1. Improvement in behavioural symptoms in patients with moderate to severe Alzheimer’s disease (AD) by memantine: a pooled data analysis Gauthier S., Loft H. and Cummings J. International Journal of Geriatric Psychiatry 2008; 23: 537-45

2. Behavioral Symptoms – a Distressing Aspect of AD Behavioral symptoms are common in moderate to severe AD represent an aspect of disease burden that is physically, emotionally, and economically challenging correlate with accelerated disease progression There is a need for treatment options for patients with behavioral symptoms Behavioral symptoms are a burdening and stressful factor for the family and caregiver Gauthier et al., Int J Geriar Psychiatry 2008

3. Included Phase III Studies Phase III, double-blind, placebo-controlled, 6-month trials Placebo Memantine Study No. MMSE InclusionNumber of treated patients Range (Mean a ) MEM-MD-1010 – 22 (17.3)202201 Peskind et al. 2006 LU-9967911 – 23 (18.7)152318 Bakchine et al. 2007 MEM-MD-1210 – 22 (16.9)216217 Porsteinsson et al. 2008 MRZ-96053 – 14 (7.9)126126 Reisberg et al. 2003 MEM-MD-015 – 14 (10.1)172178 Van Dyck et al. 2007 MEM-MD-025 – 14 (10.0)201202 Tariot et al. 2004 a all patients treated set Mecocci et al. XXX 2008

4. Symptomatic Patients with MMSE < 20 at Baseline Delusions Hallucinations Agitation/Agression Depression Anxiety Elation/Euphoria Apathy/Indifference Disinhibition Irritability/Lability Aberrant Motor Behavior Nighttime Behavior Appetite/Eating Change Pooled analysis of six studies (MMSE <20) Proportion of patients (%) 0 1020305060 Memantine Placebo 40 Gauthier et al., Int J Geriar Psychiatry 2008

5. Benefits of Memantine on Behavioral Symptoms NPI score difference FAS, OC analysis Mean change from baseline Pooled analysis of six studies (MMSE < 20) -1.5 -0.5 0 0.5 1.0 1.5 2.0 2.5 Week 1224/28Endpoint (LOCF) Improvement Decline Memantine (20 mg/day) Placebo 0 p = 0.001 p = 0.035 p = 0.008 Gauthier et al., Int J Geriar Psychiatry 2008

6. Benefits of Memantine on Individual NPI Domains at Week 24/28 Delusions Hallucinations Agitation/Aggression Depression/Dysphoria Anxiety Elation/Euphoria Apathy/Indifference Disinhibition Irritability/Lability Aberrant Motor Behavior Nighttime Behavior Appetite/Eating Change NPI domain score difference 0.40.20-0.2-0.40.6 DeclineImprovement FAS, LOCF analysisMean change from baseline Pooled analysis of six studies (MMSE < 20) Memantine Placebo p = 0.001 p = 0.005 Gauthier et al., Int J Geriar Psychiatry 2008

7. Improvement in Patients with Baseline Symptoms at Week 24/28 LOCF analysisPooled analysis of six studies (MMSE <20) Proportion of patients (%) 40 4550556575 Memantine Placebo 70 60 p = 0.045 p = 0.028 p = 0.048 Gauthier et al., Int J Geriar Psychiatry 2008 Delusions Hallucinations Agitation/Aggression Depression/Dysphoria Anxiety Elation/Euphoria Apathy/Indifference Disinhibition Irritability/Lability Aberrant Motor Behavior Nighttime Behavior Appetite/Eating Change

8. Percentage of Patients Remaining Asymptomatic at Week 24/28 LOCF analysisPooled analysis of six studies (MMSE <20) Proportion of patients (%) 70 75808590100 Memantine Placebo 95 p = 0.002 p = 0.004 p = 0.050 Gauthier et al., Int J Geriar Psychiatry 2008 Delusions Hallucinations Agitation/Aggression Depression/Dysphoria Anxiety Elation/Euphoria Apathy/Indifference Disinhibition Irritability/Lability Aberrant Motor Behavior Nighttime Behavior Appetite/Eating Change

9. Summary Statistically significant benefit of memantine on behavioral symptoms (NPI total score) Consistent effect on agitation/aggression  stated as the most problematic AD symptom less emergence in patients asymptomatic at baseline less worsening if present at onset of treatment Anti-psychotic drugs are widely used off-label to treat behavioral symptoms in AD BUT recent studies have shown no drug-placebo difference as well a substantial number of side effects compared to placebo (Schneider et al. 2006) The FDA issued a Black Box warning against their use due associations with an increased mortality risk, cognitive decline, extrapyramidal symptoms, lowered blood pressure and sedation The data support the efficacy of memantine in treating and preventing the emergence of behavioral symptoms Gauthier et al., Int J Geriar Psychiatry 2008