CC-1 Benefit-Risk Assessment Murat Emre, MD Professor of Neurology Istanbul Faculty of Medicine Department of Neurology Behavioral Neurology and Movement Disorders Unit Istanbul University

CC-2 Parkinson’s Disease Dementia  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 1-17 DV

CC-3 Statement of Need in PDD  Treatment to benefit all symptom domains – Cognition, behavior, function  Tolerability without adverse impact on – Motor symptoms – Autonomic and cardiovascular functions 1-17 DV

CC-4 Benefits of Exelon in PDD  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 1-17 DV

CC-5 Benefits of Exelon in PDD  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 1-17 DV

CC-6 Mean Changes or Scores of Efficacy Measures at Wk 24 Originals/Slides/ Emre Slide Requests/EXPRESSsummarySiide.ppt 29 ScaleExelonPlacebop value Primary ADAS-cog2.1–0.7< ADCS-CGIC Secondary ADCS-ADL–1.1– NPI CDR attention31.0– MMSE0.8– Verbal fluency1.7–0.7< Ten-Point Clock Test0.5– Positive values indicate improvements and negative values, deteriorations. CGIC figures represent mean values.

CC-7 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

CC-8 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

CC-9 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

CC-10 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. 1998;1: Rogers SL, et al. Arch Int Med. 1998;158: Rosler M, et al. BMJ. 1999;318: Burns A, et al. Dem Geriatr Cog Disord. 1999;10: Geldmacher D. Clin Geriatr Med. 2004;20:27-43.

CC-11 Clinical Relevance of Benefits ADCS-CGICExelonPlacebo Mean score at Wk Improved, %4130 Unchanged, %2628 Worsened, %3342 Marked or moderate improvement, %2014 Marked or moderate worsening, %1323

CC-12 Summary of Benefit-Risk Assessment  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 1

CC-13 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