1. GAL-INT-6 The safety and efficacy of galantamine in patients with Vascular dementia or AD with cerebrovascular disease Sean Lilienfeld MD, FCP, MMed Janssen Research Foundation

2. VaD AD Mixed Erkinjuntti T Interactions between vascular dementia and Alzheimer’s disease

3. Reminyl in vascular and mixed dementia: trial inclusion criteria Patients with dementia secondary to cerebrovascular disease (CVD) with or without AD –Probable Vascular dementia according to NINDS- AIREN criteria –Mixed dementia according to NINCDS-ADRDA criteria of possible Alzheimer’s disease with CVD and NINDS- AIREN criteria of possible VaD –MMSE at screening 10–25 and ADAS-Cog score at screening  12 –Positive radiology per NINDS-AIREN criteria

4. Inclusion Criteria Probable Vascular Dementia (NINDS-AIREN) A. Dementia (decline from previous higher level of functioning): –established by clinical examination and confirmed by neuropsychological test –deficits in two or more areas of cognition –no disturbance of consciousness, delirium, psychosis, severe aphasia, or major sensorimotor impairment precluding neuropsychological testing –absence of systemic disorders or other brain diseases such as Alzheimer’s Disease (EXCEPT CEREBROVASCULAR DISEASE) that could account for the dementia

5. Inclusion Criteria Probable Vascular Dementia (NINDS-AIREN) B. Cerebrovascular disease: –focal neurologic signs consistent with previous stroke (even with negative stroke history) –evidence of relevant cerebrovascular disease by CT or MRI scan

6. Inclusion Criteria Probable Vascular Dementia (NINDS-AIREN) C. A relationship must exist between the dementia and the cerebrovascular disease: –onset of dementia within 3 months of a recognised stroke –abrupt deterioration in cognitive functions –fluctuating, stepwise progression of cognitive deficits

7. Inclusion Criteria Mixed Dementia (Possible AD with CVD) NINCDS-ADRDA criteria for possible Alzheimer's disease and NINDS-AIREN criteria for possible Vascular Dementia –Dementia established by clinical examination and confirmed by neuropsychological test –Deficits in two or more areas of cognition –Progressive worsening of memory and other cognitive functions no disturbance of consciousness –Absence of systemic disorders or other brain diseases (EXCEPT AD and CEREBROVASCULAR DISEASE) that could account for the dementia

8. Inclusion Criteria Mixed Dementia (Possible AD with CVD) Radiologic evidence (satisfying the NINDS-AIREN radiologic criteria) as documented on a CT or MRI scan less than 12 months old of: –Multiple (2 or more) basal ganglion/white matter infarcts or lacunes and/or –Single strategically placed infarct in angular gyrus/thalamus/basal forebrain/Anterior Cerebral Artery or Posterior Cerebral Artery territory and/or –Extensive periventricular white matter lesions.

9. Exclusion Criteria Other neurodegenerative disorders Other causes of cognitive impairment Relevant medical conditions eg. ulcers, bladder obstruction, severe hepatic, renal, pulmonary, cardiac diseases

10. NINDS-AIREN Radiology multiple large-vessel infarcts single strategically placed infarct [angular gyrus, thalamus, basal forebrain, posterior or anterior cerebral artery territory] multiple basal ganglia and white matter lacunes extensive periventricular white matter lesions combinations of these

11. Patient characteristics PlaceboReminyl 24 mg/day (n = 196)(n = 396) Female46%48% Mean age (years)75.275.0 Mean MMSE score20.220.7 Diagnosis Mixed dementia50%48% Vascular dementia41%43% Uncertain per MD9%9%

12. ADAS-cog Scores: Placebo patients Over 6 Months -2 Mean change +/- SE in ADAS-cog/11 Baseline 2 1 0 -3 Time (months) Combined Placebo (n = 162) 1 234 6 5 Deteriorated Treatment group Improved Mixed D Placebo (n = 87) Probable VaD Placebo (n = 67)

13. ADAS-cog Scores: Placebo patients Over 6 Months 1 Baseline 3 2 0 -2 Time (months) Mixed D Placebo (n = 87) 1 234 6 5 Deteriorated Mean change +/- SE in ADAS-cog/11 Treatment group Improved Probable VaD Placebo (n = 67)  = 2.2 p = 0.013

14. NPI Scores: Placebo patients Over 6 Months Mean change (+/- SE) in total NPI Baseline 2 1 0 -2 Time (months) Placebo 1 234 6 5 Deteriorated Treatment group Improved Probable VaD Placebo Mixed D Placebo

15. NPI Scores: Placebo patients Over 6 Months Mean change (+/- SE) in total NPI Baseline 2 1 0 -2 Time (months) 1 234 6 5 Deteriorated Treatment group Improved Probable VaD Placebo Mixed D Placebo  = 0.4 p = 0.43

16. DAD Scores: Placebo patients Over 6 Months -4 Baseline 2 1 0 -6 Time (months) Placebo 1 234 6 5 Improved Mean change (+/- SE) in total DAD Treatment group -2 -3 -5 Deteriorated Mixed D Placebo Probable VaD Placebo

17. DAD Scores: Placebo patients Over 6 Months -4 Baseline 1 0 -8 Time (months) Mixed D Placebo 1 234 6 5 Improved Mean change (+/- SE) in total DAD Treatment group -2 -3 -7 -6 -5 Deteriorated Probable VaD Placebo  = 4.7 p = 0.032

18. Efficacy results ADAS-cog positive CIBIC-plus positive NPI positive DAD positive

19. Conclusions Using NINDS-AIREN criteria physicians were able to differentiate patients with “probable” vascular dementia and “mixed” dementia Observed rates of deterioration in a cognitive scale, a neuropsychiatric scale and a functional scale, are different in the 2 placebo groups, thus these patients are indeed different clinical populations

20. Conclusions Patients with “mixed” dementia deteriorate at rates similar to those seen in clinical trials in patients with probable AD over 6 months whereas patients with probable VaD remain essentially at baseline over 6 months

21. Galantamine Significantly Improved Both Primary Endpoints and Both Secondary Endpoints The current efficacy tools are able to detect differences between actively treated and placebo treated patients with a magnitude similar to that seen in trials in patients with AD