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Rationale for Indication of Parkinson’s Disease Dementia (PDD)

and Study Design

Roger Lane, MD, MPH

Disease Area Section Head for DementiaNeuroscience Clinical Development and Medical Affairs

Novartis 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 NPatient 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

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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. 2001;16:1171-1174.Bullock & Cameron. Current Medical Research and Opinions. 2002;18:258-264.Giladi N, et al. Acta Neurol Scand. 2003;108:368-373;

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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. 1993;98:431-438; ‡ Rakonczay Z. Acta Biologica Hungarica. 2003;54:183-189; § Eskander MF, et al. Brain Res. 2005;1060:144-152.

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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

Exelon’s brain regional selectivity may avoid unwanted brainstem/subcortical effects

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EXPRESS StudyObjective and Study Design

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 2:1, 3 to 12 mg/day Exelon: placebo

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Study Design

RANDOMIZATION

24-wk core study 2311

24-wk extension study 2311E1

Exelon treatment (Exe-Exelon) 1.5 - 6 mg bid

Exelon treatment (Plc-Exelon) 1.5 - 6 mg bid

Exelon treatment1.5 - 6 mg bid

Placebo treatment 1.5 - 6 mg bid

Wk –3 Wk –1 Wk 0 Wk 16 Wk 24 Wk 40 Wk 48

2nd titrationperiod

1st maintenanceperiod

1st titrationperiod

Screen 2nd maintenanceperiod

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Patient Selection

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EXPRESS Inclusion Criteria

UK Parkinson’s 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

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EXPRESS Exclusion Criteria

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

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EXPRESS Outcome Measures

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 < 0.05 for both primary endpoints at week 24

15-15

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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

Secondary efficacy measures

– ADCS-ADL

– Neuropsychiatric Inventory (NPI)

– CDR attention battery

– MMSE

– D-KEFS letter fluency test

– Ten-Point Clock Test

15-15

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EXPRESS Outcome Measures

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