1. Long-Term Treatment with the NMDA Antagonist Memantine Results of a 24-Week, Open-Label Extension Study in Moderately Severe to Severe Alzheimer's Disease Reisberg B., Möbius H.J., Stöffler A., Schmitt F., Doody R. and Ferris S. Neurobiology of Aging 2002, 1 Suppl.: S.555

2. Study Design No. of patients N = 175 (outpatients; completer of double-blind study) 80 (95%) placebo-treated and 95 (98%) memantine-treated patients entered the open label extension phase DiagnosisProbable Alzheimer’s disease Age  50 years (mean 76) SeverityMMSE 3 - 14 (mean 7.15) FAST  6a, GDS 5 - 6 Dose; duration20 mg memantine/day; 24 weeks Primary efficacyGlobal: CIBIC-plus parameterFunction: ADCS-ADL 19 Secondary efficacyCognition: SIB parameterFunction: FAST Reisberg et al., Neurobiol Aging 2002

3. CIBIC-Plus global score Improvement Worsening Double-blind phaseOpen-label extension Week OC analysis 4.0 = no change Benefit of Memantine on Clinical Global Impression (CIBIC-Plus) 3.8 4.0 4.2 4.4 4.6 4.8 5.0 012284052 Memantine (20 mg/day) Placebo N = 95 N = 75 N = 80 N = 65 N = 69 N = 74 N = 79 N = 95 N = 80 Reisberg et al., Neurobiol Aging 2002

4. ADCS-ADL 19 score difference Double-blind phaseOpen-label extension Improvement Worsening Week OC analysis Mean change from baseline Benefit of Memantine on Activities of Daily Living (ADCS-ADL 19 ) N = 95 N = 75 N = 80 N = 65 N = 71 2 0 -2 -4 -6 -8 -10 -12 0412284052 Memantine (20 mg/day) Placebo N = 95 N = 80 N = 95 N = 80 N = 95 N = 80 N = 75 Reisberg et al., Neurobiol Aging 2002

5. Benefit of Memantine on Cognition (Severe Impairment Battery) Improvement Worsening SIB score difference Double-blind phaseOpen-label extension Week OC analysis Mean change from baseline 5 0 -5 -10 -15 -20 Memantine (20 mg/day) Placebo N = 95 N = 79 N = 94 N = 80 N = 95 N = 80 N = 74 N = 69 0412284052 N = 95 N = 80 N = 75 N = 70 Reisberg et al., Neurobiol Aging 2002

6. Benefit of Memantine on Functional Domain (FAST) Improvement Worsening Double-blind phaseOpen-label extension Week OC analysis Mean change from baseline FAST score difference -0.2 0 0.2 0.4 0.6 0.8 1 N = 95 N = 80 N = 73 N = 80 N = 66 012284052 Memantine (20 mg/day) Placebo N = 95 N = 80 N = 71 N = 76 Reisberg et al., Neurobiol Aging 2002

7. Good Safety and Tolerability of Memantine Most frequently reported AE in the open-label extension MemantinePlacebo - Memantine- Memantine (N = 95)(N = 80) Agitation 17%19% Urinary tract infection13%13% Inflicted injury6%9% Insomnia8%6% Pneumonia1%6% Upper respiratory tract infection1%5% Urinary incontinence7%4% Hallucination6%0% Reisberg et al., Neurobiol Aging 2002

8. Summary Patients who switched from placebo to memantine improved relative to their projected rate of decline in three independent domains: global impression, function and cognition Long-term treatment with memantine was safe and well tolerated Results support the use of memantine as long-term treatment of patients with moderate to severe AD Reisberg et al., Neurobiol Aging 2002