BenefitRisk Assessment

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Benefit-Risk Assessment

• Murat Emre, MD
• Professor of NeurologyIstanbul Faculty of
  MedicineDepartment of NeurologyBehavioral
  Neurology and Movement Disorders UnitIstanbul
  University

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Parkinsons Disease Dementia
1-17 DV

• Readily diagnosable clinical condition
• Develops in the context of established PD
• Cognitive decline with a typical profile
• Frequent neuropsychiatric symptoms
• Functional disability
• Exclusion of symptomatic dementias
• No symptomatic treatments available for PDD
• Increased burden for patients and families
• Reason for nursing home placement
• Considerable unmet need

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Statement of Need in PDD
1-17 DV

• Treatment to benefit all symptom domains
• Cognition, behavior, function
• Tolerability without adverse impact on
• Motor symptoms
• Autonomic and cardiovascular functions

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Benefits of Exelon in PDD
1-17 DV

• Statistically significant benefits were seen in
• Primary efficacy measures for cognition and
  overall status (ADAS-cog and ADCS-CGIC)
• All secondary efficacy outcome measures
• Attention
• Executive function
• Behavioral symptoms
• Activities of daily living

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Benefits of Exelon in PDD
1-17 DV

• Moderate but consistent benefits in
• Cognition
• Overall cognition ADAS-cog
• Executive function Verbal fluency,
  clock-drawing test
• Attention Composite measure of attention
• Behavioral symptoms Total NPI score
• Function ADCS-ADL
• Clinical global outcome ADCS-CGIC

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Mean Changes or Scores of Efficacy Measures at
Wk 24
29
Originals/Slides/04-21-06 Emre Slide
Requests/EXPRESSsummarySiide.ppt
Positive values indicate improvements and
negative values, deteriorations.CGIC figures
represent mean values.
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Risks Associated With Exelon in PDD

• Gastrointestinal AEs
• Occurred mostly during Exelon dose titration
• Most of mild or moderate severity and not leading
  to discontinuation (nausea 29 incidence, 4
  discontinuation)
• Lower incidence and discontinuation rates than in
  Exelon AD studies

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Risks Associated With Exelon in PDD

• AEs potentially associated with PD
• 11 more in the Exelon group
• Single episodes of mild or moderate severity
  decreased incidence after completion of the
  dose-titration periods
• Tremor was the most frequent individual PD
  symptom (10 vs 4), discontinuation 1.7
• No difference from placebo in the total UPDRS
  scores
• Exposure over 48 wk not associated with a
  worsening compared with those exposed over 24 wk

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Risks Associated With Exelon in PDD

• Cardiovascular safety
• No cardiovascular or autonomic safety issues
  identified with the use of Exelon in PDD
• Less frequent orthostatic hypotension and syncope
  with Exelon
• Fewer deaths and SAEs among Exelon-treated
  patients
• Exelon in PDD is not associated with a risk
  beyond that described in the product label for
  patients with AD

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Clinical Relevance of Benefits

• Based on previous dementia trials with ChEIs,
  the treatment effect on ADAS-cog ranges from 2
  to 4 points
• 2.9 points for Exelon in the core study
• 2.1 points for Exelon in AD study
• In PDD, larger improvement above baseline with
  Exelon and less decline with placebo as compared
  with AD studies

Corey-Bloom J, et al. Int J Geriatr Psychopharm.
1998155-65. Rogers SL, et al. Arch Int Med.
19981581021-1031. Rosler M, et al. BMJ.
1999318633-640. Burns A, et al. Dem Geriatr Cog
Disord. 199910237-244. Geldmacher D. Clin
Geriatr Med. 20042027-43.
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Clinical Relevance of Benefits
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Summary of Benefit-Risk Assessment
1

• Exelon provided moderate but consistent benefits
  across all primary and secondary measures in all
  symptom domains
• AEs consistent with the established safety
  profile for Exelon risk of worsening tremor in
  10 of patients
• No additional safety concerns beyond those
  described in current label

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Conclusion

• There is currently no approved treatment for PDD
• Exelon treatment associated with benefits in
  cognition, behavior, and activities of daily
  living
• Tolerability risks, such as nausea and tremor,
  are easy to monitor, clinically recognizable,
  and manageable
• The benefits of Exelon treatment in PD patients
  with dementia outweigh the risks