# Presentation: 802782

## Benefit-Risk Assessment

**Murat Emre, MD**
**Professor of Neurology****Istanbul Faculty of Medicine****Department of Neurology****Behavioral Neurology and Movement Disorders Unit****Istanbul University**

## 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**

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## 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 **

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## 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**

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## 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  **

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## Mean Changes or Scores of Efficacy Measures at Wk 24

- Originals/Slides/04-21-06 Emre Slide Requests/EXPRESSsummarySiide.ppt

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| Scale | Exelon | Placebo | p value |
| --- | --- | --- | --- |
| Primary |  |  |  |
| 	ADAS-cog | 2.1 | –0.7 | < 0.001 |
| 	ADCS-CGIC | 3.8 | 4.3 | 0.007 |
| Secondary |  |  |  |
| 	ADCS-ADL | –1.1 | –3.6 | 0.023 |
| 	NPI | 2.0 | 0.0 | 0.015 |
| 	CDR attention | 31.0 | –142.7 | 0.009 |
| 	MMSE | 0.8 | –0.2 | 0.028 |
| 	Verbal fluency | 1.7 | –0.7 | < 0.001 |
| 	Ten-Point Clock Test | 0.5 | –0.6 | 0.019 |

**Positive values indicate improvements and negative values, deteriorations.****CGIC figures represent mean values.**

## 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**

## 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**

## 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**

## 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;1:55-65.**
**Rogers SL, et al. *****Arch Int Med*****. 1998;158:1021-1031.**
**Rosler M, et al. *****BMJ*****. 1999;318:633-640.**
**Burns A, et al. *****Dem Geriatr Cog Disord*****. 1999;10:237-244.**
**Geldmacher D. *****Clin Geriatr Med*****. 2004;20:27-43.**

## Clinical Relevance of Benefits 

| ADCS-CGIC  | Exelon | Placebo |
| --- | --- | --- |
| Mean score at Wk 24 | 3.8 | 4.3 |
| Improved, % | 41 | 30 |
| Unchanged, % | 26 | 28 |
| Worsened, % | 33 | 42 |
| Marked or moderate improvement, % | 20 | 14 |
| Marked or moderate worsening, % | 13 | 23 |

## 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 **

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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**