1. Effects of Memantine on behavioural symptoms in Alzheimer’s disease patients: an analysis of the Neuropsychiatric Inventory (NPI) data of two randomised, controlled studies Gauthier S., Wirth Y. and Möbius H.J. International Journal of Geriatric Psychiatry 2005, 20: 1-6

2. Baseline Characteristics Monotherapy Study Combination Study Patients completing 97 (77%)84 (67%)172 (85%)150 (75%) study, n (%) Gender, female 91 (72%)79 (63%)128 (63%)134 (67%) n (%) Mean age (years)75.976.375.575.5 Race, Caucasian 112 (89%)115 (91%)182 (90%)186 (93%) n (%) Mean MMSE 7.78.19.910.2 score at baseline NPI total score, 21.4 (±15.8)19.5 (±15.6) 13.7 (±14.1) 13.9 (±12.8) Mean (± SD) MemantinePlaceboMemantine**Placebo** (N = 126)(N = 126)(N = 202)(N = 201) **stabilized on donepezil Gauthier et al., Int J Geriat Psychiatr 2005

3. Behavioral Outcome Monotherapy Study (Reisberg et al., 2003) Combination Therapy Study (Tariot et al., 2004) Analysis of behavioral symptoms by the 12-item version of the Neuropsychiatric Inventory (NPI) 9 of 12 items in favor of memantine 10 of 12 items in favor of memantine 252 Patients 403 Patients Gauthier et al., Int J Geriat Psychiatr 2005

4. Single Domain NPI Data Analysis from the Monotherapy Study (Reisberg et al., 2003) Gauthier S., Wirth Y. and Möbius H.J. International Journal of Geriatric Psychiatry 2005, 20: 1-6

5. No. of patients N = 252 (outpatients) DiagnosisProbable Alzheimer’s disease DesignDouble-blind, randomized, placebo- controlled, multicenter study Age  50 years (mean 76) SeverityMMSE 3 – 14 (mean 7.9) GDS 5 – 6 FAST  6a Dose; duration20 mg memantine/day; 28 weeks Primary efficacy Global: CIBIC-plus parameters Function: ADCS-ADL 19 Secondary efficacyCognition: SIB, Behavior: NPI parametersMMSE, FAST, GDS, Resource Utilisation in Dementia (RUD) Study Design Monotherapy Study Reisberg et al., N Engl J Med 2003

6. Baseline Characteristics Monotherapy Study Patients completing 97 (77%)84 (67%) study, n (%) Gender, female 91 (72%)79 (63%) n (%) Mean age (years)75.976.3 Race, Caucasian 112 (89%)115 (91%) n (%) Mean MMSE 7.78.1 score at baseline NPI total score, 21.4 (±15.8)19.5 (±15.6) Mean (± SD) MemantinePlacebo(N = 126) Reisberg et al., N Engl J Med 2003

7. Benefits of Memantine on Behavioral Symptoms * p < 0.05 versus placebo Merz, data on file Mean change from baseline NPI score difference Week -2 0 1 2 3 4 5 6 0412 Improvement Decline 8 Memantine (20mg/day) Placebo * 16202824 ITT, LOCF analysis

8. Benefits of Memantine on Individual NPI Domains (I) * p < 0.05, # p < 0.10 versus placebo Decline Delusions Agitation/Aggression Depression/Dysphoria Apathy/Indifference Disinhibition Night-time Behavior 1.00.50-0.5 Memantine Placebo 1.5 Improvement * * # NPI domain score difference Mean change from baseline ITT, LOCF analysis Gauthier et al., Int J Geriat Psychiatr 2005

9. Benefits of Memantine on Individual NPI Domains (II) Gauthier et al., Int J Geriat Psychiatr 2005 Hallucinations Anxiety Elation/Euphoria Irritability/Lability Aberrant Motor Behavior Appetite/Eating Change Decline 1.00.50-0.51.5 Improvement Memantine Placebo Mean change from baseline ITT, LOCF analysis NPI domain score difference

10. Benefits of Memantine on Individual NPI Domains * p < 0.05, # p < 0.10 versus placebo 1.00.50-0.51.5 Decline Improvement Delusions Agitation/Aggression Depression/Dysphoria Apathy/Indifference Disinhibition Night-time Behavior Hallucinations Anxiety Elation/Euphoria Irritability/Lability Aberrant Motor Behavior Appetite/Eating Change * * # Memantine Placebo NPI domain score difference Mean change from baseline ITT, LOCF analysis Gauthier et al., Int J Geriat Psychiatr 2005

11. Prevalence of Behavioral Symptoms at Baseline (I) Gauthier et al., Int J Geriat Psychiatr 2005 Delusions Agitation/Aggression Depression/Dysphoria Apathy/Indifference Disinhibition Night-time Behavior 20406080 Memantine Placebo 0100 [%] Prevalence of symptoms at baseline Patients showing symptom [%]

12. Prevalence of Behavioral Symptoms at Baseline (II) Hallucinations Anxiety Elation/Euphoria Irritability/Lability Aberrant Motor Behavior Appetite/Eating Change 20406080100 Memantine Placebo 0 [%] Prevalence of symptoms at baseline Patients showing symptom [%] Gauthier et al., Int J Geriat Psychiatr 2005

13. Emergence of Behavioral Symptoms (I) * p < 0.05 versus placebo Delusions Agitation/Aggression Depression/Dysphoria Apathy/Indifference Disinhibition Night-time Behavior 20406080 Memantine Placebo 0 * 100 [%] Emergence of new behavioral symptoms post baseline 86 68 52 44 57 69 50 47 85 92 78 85 Patients with new symptom [%] Gauthier et al., Int J Geriat Psychiatr 2005

14. Emergence of Behavioral Symptoms (II) Gauthier et al., Int J Geriat Psychiatr 2005 Hallucinations Anxiety Elation/Euphoria Irritability/Lability Aberrant Motor Behavior Appetite/Eating Change 20406080100 Memantine Placebo 0 [%] Emergence of behavioral symptoms post baseline 92 94 63 61 108 101 69 79 51 42 69 88 Patients with new symptom [%]

15. Improvement of Behavioral Symptoms (I) * p < 0.05 versus placebo Delusions Agitation/Aggression Depression/Dysphoria Apathy/Indifference Disinhibition Night-time Behavior 20406080 Memantine Placebo 0 * 100 [%] Improvement of behavioral symptoms at endpoint 33 52 67 76 63 70 72 35 27 42 34 50 Patients with improved symptom [%] Gauthier et al., Int J Geriat Psychiatr 2005

16. Improvement of Behavioral Symptoms (II) Gauthier et al., Int J Geriat Psychiatr 2005 Hallucinations Anxiety Elation/Euphoria Irritability/Lability Aberrant Motor Behavior Appetite/Eating Change 20406080100 Memantine Placebo 0 [%] Improvement of behavioral symptoms at endpoint 27 26 56 59 12 51 40 69 77 51 31 9 Patients with improved symptom [%]

17. Benefits of Memantine Treatment on Agitation/Aggression Patients [%] * p < 0.05 versus placebo Emergence post baseline 204060800100 [%] * 44 52 * 67 76 Improvement post baseline Prevalence at baseline Prevalence, Emergence and Improvement of the symptom Agitation/Aggression Memantine Placebo

18. Good Safety and Tolerability of Memantine Most frequently reported adverse events (incidence >10%) MemantinePlacebo No. of patients126 (100%)126 (100%) No. of patients with AEs106 (84%)109 (87%) Agitation* 23 (18%)40 (32%) Urinary incontinence14 (11%)14 (11%) Urinary tract infection7 (6%)17 (13%) Insomnia13 (10%)10 (8%) Diarrhoea12 (10%)10 (8%) adapted from Reisberg et al., N Engl J Med 2003 * p < 0.05 versus placebo

19. Single Domain NPI Data Analysis from the Combination Study (Tariot et al., 2004) Gauthier S., Wirth Y. and Möbius H.J. International Journal of Geriatric Psychiatry 2005, 20: 1-6

20. No. of patients N = 403 (outpatients) DiagnosisProbable Alzheimer’s disease DesignDouble-blind, randomized, placebo- controlled, multicenter study Patients on donepezil for at least 6 months (stable dose for 3 months) Age  50 years (mean 75.5) SeverityMMSE 5 – 14 (mean 10) Dose; duration20 mg memantine/day; 24 weeks Primary efficacy Cognition: SIB parameters Function: ADCS-ADL 19 Secondary efficacyGlobal: CIBIC-Plus, parametersBehavior: NPI and BGP (Care dependence subscale) Study Design Combination Study Tariot et al., JAMA 2004

21. Baseline Characteristics Combination Study Patients completing 172 (85%)150 (75%) study, n (%) Gender, female128 (63%)134 (67%) n (%) Mean age (years)75.575.5 Race, Caucasian 182 (90%)186 (93%) n (%) Mean MMSE 9.910.2 score at baseline NPI total score, 13.7 (±14.1)13.9 (±12.8) Mean (± SD) Memantine**Placebo** (N = 202)(N = 201) Tariot et al., JAMA 2004 * * stabilized on donepezil

22. Week * p < 0.05 versus placebo Benefits of Memantine on Behavioral Symptoms Tariot et al., JAMA 2004 * * stabilized on donepezil Mean change from baseline NPI score difference -3 -2 0 1 2 3 4 5 0412 Improvement Decline 8 Memantine** Placebo** * 162024 LOCF analysis*

23. Benefits of Memantine on Individual NPI Domains (I) * p < 0.05 versus placebo * * stabilized on donepezil Gauthier et al., Int J Geriat Psychiatr 2005 Delusions Agitation/Aggression Depression/Dysphoria Apathy/Indifference Disinhibition Night-time Behavior 0.60.30-0.3-0.60.9 Decline Improvement Memantine** Placebo** NPI domain score difference Mean change from baseline ITT, LOCF analysis *

24. Benefits of Memantine on Individual NPI Domains (II) * p < 0.05 versus placebo Hallucinations Anxiety Elation/Euphoria Irritability/Lability Aberrant Motor Behavior Appetite/Eating Change * * 0.60.30-0.3-0.60.9 Decline Improvement Memantine** Placebo** NPI domain score difference Mean change from baseline ITT, LOCF analysis Gauthier et al., Int J Geriat Psychiatr 2005 * * stabilized on donepezil

25. Benefits of Memantine on Individual NPI Domains * p < 0.05 versus placebo 0.60.30-0.3-0.60.9 Decline Improvement Delusions Agitation/Aggression Depression/Dysphoria Apathy/Indifference Disinhibition Night-time Behavior Hallucinations Anxiety Elation/Euphoria Irritability/Lability Aberrant Motor Behavior Appetite/Eating Change Memantine** Placebo** * * * NPI domain score difference Mean change from baseline ITT, LOCF analysis Gauthier et al., Int J Geriat Psychiatr 2005 * * stabilized on donepezil

26. Good Safety and Tolerability of Memantine (I) Tariot et al., JAMA 2004 Most frequently reported adverse events (incidence  5%) No. of patients N = 202 (100%)N = 201 (100%) No. of patients with AEs 158 (78%) 145 (72%) Agitation19 (9.4%)24 (11.9%) Confusion16 (7.9%) 4 (2.0%) Dizziness14 (6.9%)16 (8.0%) Headache13 (6.4%) 5 (2.5%) Memantine** Placebo** Urinary tract infection12 (5.9%)10 (5.0%) Urinary incontinence11 (5.4%) 6 (3.0%) Diarrhea 9 (4.5%)17 (8.5%) Fecal incontinence 4 (2.0%)10 (5.0%) * * stabilized on donepezil

27. Good Safety and Tolerability of Memantine (II) Tariot et al., JAMA 2004 Most frequently reported adverse events (incidence  5%) No. of patients N = 202 (100%)N = 201 (100%) Fall15 (7.4%)14 (7.0%) Accidental injury10 (5.0%)16 (8.0%) Memantine** Placebo** Influenza-like symptoms15 (7.4%)13 (6.5%) Upper respiratory tract infection10 (5.0%)13 (6.5%) Peripheral edema10 (5.0%) 8 (4.0%) * * stabilized on donepezil

28. Summary Memantine: positively influenced behavioral symptoms of patients with moderate to severe AD. was significantly superior versus placebo on the domains Agitation/Aggression Delusions Irritability/Lability Appetite/Eating Change beneficial effects were most pronounced and consistent on Agitation/Aggression showing a reduction if present at onset of treatment a delay in emergence in asymptomatic patients.