1. The Management of Alzheimer’s Disease and Related Dementias The Role of Cholinesterase Inhibitors in the Treatment of Alzheimer’s Disease and Related Dementias Steven G. Potkin, MD

2. ABC: The Key Symptom Domains of AD and Their Assessment Instruments Activities of daily living –PDS –ADFACS –ADCS/ADL Behavior –NPI –BEHAVE-AD Cognition –ADAS-Cog –MMSE

3. 0 200,000 400,000 600,000 800,000 1,000,000 1,200,000 1,400,000 Mild 4 Moderate 4 Severe 4 Number of patients 1 Diagnosed 2 Treated with AChE inhibitor 3 1 Mattson Jack; 2 MMI MDAD, 2001; 3 On CHeI—midpoint of last year’s treatment by severity rates and rates reported in Reminyl uptake 2001; 4 Decision Resources. Number of Patients Disease Stages Potential to Increase Diagnosis and Treatment Across Disease Stages

4. Hauber AB, Gnanasakthy, Snyder EH, et al. Pharmacoeconomics. 2000(April);17(4):351-360 Probability of Institutionalization 0.0 0.2 0.4 0.6 0.8 1.0 Mild (MMSE: 21–30) Moderate (MMSE: 11–20) Severe (MMSE: 0–10) Severity of AD 0.017 0.345 0.867 Increased Probability of Institutionalization by Disease Severity

5. Inability to handle money Inability to tell time Time doing hobbies Dresses properly Forgetfulness Time rearranging objects Conducting family finances Ability to use phone Confusion Eating manners Mild AD (GDS 3) Moderate AD (GDS 4) Severe AD (GDS  5 or 6) 80 70 60 50 40 30 20 Adapted from Grossberg, 1999. More impairment Mean PDS Score Effects of Disease Severity on Impairment of ADL in Patients With AD

6. Improvement Deterioration Baseline48121620 1 0 –1 –2 –3 –4 –5 –6 ADCS/ADL Scores Mean (± SEM) Change from Baseline Time (Weeks) AD Cooperative Study Activities of Daily Living Inventory; OC analysis Tariot et al, 2000. Placebo (n = 234) Galantamine 8 mg/day (n=106) Galantamine 16 mg/day (n=211) Galantamine 24 mg/day (n=212) Effects of Galantamine on ADL: ADCS/ADL Scores Mean Change from Baseline

7. * Mohs et al, 2001; Feldman et al, 2001; Winblad et al, 2001. *P<.05 vs placebo **P<.01 vs placebo OC analysis 0 10 20 30 Change from Baseline (%) Donepezil Placebo Clinical decline Assessment scale PDSADFACSDAD n=181n =196n = 97n=126n=95n=121 MMSE=17.1 MMSE=19.35 MMSE=12.05 ** Effect of Donepezil on ADL at Endpoint: Change in Assessment Scale Score from Baseline

8. Corey-Bloom et al, 1998. 2 1 0 –1 –2 –3 –4 –5 –6 –7 Mean Change from Baseline 0121826 Improvement Decline 6–12 mg (n=231) 1–4 mg (n=233) Placebo (n=235) * *P<.05 vs placebo; **P<.001 vs placebo Weeks ** Effects of Rivastigmine on ADL: Progressive Deterioration Scale (PDS)

9. Improvement in ADL: Rivastigmine Treatment vs Placebo (PDS) Potkin et al, 2002. Item Mild (GDS ≤3) Moderate (GDS=4) Severe (GDS ≥5) Ability to handle money Ability to tell time Time spent on hobbies Participating in family finanaces Ability to dress properly Reduced forgetfulness Time rearranging objects Ability to use the phone Comfort in different settings Proper eating manners

10. Agitation Diurnal rhythm Irritability Wandering Aggression Hallucinations Mood change Socially unacceptable behavior Delusions Sexually inappropriate behavior Accusatory behavior Suicidal ideation Paranoia Depression Months before/after Diagnosis Anxiety Social withdrawal 100 80 60 40 20 0 –40–30–20–100102030 Frequency (% of Patients) Jost and Grossberg, 1996. Peak Frequency of Behavioral Symptoms as AD Progresses

11. N=69; CDR=clinical dementia rating scale; most common psychotic symptoms: agitation, wandering, irritability, withdrawal, physical assault Farber NB, et al. Arch Gen Psychiatry. 2000(Dec):57(12):1165-1173 Patients Affected (%) 0 20 40 60 80 CDR 0.5CDR 1CDR 2CDR 3 Psychotic Symptom Frequency Increases With Disease Severity

12. NPI=neuropsychiatric inventory; Tariot et al, 2000. N=978 Effect of Galantamine on Behavioral Symptoms: NPI Total Scores –3 –2 –1 0 1 2 3 4 Mean (± SEM) Change in NPI Score from Baseline Baseline12345 Placebo Galantamine 8 mg/d Galantamine 16 mg/d Galantamine 24 mg/d Time (Months) Improvement Deterioration

13. –3 –2 –1 0 1 2 3 4 Mean Change from Baseline NPI-NH Individual Item Score at Week 24 Delusions Hallucinations Agitation/aggression Depression/dysphoria Anxiety Elation/euphoria Apathy/indifference Disinhibition Irritability/lability Aberrant motor behavior Night-time behavior Appetite/eating Placebo (n = 105) Donepezil (n = 103) Improvement Baseline Decline ITT, LOCF analysis NPI-NH=neuropsychiatric inventory-nursing home version Tariot et al, 2001 Donepezil Behavioral Effects in Nursing Home Patients at Week 24: Mean Change from Baseline in NPI-NH Individual Items

14. * * * *** * * * Mean change from baseline -3 -2 0 1 2 3 4 *P<.05 vs baseline; **P<.001 vs baseline; OC analysis Improvement Agitation Irritability Anxiety Aberrant motor behavior Apathy Depression Delusions Disinhibition Hallucinations Euphoria Night-time behavior Appetite Cummings et al, 2002. N=99 Rivastigmine: Change on NPI-NH at Week 52 for Patients Who Had the Symptom at Baseline

15. –3 –2 –1 0 1 2 3 Mean Change from Baseline n=234n=212 n=103 n=98 Improvement Placebo Galantamine (24 mg/day Placebo Donepezil (10 mg/d) Open-label Rivastigmine (3–12 mg/d) MMSE=17.7MMSE=14.4 MMSE=11.8MMSE=9.2MMSE=10.8 NPI-10 1 NPI-12 2 NPI-12 3 NPI-12 4 NPI-12 5 OC analysisITT, LOCF analysis OC analysis OC analysisOC analysis OutpatientsNursing homeCommunity/Nursing homeNursing home assisted living Adapted from Tariot et al, 1 2000; Tariot et al, 2 2001; Feldman et al, 3 2001; Cummings et al, 4 2000; Bullock et al, 5 2001. Placebo Donepezil (10 mg/d) n=125 n=119 Baseline n=113 Open-label Rivastigmine (3–12 mg/d) NPI Improvement following AChE Inhibitors and Dual AChE and BuChE Inhibitors Treatment in Five Studies (Mean Change per Item after Approximately 6 Months)

16. Increased Dose Terminated Medication Antipsychotics (n=55) Anxiolytics (n=33) Antidepressants (n=57) Reduced Dose Nursing Home AD Patients at Week 26 Anand R, et al. Neurobiol Aging. 2000;21:5220 0 5 10 15 20 25 30 35 Effects of Rivastigmine on Psychotropic Medication Use Patients Taking Psychotropic Drugs During Rivastigmine Treatment (%)

17. Rivastigmine and Donepezil Administration Increases Basal ACh Release in Aged Rats Chronic (21 Days) Ach (fmol/µL) 18 hours after the last administration; N=4–8; *P<.005 vs controls Scali et al. J Neural Transm. 2002;109(7-8):1067-1080

18. Most Frequent Adverse Events with 1-Week Dose Titration of ChE Inhibitors Physicians’ Desk Reference, 2003; Raskind MA, et al. Neurology. 2000(June 27);54(12):2261-2268 DonepezilGalantamineRivastigmine Adverse Event (%) Placebo (n=315) 10 mg/Day (n=315) Placebo (n=213) 24 mg/Day (n=212) Placebo (n=868) 6–12 mg/Day (n=1,189) Nausea61913371247 Vomiting38821631 Anorexia27614317 Diarrhea51510121119

19. Adverse Events with 1- vs 4-Week Titration of Galantamine Physicians’ Desk Reference, 2003; Raskind MA, et al. Neurology. 2000(June 27);54(12):2261-2268 1-Week Titration (%)4-Week Titration (%) Adverse Event (%) Placebo (n=213) 24 mg/Day (n=212) Placebo (n=286) 24 mg/Day (n=273) Nausea1337517 Vomiting821110 Diarrhea101266 Anorexia61439

20. Tolerability of Donepezil: Incidence of Common Adverse Events by Titration Rate Physicians’ Desk Reference, 2003. No Titration1-wk Titration6-wk Titration Adverse Event (%) Placebo (n=315) 5 mg/Day (n=311) 10 mg/Day (n=315) 10 mg/Day (n=269) Nausea 65196 Diarrhea 58159 Insomnia 66146 Fatigue 3483 Vomiting 3385 Muscle cramps 2683 Anorexia 2373

21. Slow (4 Weeks)-Dose Titration with Rivastigmine Provides Low Potential for AEs Shua-Haim et al, 2001. N=212 Adverse EventN% Nausea/vomiting83.8 Abdominal pain10.5 Diarrhea52.4 Agitation73.3 Confusion41.9 Hallucinations10.5 Total2612.4

22. Acute Titration-Related AEs with ChE Inhibitor Therapy Cholinergically mediated AEs include nausea, vomiting, abdominal pain, dizziness, diarrhea, weight loss/anorexia Tend to be transient, most frequent during dose escalation and of mild to moderate intensity Nausea and vomiting are centrally mediated, caused by too rapid an increase in brain ACh levels Slow-dose escalation and administration with food are proven ways to reduce the incidence of these AEs, especially with rivastigmine and galantamine Go slowly; give with food with Exelon and Reminyl

23. Erythrocyte: Globular Dimer G2 Muscle: Asymmetric A12 CNS: Brain PNS: Skeletal muscle Erythrocyte Globular Tetramer G4 Globular Monomer G1 Darvesh S. et al. Nature Reviews. 2003: 4:131-138. Molecular Forms of AChE

24. Corte x Hippocampus Rivastigmine Heptylphysostigmine Human Brain AChE 7654321076543210 Ratio IC G4/G1 507 Inhibitory Influence of ChE Inhibitors on Molecular Forms Human Control Cortex G1/G4 16.0S11.4S G1 G4 Ratio G4/G1: 2.1 ChE Activity nmol x min –1 xml –1 Fraction 4.8S 75 50 25 0 Physostigmine Donepezil 05101520253035 Enz et al, 1993. Ratio G4/G1: 2.1 G1G4 16.0S11.0S4.8S Fraction Nr. 05101520253035 75 50 25 0 Human Alzheimer Cortex G1/G4 G1 preferring G4 preferring

25. Enz, et al. Prog Brain Res. 1993;98:431-8. Number of Fraction 0102030 0.00 0.50 1.00 0102030 0 25 50 0102030 0 25 50 0102030 0 25 50 0102030 0 25 50 Caudate nucleus Normal Adult Brain AD AChE (µmol/Min. x mL Fraction) Frontal cortex Nucleus basalis G1G4 G1G4 0102030 0.00 0.50 1.00 AChE Isoforms in Normal and AD Brains

26. ChE Inhibitors: Tolerability **Clinical significance is unclear; CV=cardiovascular; EPS=extrapyramidal symptoms; +/- little or none; + mild; ++ moderate Inglis, 2002. DonepezilRivastigmineGalantamine Cholinergically mediated acute AEs Yes Drug–drug interactions Yes*None knownYes* Chronic AEs Sleep disturbances +++/– CV problems ++/–+  EPS +++/– Behavioral disturbances ++/–+

27. 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 Rivastigmine Donepezil *P<.05; **P<.01 vs rivastigmine Rizzo et al, 2001. Adverse Events per 100,000 Prescriptions All AdverseSerious Adverse Major Reactions Reactions Reactions from Clinical Trials * ** Adverse Events per 100,000 Prescriptions for Rivastigmine and Donepezil

28. 2C9/10/19 1A2 3A4 2D6 31% 54% 11% 4% CYP450=cytochrome P450A Anzenbacher P, Anzenbacherova E. Cell Mol Life Sci. 2001(May);58(5-6):737-747; Scordo MG, Spina E. Pharmacogenomics. 2002(March);3(2):201-218; Grossberg GT, et al. Int J Geriatr Psychiatry. 2000(March);15(3):242-247 Significance of Drug-Drug Interaction 5 CYP450 isoenzymes account for ~99% of all drug metabolism ~85% of drug metabolism is mediated by 2 members of the CYP450 system: CYP3A4 and CYP2D6 Safety of rivastigmine: no clinically relevant interactions with 22 therapeutic classes of drugs

29. ChE Inhibitors: Pharmacokinetic Characteristics Physicians’ Desk Reference, 2002; Nordberg and Svensson, 1998; Polinsky, 1998; Inglis, 2002. AChE Inhibitors Dual AChE/ BuChE Inhibitor Characteristic DonepezilGalantamineRivastigmine Plasma half-life (hour) Brain half-life ~70 70 ~6 6 ~1 12 Elimination pathway Liver 50% kidney 50% liverKidney Metabolism by 2D6/3A4 isoenzymes Yes Minimal Administer with food? NoYes Enhanced G1 inhibition NoUnknownYes

30. Anand, et al, 2000. Last Prescribed Dose of Rivastigmine (mg/d) Improvement Limits Predicted response –2.0 –1.0 0.0 1.0 2.0 3.0 4.0 024681012 1.5 1.0 0.5 0.0 –0.5 –1.0 –1.5 Last Prescribed Dose (mg/day) Mean change from baseline on MMSE 024681012 Predicted response Limits Improvement Predicted response Limits 2.0 1.0 0.0 –1.0 –2.0 –3.0 –4.0 –5.0 –6.0 –7.0 –8.0 Last Prescribed Dose (mg/day) 024681012 Improvement Mean change from baseline on PDS Mean Change from Baseline on ADAS-Cog ADAS-CogPDS MMSE Linear Dose Response of Rivastigmine in ADAS-Cog, PDS, and MMSE Mean Change from Baseline at Week 26

31. 6–12 mg/d1–4 mg/dPlacebo –3 –2 –1 0 1 2 3 4 5 ADAS-Cog Score Mean Change from Baseline MHIS = 0MHIS >0 *** ** * Improvement Decline OC analysis, week 26 *P<.002 vs placebo; **P=.02 vs 6–12 mg/day (MHIS = 0); ***P<.001 vs placebo MHIS=modified Hachinski ischemic scale Adapted from Kumar, et al, 2000. (n = 287)(n = 244) Effects of Rivastigmine on Cognition in Patients With AD (MHIS score = 0) and AD with Vascular Risk Factors (MHIS >0)

32. -7 -6 -5 -4 -3 -2 0 OC analysis, week 26 *P<.05 vs placebo; **P<.001 vs placebo Adapted from Kumar, et al, 2000. Improvement Decline PDS Score Mean Change from Baseline MHIS=0MHIS >0 (n=287)(n=244) 6–12 mg/d1–4 mg/dPlacebo * ** Effects of Rivastigmine on ADL in Patients with AD (MHIS score=0) and AD With Vascular Risk Factors (MHIS >0)

33. VAD=vascular dementia MID=multi-infarct dementia Evolution of VAD Syndrome Alzheimer: (1895) arteriosclerotic brain degeneration Tomlinson: (1967) volume of brain infarction Hachinski: (1967) MID cumulative multiple small strokes Roman: (1967) VAD –Infarcts—size, location, and number –Risk factors—DM, hypertension, hyperlipidemia

34. Other=(AD + CVD DLB, FTD, unknown); CVD=cerebrovascular disease; DLB=Lewy bodydementia FTD=frontotemporal dementia Lobo, et al, Neurology. 2000. AD 53.7% VAD 15.8% Other 30.5% Prevalence of Dementias: European Study of 2346 Cases

35. Vascular Risk Factors Hyperlipidemia Hypertension Diabetes Obesity Smoking history Alcohol history TIA FHx, Hx: Strokes, cardiac/periph vas disease Coagulopathy EKG abnormalities Atrial fib or arrhythmias

36. Scheltens, 2001. VAD: MRI Required for Clinical Diagnosis

37. *P<0.01 Sakurada, et al, 1990. * * * 9964n = Hippocampal ChAT Activity

38. *P<.05 Sakurada, et al, 1990. * 9964n = Hippocampal Muscarinic Receptors

39. *P<.05 vs placebo Erkinjuntti, et al, 2002. 3 2 1 0 –1 –2 –3 –4 –5 ADAS-Cog Score Mean Change from Baseline * VADAD + CVD (n=188)(n=239) Improvement Effects of Galantamine Treatment for 26 Weeks on Cognition in VAD and AD Patients With CVD

40. *P<.001 vs cardioaspirin and P<.05 vs baseline Moretti, et al, 2002. Rivastigmine (3–6 mg/d) Cardioaspirin -4.0 -3.0 -2.0 0 1.0 Improvement Decline 0138121622 Months Change from Baseline in NPI Score at 22 Months * Rivastigmine in Subcortical VAD: Efficacy up to 22 Months in an Open-label Study

41. *P<.001 improvement vs cardioaspirin and P<.01 vs baseline TPC=ten point clock drawing Moretti, et al, 2002. Rivastigmine (3–6 mg/day) Cardioaspirin 4.0 3.0 2.0 1.0 0 Improvement Decline 0138121622 Months Change from baseline in TPC score at 22 months * Rivastigmine in Subcortical VAD: Efficacy up to 22 Months

42. *P<.01 vs cardioaspirin and P<.05 vs baseline RSS=relative stress scale Moretti, et al, 2002. Rivastigmine (3–6 mg/day) Cardioaspirin -10.0 -7.5 -5.0 -2.5 0 -2.5 Improvement Decline 0138121622 Months Change from baseline in RSS score at 22 months * Rivastigmine in Subcortical VAD: Efficacy up to 22 Months

43. 15 10 5 0 15 10 5 0 4321043210 *Lewy body variant of AD Perry, et al, 1985, 1994. NCADDLBPD NCADDLB*PD Normal controls (NC) AD DLB Parkinson’s disease (PD) Parietal cortex Temporal cortex Occipital cortex Decreased Cholinergic Activity Associated With Neuropathology of AD, DLB, and PD ChAT (nmol/h/mgP)

44. Brain Infarction and the Clinical Expression of Alzheimer disease: The Nun Study (N=61) Participants with AD pathology and brain infarcts had poorer cognitive function and a higher prevalence of dementia than those without infarcts (OR 20.7) Fewer neuropathologic lesions of AD appeared to result in dementia in those with lacunar infarcts in the basal ganglia, thalamus, or deep white matter Cerebrovascular disease can play an important role in determining the presence and severity of the clinical symptoms of AD

45. Campbell, Stephens, Ballard, 2001. Dementia With Lewy Bodies 15%–25% of all dementia in the elderly Onset ~75–80 years Duration ~3.5 years (<1–20) Slight male predominance Characterized by –Fluctuating cognitive impairment (~80%) –Persistent visual hallucinations (>60%) –Systematized delusions (~70%) –Depression (38%) –Parkinsonism (65%–70%) –Neuroleptic sensitivity (>50%)

46. Dementia With Lewy Bodies (cont’d) DLB is underdiagnosed and may constitute 15% of all dementias Supportive Features Transient loss of consciousness 40% Falls and syncope50% Systematized delusions70% Neuroleptic sensitivity50% Depression50% REM sleep behavior disorder25%

47. * * * * *P<.05 Ballard C, Walker M. Curr Psychiatry Rep. 1999(Oct);1(1):49-60 0 10 20 30 40 50 60 70 80 DLB AD Visual Hallucinations Auditory Hallucinations Delusions Misidentification Depression Percentage of Patients with Symptoms Neuropsychiatric Symptoms in DLB vs AD

48. Ranked by Frequency of Occurrence (% of Patients) McKeith IG, Ballard CG, Perry RH, et al. Neurology. 2000(March 14);54(5):1050-1058 Apathy/indifference72.5Appetite; eating disorder34.2 Anxiety70.0Elation/euphoria18.3 Depression/dysphoria65.8Disinhibition16.7 Delusions58.3 Agitation/aggression55.0 Irritability/lability55.0 Aberrant motor behavior53.3 Symptoms in >50% of Patients (%) Symptoms in <50% of Patients (%) Behavioral Symptoms at Baseline (NPI)

49. 0 1 2 AD (n=12) DLB (n=4) Average BEHAVE-AD Score Baseline6 monthsBaseline6 months P=NS 0 1 2 Increase in MMSE Score ADDLB 3 4 5 P=NS NS=nonsignificant Samuel, et al, 2000. Behavioral and Cognitive Responses to Donepezil in AD and DLB (Open-label, 5 mg/d for 6 Months)

50. *P<.01 vs placebo; **P<.001 vs placebo † Responder definition recommended by NPI author (J Cummings) Adapted from McKeith, et al, 2000. Baseline Improvement NPI 10-Item Score * Mean Change from Baseline –8 –7 –6 –5 –4 –3 –2 –1 0 Rivastigmine Placebo 1220 Weeks Rivastigmine 3–12 mg/d (n=59) Placebo (n=61) NPI 10-Item Score—Percentage of Patients Improving by  30% from Baseline † * 70 60 50 40 30 20 10 0 Patients Improving (%) Week 20 Effects of Rivastigmine on Behavioral Symptoms in DLB (Double Blind)

51. Perry, et al, 1985; Korczyn, 2001. PD and Dementia At least one-third of PD patients develop dementia Patients with PD have degeneration of the nucleus basalis of Meynert and low brain ChAT levels The dementia of PD is not improved by dopaminomimetic drugs ChE inhibitor therapy in PD is indicated

52. Baseline Rivastigmine 3–12 mg/d *P<.02; ** P<.015; OC analysis Reading PJ, Luce AK, McKeith IG. Mov Disord. 2001(Nov);16(6):1171-1174 8642086420 NPI Hallucination and Sleep Scores Increasing Symptoms * N=12 ** 8642086420 Hallucination Sleep NPI Hallucination and Sleep Scores in PD Patients Receiving Rivastigmine

53. * ** *P<.05; **P<.01 vs baseline; OC analysis; Reading PJ, Luce AK, McKeith IG. Mov Disord. 2001(Nov);16(6):1171-1174 0 5 10 15 20 25 30 35 MMSE UPDRS 10 15 20 25 30 35 Improvement 0 2 4 6 8 10 12 NPI Caregiver Distress 0 5 Improvement Baseline Rivastigmine 3–12 mg/d Rivastigmine in PD: Cognition, Motor Function, and Caregiver Burden

54. Effects of Rivastigmine Treatment on ADAS-Cog and UPDRS Motor Scores in PDD N=28 *P=.004 vs baseline Giladi, et al, 2003. BaselineWeek 12Week 26 Mean rivastigmine dose (mg/d)7.27.5 ADAS Cog total score30.823.623.5* UPDRS motor43.942.943.6 ADAS-Cog Subscores Showing Statistically Significant Improvement from Baseline at Week 26P Naming0.05 Recognition0.007 Word finding0.02 Remembering instructions0.008 Concentration0.0005

55. Effects of Rivastigmine Treatment on Clinical Global Impression of Change from Baseline *P<.0001 CGIC=clinical global impression of change CGIC Scale: 3=marked improvement, 2=moderate improvement, 1=mild improvement, 0=no change, -1=mild worsening, -2=moderate worsening, -3=marked worsening; N=28 Giladi, et al, 2002. Week 12Week 26 Mean dose (mg/d)7.37.5 Patient perspective1.6*1.5* Caregiver perspective1.7*1.3* Neurologist perspective1.8*1.7*

56. Emre, 2002. Reasons to Consider Switching ChE Inhibitors Switching should be considered when there is –A lack of initial response to treatment –Loss of response during long-term treatment Switching should not be considered in patients responding to current treatment

57. Switching: Medical Rationale Therapeutic strategy performed routinely in daily medical practice Employed across a spectrum of medical conditions –Depression (SSRIs) –Migraine (triptans) –Microbial infection (antibiotics) –Heart failure (ACE inhibitors) Purpose of switching is to maximize the benefits of treatment

58. N=17; 12-month, open-label extension of a 6-week open-label trial; week 18 vs baseline; Rasmusen L, et al. Clin Ther. 2001;23(suppl A):A25-A30; Bullock R, Connolly C. Int J Geriatr Psychiatry. 2002(March);17(3):288-289 No. of Donepezil Nonresponders Who Responded to Galantamine 1 Per ADAS- cog Per ADCS/ ADL 9 8 0 20 40 60 80 100 Side Effects Donepezil Group (n=18) Lack/Loss of Efficacy Group (N=22) Patients in Whom Switch Was Beneficial (%) 2 0 4 8 12 16 20 Changing from Donepezil to Galantamine and Rivastigmine

59. 15.4 74.4 11.5 54.5 Rivastigmine Responders Auriacombe S, Pere JJ, Loria-Kanza Y, Vellas B. Curr Med Res Opin. 2002;18(3):129-138 Discontinued Rivastigmine Due to AEs 0 20 40 60 80 Patients (%) 0 20 40 60 80 Patients (%) Lack of efficacy of donepezil (n=304) Unable to tolerate donepezil (n=78) Rivastigmine Responders Discontinued Rivastigmine Due to AEs Lack of Tolerability and Efficacy With Donepezil Do Not Preclude Response to Rivastigmaine

60. Emre, 2002; Morris, 2002. *Patients may derive clinical benefit from escalating the dose further to 9 mg daily (4.5 mg twice daily), and 12 mg daily (6 mg twice daily), at intervals of no less than 4 weeks. No washout period required Washout for 7 days or until symptoms resolve Initiate rivastigmine therapy at 3 mg daily (1.5 mg twice daily) Minimum of 4 weeks Monitor patient for efficacy, safety, and tolerability, as with standard dosing guidelines Escalate dose to 6 mg daily (3 mg twice daily) and recheck in 4 weeks* Safety or tolerability problem Unsatisfactory treatment on donepezil Patient experiencing lack of response or loss of efficacy Donepezil or galantamine to rivastigmine Donepezil or rivastigmine to galantamine NO Is the patient stabilized on current therapy (ie, no tolerability problems)? YES No washout period required Initiate galantamine therapy at 8 mg daily (4 mg twice daily) 4 weeks Monitor patient for efficacy, safety, and tolerability, as with standard dosing guidelines Escalate dose to 16 mg daily (8 mg twice daily) and recheck in 4 weeks 7-day washout is recommended or until symptoms resolve Guidelines for Switching ChEIs

61. Medical Rationale for Switching Switching is a relatively new concept in AD treatment Many physicians stop ChE inhibitor treatment altogether if patient fails to show response or loses response to current agent However, evidence suggests that switching between ChE inhibitors represents a valuable therapeutic option to maximize treatment benefits over a longer period

62. Reisberg B, Doody R, Stoffler A, et al. N Engl J Med. 2003(April 3);348(14):1333-1341 Memantine in Moderate-to-Severe AD 252 patients randomly assigned to placebo or 20 mg of memantine for 28 weeks Memantine superior to placebo on –CIBIC-plus –ADCS-ADL severe –Severe Impairment Battery (SIB) No AEs observed Memantine recently FDA approved for moderate to severe AD

63. Summary AChE inhibitors and dual ChEIs are proven effective in the treatment of the ABC of AD Patients with severe AD maintain robust behavioral responses to ChEI Behavioral disturbances often result in patient institutionalization As AD progresses, the number and severity of behavioral disturbances increases ChE inhibitors can reduce the need for concomitant antipsychotics, antidepressants and anxiolytic medications

64. Summary AD associated with vascular risk factors, cerebral vascular disease, and vascular angiopathy Cholinergic deficits in VAD, AD, and mixed dementias There is increasing evidence of efficacy for ChEIs in PDD, DLB, and VAD, which may result in an extended role for these agents All ChEIs have differing modes of action and pharmacokinetic profiles; therefore, switching can be efficacious