Rationale for Indication of Parkinson

1
Rationale for Indication of Parkinsons Disease
Dementia (PDD) and Study Design

• Roger Lane, MD, MPH
• Disease Area Section Head for DementiaNeuroscienc
  e Clinical Development and Medical
  AffairsNovartis Pharmaceuticals Corporation

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Rationale for Pursuing PDD Indication

• Unmet medical need this patient population not
  previously studied systematically
• Distinct neuropathology associated with
  cholinergic deficit
• Idiopathic PD diagnosis preceding onset of a
  generic dementia syndrome predicts
• Characteristic deficits of PDD
• Alpha-synuclein related neuropathology
• Findings from small open studies in PDD
• Pharmacologic profile of Exelon

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Summary of Exelon Open-LabelStudies in PDD
Reference N Patient population, characteristics Duration/dose
Reading, et al (2001) 15 PD for a mean of 12 yrs with hallucinations in past 3 mo, mean age 71 yr, baseline MMSE 20 14 wk, 3-wk washout/ 1.5 - 6 mg bid
Bullock Cameron (2002) 5 PD for a mean of 10 yrs, mean age 75 yr, baseline MMSE 20.6 Ranged 20 - 52 wk/ Exelon 1.5 - 6 mg bid
Giladi, et al(2003) 28 PD for a mean of 7 yrs, mean age 75 yr, baseline MMSE 19.5 26 wk, 8-wk washout/ Exelon 1.5 - 6 mg bid

Table 2-1 p 17 SCE
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Open-Label Studies of Exelon in PDDConclusions

• Efficacy
• Improvements in cognition, attention, behavior
  (visual hallucinations, sleep), global
  performance, and performance of activities of
  daily living (ADLs)
• Tolerability and safety
• GI side effects appeared lower in PDD than in AD
• Tremor may emerge at higher dose, otherwise motor
  function unaffected/improved
• No signs of worsened sleep or autonomic function

Reading PJ, et al. Movement Disorders.
2001161171-1174. Bullock Cameron. Current
Medical Research and Opinions. 200218258-264. Gi
ladi N, et al. Acta Neurol Scand.
2003108368-373
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Pharmacological Profile of Exelon

• Slowly reversible and sustained inhibition of
  acetylcholinesterase (AChE) and
  butylcholinesterase (BChE)
• Preferential selectivity for glial-derived
  isoforms of AChE and BChE involved in
  neurodegeneration
• May avoid unwanted effects in brainstem nuclei
  and in striatum
• Low incidence of sleep disturbance, parkinsonian
  symptoms, and cardiotoxicity in AD
• Metabolism by target enzymes means low potential
  for PK drug-drug interactions

Enz A, et al. Prog Brain Res. 199398431-438
Rakonczay Z. Acta Biologica Hungarica.
200354183-189 Eskander MF, et al. Brain Res.
20051060144-152.
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Summary of Rationale for Pursuing PDD Indication

• Dementia arising in context of established PD
  predicts
• Distinct neuropathology
• Cholinergic deficit
• Uncontrolled clinical data indicated efficacy
  without unexpected safety concerns
• Exelons brain regional selectivity may avoid
  unwanted brainstem/subcortical effects

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EXPRESS StudyObjective and Study Design
1

• Objective
• Evaluate the efficacy and safety of Exelon in
  patients with PDD
• Study design
• 24-wk, double-blind, randomized,
  placebo-controlled, parallel-group, multicenter
  study and an additional 24-wk open-label study
• 540 patients with PDD planned from 12 countries
  in Europe and Canada
• Randomized 21, 3 to 12 mg/day Exelon placebo

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Study Design
24-wk core study 2311
24-wk extension study 2311E1
RANDOMIZATION
Exelon treatment (Exe-Exelon) 1.5 - 6 mg bid
Exelon treatment1.5 - 6 mg bid
Exelon treatment (Plc-Exelon) 1.5 - 6 mg bid
Placebo treatment 1.5 - 6 mg bid
2nd titrationperiod
1st maintenanceperiod
1st titrationperiod
2nd maintenanceperiod
Screen
Wk 3
Wk 1
Wk 0
Wk 16
Wk 24
Wk 40
Wk 48
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Patient Selection
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EXPRESS Inclusion Criteria
13-11 DV

• UK Parkinsons Disease Society (PDS) Brain Bank
  criteria for PD
• Diagnostic and Statistical Manual of Mental
  Disorders-4th Edition (DSM-IV-TR) diagnostic
  criteria for PDD as defined in dementia due to
  other general medical conditions (294.1)
• Mini-Mental State Examination (MMSE) score of 10
  to 24
• Onset of symptoms of dementia 2 yr after first
  diagnosis of PD

CSR pg 19, 20
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EXPRESS Exclusion Criteria
13-11 DV

• Primary neurodegenerative disorder other than PD
  including
• Probable or possible VaD using NINDS-AIREN
  criteria
• MRI and CT scan at screening or within 6 months
  prior
• Required in all patients

CSR pg 19, 20
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EXPRESS Outcome Measures
15-15

• Primary efficacy measures
• ADAS-cog
• Sample size based on estimated treatment
  difference 2.25 (SD 7.5)
• ADCS-CGIC
• Sample size based on estimated treatment
  difference 0.4 (SD 1.3)
• Statistical significance required at p lt 0.05 for
  both primary endpoints at week 24

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ADAS-cog Is an Appropriate Primary Outcome to
Assess the Dementia in PDD

• Shared cholinergic deficit contributes to
  neuropsychological deficits in both AD and PDD
• ADAS-cog is well-validated in AD for assessment
  of relevant cognitive domains of dementia
• Pilot study in PDD showed ADAS-cog sensitive to
  treatment effects
• Supplementary study showed ADAS-cog to have
  similar sensitivity to disease severity and
  test-retest reliability in PDD as in AD

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EXPRESS Outcome Measures
15-15

• Secondary efficacy measures
• ADCS-ADL
• Neuropsychiatric Inventory (NPI)
• CDR attention battery
• MMSE
• D-KEFS letter fluency test
• Ten-Point Clock Test

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EXPRESS Outcome Measures
15-15

• Safety evaluations
• Adverse events
• UPDRS part III (motor scale)
• Laboratory tests and ECG
• Vital signs and body weight

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Summary of Study Design

• Design and primary outcome similar to those of
  other dementia studies
• Placebo-controlled assessment of symptomatic
  efficacy, tolerability, and safety
• Open extension to assess longer-term safety and
  maintenance of efficacy
• Reliable dementia scales with concurrent study to
  assess sensitivity to dementia severity and
  test-retest reliability in PDD
• Study population had an established PD diagnosis
  at least 2 years before the onset of dementia
  symptoms