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

1. 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 AffairsNovartis Pharmaceuticals Corporation

2. Rationale for Pursuing PDD Indication • Unmet medical need – this patient population not previously studied systematically • Distinct neuropathology associated withcholinergic 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

3. Summary of Exelon Open-LabelStudies in PDD Table 2-1 p 17 SCE

4. 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;

5. 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.

6. 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

7. 1 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

8. Study Design 24-wk extension study 2311E1 24-wk core study 2311 RANDOMIZATION Exelon treatment1.5 - 6 mg bid Exelon treatment (Exe-Exelon) 1.5 - 6 mg bid Placebo treatment 1.5 - 6 mg bid Exelon treatment (Plc-Exelon) 1.5 - 6 mg bid 1st titrationperiod 1st maintenanceperiod 2nd titrationperiod 2nd maintenanceperiod Screen Wk –3 Wk –1 Wk 0 Wk 16 Wk 24 Wk 40 Wk 48

9. Patient Selection

10. 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 13-11 DV EXPRESS Inclusion Criteria CSR pg 19, 20

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

12. 15-15 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

13. 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

14. 15-15 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. 15-15 EXPRESS Outcome Measures • Safety evaluations • Adverse events • UPDRS part III (motor scale) • Laboratory tests and ECG • Vital signs and body weight

16. 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