Alan Breier, M.D.

1
Lilly Research Laboratories A Division of Eli
Lilly and Company
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
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
• gt50 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 (gt65 yrs.)
US Experience (1998-1999)
Days of Therapy (in millions)
Dementias 14.7 30 Depression 10.4
21 Schizophrenia 8.8 18 Bipolar 4.7
9 Other 11.2 22 Total 50.0 100
Source IMS Medical MIDAS Moving Annual Total
Q399
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
Acute Agitation

• 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

11
Acute Agitation 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
Acute Agitation Validated Rating Instruments

• 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

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