheimer's type (DAT) Prominent delusions and/or hallucinations - severity e.g., causes impairment/distress - persistence Psychotic symptoms not due to other medical conditions, delirium or Axis I disorders

7. Psychosis Associated with Alzheimer's Disease DSM-IV Provides a Diagnostic Approach The essence of DSM-IV (Introduction, Page 23) - diagnosis based on clinical judgement and symptom persistence and severity Psychosis associated with Alzheimer's disease - diagnostic criteria for DAT with delusions (290.12, 290.20) - diagnostic criteria for psychotic disorder due to AD with hallucinations (293.82)

8. DSM-IV Diagnosis of Psychosis Associated with Alzheimer's Disease Patient meets diagnostic criteria for dementia of the Alzheimer's type Psychotic symptoms are not due to other medical conditions or Axis I disorders Delusions are the predominant feature: 290.12 or 290.20 Hallucinations are the predominant feature: 293.82 Validated rating instruments (e.g., NPI, BEHAVE-AD) may be used to further characterize psychotic symptoms

9. Behavioral Disturbances of Alzheimer's Disease Acute agitation Aggression Sleep Disturbances Anxiety Depression

10. Common features across a number of disease states - a behavioral syndrome comprising hostility, tension, uncooperativeness, poor impulse control, and/or excitement Strong face validity and reliability Causes significant adverse impact on patients Commonly warrants pharmacological intervention Acute Agitation

11. Support for a Broad Indication Not unique or specific to AD - core clinical characteristics are relatively similar across disease states Consistent with the regulatory models of pain and fever Indication should be supported with data from a number of different disease states

12. Acute Agitation Assessment Approach for Registration Trials Abrupt onset of agitation: poor impulse control, uncooperativeness, hostility, tension, and/or excitement Sufficient intensity and severity - requires treatment and/or results in impairment/distress Validated rating instruments may be used to characterize severity and phenomenology

13. PANNS excited component - high face validity (items: poor impulse control, tension, hostility, uncooperativeness, excitement) - factor analysis (Kay & Sovy, 1990; Lancon 1998); further validated by Lilly in agitated and non-agitated patients Other validated instruments (examples) - Cohen-Mansfield Agitation Inventory - validated in patients with dementia - Corrigan Agitated Behavior Scale - used in clinical trials of acute agitation in schizophrenia, ER setting Acute Agitation Validated Rating Instruments

14. Conclusion Urgent need to develop new therapeutics for AD patients with psychosis and behavioral disturbances Psychosis associated with AD warrants a distinct indication Diagnostic approaches available now for registration trials of psychosis associated with AD Acute agitation is a non-specific behavioral syndrome that warrants a broad indication across many diseases