1. Clinical Update: Full Spectrum Treatment of Alzheimer’s Disease

2. Alzheimer’s Disease Economic Consequences ► Third most expensive disease in the U.S. ► Costs over $100 billion/year ► Further $33 billion in lost productivity and other employer costs ► 3/4 of patients admitted to residential care within 5 years of diagnosis Evans DA, Scherr PA, Smith LA, et al. Aging (Milano). 1990(Sept);2(3):298-302; Ernst RL, Hay JW. Am J Public Health. 1994(Aug);84(8):1261-1264; Alzheimer’s Association, 2002

3. Growth of the Problem Alzheimer’s Prevalence in the U.S. by Age (1997) Projected Dementia Patients in the U.S. (in Millions) 70 50 30 10 45 55 65 75 85 90 Percentage 200020102020203020402050 4.0 5.8 6.8 8.7 11.8 14.3 Age (Years) Year Guttman R, Altman RD, Nielsen NH. Arch Fam Med. 1999(July-Aug);8(4):347-353 0

4. Suggested Diagnostic Workup for Dementia ► Diagnostic interview: Both the patient and a reliable informant ► Office-based clinical assessment l Comprehensive physical examination l Neurologic and mental status evaluation l Brief quantified cognitive function evaluation (MMSE) ► Laboratory evaluation and imaging: CBC, chemistries, liver function, thyroid, vitamin B 12; CT head scan or non contrast MRI ► Neuropsychologic testing or functional scan (PET) if diagnosis is unclear Alva, Clin Geriatr Med 19 (2003)763-776

5. The Stages of Alzheimer’s Disease Mild Moderate Severe Memory Loss Language Problems Mood and Personality Changes Diminished Judgment Behavioral, Personality Changes Unable to Learn or Recall New Information Long-Term Memory Affected Wandering, Agitation, Aggression, Confusion Require Assistance with ADLs Unstable Gait Incontinence Motor Disturbances Bedridden Dysphagia Mute Poor/No ADLs Vacant LTC Placement Common Stage Symptoms ADL = activities of daily living LTC = long-term care

6. AP = amyloid plaques; NFT = neurofibrillary tangles Courtesy of George Grossberg M.D.; St. Louis University Neuropathological Changes Characteristic of AD Normal AP AD NFT

7. ADAS-Cog Mean Change from Baseline Decline in ADAS-Cog score based on the natural history of untreated patients with moderate AD* -6 0 6 12 18 06121426385062748598 Improvement Decline Model-Based Analysis: ADAS-Cog Score Mean Change from Baseline N=133 Rogers and Friedhoff, 1998; *Stern et al, 1994

8. Cognitive Decline in AD Correlates with Rate of Cerebral Atrophy y = 0.48x + 0.34 r = 0.8 Fall in MMSE Score Loss of Brain Volume (%) Fox, DRG98 12 10 8 6 4 2 0 0 2 4 6 8 10 12 14 16 18

9. UCI Brain Imaging Center Alzheimer’s DiseaseNormal Control Decreased Temporoparietal Occipital Lobe Cerebellum 0.0019.36 Frontal Lobe mg/100g/min

10. Management of the AD Patient ► Maintain quality of life ► Maximize function ► Stabilize cognition ► Treat mood and behavior problems ► Ease caregiver burden Source:Cefalu C, Grossberg GT. Diagnosis and Management of Dementia. American Family Physician Monograph, No. 2. Leawood, Kan: American Academy of Family Physicians; 2001. Treatment Goals

11. Treatment Consideration: When to Begin? ► Current guidelines (AAN) recommend that all patients with AD be treated at time of diagnosis l Well established rationale for ChEI treatment in patients diagnosed with mild or moderate AD l Well established rationale for treating patients diagnosed with moderate to severe AD with memantine l Patients with severe AD have been shown to benefit from treatment 1-3 ► Establish realistic expectations of treatment Sources:1. Winblad B, et al. Int J Geriatr Psychiatry. 1999;14:135-146. 2. Reisberg B, et al. N Engl J Med. 2003;348:1333-1341. 3. Tariot P, et al. J Am Geriatr Soc. 2003;51(S4):S225-S226.

12. Neurotransmitter Basis for Current Dementia Drug Treatment Interventions ► Acetylcholine and glutamate are 2 neurotransmitter systems known to be important in learning and memory l Acetylcholine Cholinergic neurons are lost in AD Theory: increase available acetylcholine to improve or maintain cognitive function l Glutamate Excessive or erratic glutamate stimulation impairs learning and can cause neuronal toxicity Theory: normalize glutamatergic neurotransmission to maintain or improve cognition and prevent neurotoxicity

13. ACh = acetylcholine; AChE = acetylcholinesterase; BuChE = butyrylcholinesterase; ChAT = choline acetyltransferase; CoA = coenzyme A; MR = muscarinic receptor; NR = nicotinic receptor Adapted from: Adem, 1992 Normal Cholinergic Function Postsynaptic Neuron AChE Acetyl CoA Choline ACh Presynaptic Neuron Synaptic Cleft Cholinergic Receptors Acetate Choline + + Astrocyte ACh AChE BuChE ChAT Noncholinergic Action MR NR MR NR MR

14. Pharmacotherapy for Mild to Moderate Alzheimer’s Disease FDA Approved: ► Cholinesterase inhibitors (ChEIs) l Tacrine l Donepezil l Galantamine l Rivastigmine l Monotherapy as standard treatment New Developments in Mild AD: ► NMDA-receptor antagonist (memantine) – Monotherapy l Combination Therapy

15. Important Considerations in Alzheimer’s Disease Treatment* Galantamine Plasma protein binding Rivastigmine  40% Donepezil   96% 18% None Known † No ketoconazole, quinidine, and other drugs metabolized by CYP2D6/3A4 None stated amitriptyline, cimetidine, erythromycin, fluoxetine, fluvoxamine, ketoconazole, paroxetine, quinidine, and other drugs metabolized by CYP2D6/3A4 Yes Listed drug-drug interactions Dosage adjustment required for renal/ hepatic impairment Memantine 45% carbonic anhydrase inhibitors, sodium bicarbonate Yes Metabolism Elimination pathway Not Hepatic CYP450 Partially Hepatic Kidney (inactive metabolite) Liver 50% Kidney 50% Liver Kidney *Data as listed in US prescribing information for rivastigmine, donepezil, galantamine, and memantine. † Minimal metabolism occurs via the major cytochrome P450 isoenzymes. Based on in vitro studies, no pharmacokinetic drug interactions with drugs metabolized by CYP1A2, 2D6, 3A4/5, 2E1, 2C9, 2C8, or 2C19 are expected.

16. ChEI Monotherapy in Mild to Moderate AD: Efficacy Mean Change From Baseline Improvement Decline.2.1 0 –.1 –.2 –.3 –.4 –.5 1218 26 † * * * Week Placebo Rivastigmine 1- 4 mg Rivastigmine 6-12 mg Global: CIBIC-Plus 2 Rivastigmine Time (Months) –4 –2 0 –5 –3 –1 1 12345 Galantamine 8 mg/day Galantamine 16 mg/day Galantamine 24 mg/day Placebo † † Function: ADCS-ADL 3 Galantamine *P<.05; † P<.01; ‡ P≤.001. CIBIC-Plus = Clinician's Interview-Based Impression of Change with caregiver input; ADCS-ADL = Alzheimer's Disease Cooperative Study – Activities of Daily Living inventory. Sources: 1. Winblad B, et al. Neurology. 2001;57:489-495. (Data represent change in least squares [LS] mean) 2. Corey-Bloom J, et al. Int J Geriatr Psychopharmacol. 1998;1550:55-65 3. Tariot PN, et al. Neurology. 2000;54:2269-2276 Cognition: MMSE 1 Donepezil –2.5 –2.0 –1.5 –1.0 –0.5 0 0.5 1.0 Donepezil Placebo Week 52362412 ‡ 0 LOCF ‡ * ‡ (LS)

17. ChEI Drug-Drug and Drug-Disease Interactions ► Pharmacodynamic l Digoxin, β blockers — ChEIs may exert vagotonic effects on sinoatrial and atrioventricular nodes l ChEIs may exaggerate succinylcholine-type muscle relaxation during anesthesia l Concurrent anticholinergic or cholinergic pharmacotherapy ► Pharmacokinetic l None — rivastigmine l Minimal — donepezil l Moderate — galantamine + CYP450 inhibitors (2D6, 3A4) ► Renal impairment l Clearance of galantamine decreased in renal insufficiency Source: Bentué-Ferrer D, et al. CNS Drugs. 2003;17:947-963.

18. Treatment Consideration: When to Increase Dose or Switch Agents? ► Dose escalation may need to be slower than suggested in Physicians’ Desk Reference ► Side effects to treatment are justifiable reasons to switch ► Typically, switching ChEIs can be done without washout period and with shorter titration periods ► Evidence shows that memantine, a non- cholinergic agent, is effective as monotherapy and in combination therapy with a ChEI 1,2 Sources: 1. Reisberg B, et al. N Engl J Med. 2003;348:1333-1341. 2. Tariot P, et al. JAMA. 2004;291:317-324.

19. Treatment Consideration: When to Stop? ► May not tolerate cholinergic side effects despite slow and careful escalation ► When medication is prescribed, give it time to work; gauge different domains ► Establishing benefit in an individual patient may be influenced by their staging ► Studies suggest that most subjects benefit and that long-term treatment is useful ► May see some deterioration when medication is stopped

20. Memantine in Mild to Moderate AD: Clinical Trials ► Monotherapy Trials: l US 24-week trial Statistically significant advantage of memantine over placebo at end point on cognitive and global measures l European 24-week trial Numerical advantage at end point for memantine (not statistically significant) over placebo for cognitive and global measures ► Combination Therapy Trials: l US 24-week trial of patients on stable ChEI therapy Numerical advantage at end point of memantine over placebo for cognitive, functional, and global measures (not statistically significant) Source: Peskind E, et al. Presented at the 8th Congress of the European Federation of Neurological Societies; September 4-7, 2004; Paris, France.

21. Decline Memantine Monotherapy in Mild to Moderate AD: US 24-Week Trial Results Source: Peskind E, et al. Presented at the 8th Congress of the European Federation of Neurological Societies; September 4-7, 2004; Paris, France. September 4-7, 2004; Paris, France. Cognition: ADAS-Cog Improvement LS Mean Change From Baseline (SE) *.003 *.009 *.003 *.002 4 8 12 18 24 -3 -2 0 1 2 3 Treatment Week Treatment Week Memantine Placebo195 195 195 191 191 n = 195 198 198 198 197 197 195 195 n = 198 0 Improvement Decline Treatment Week Treatment Week Mean Score (SE) Global Change: CIBIC-Plus 4 812 18 24 *.021*.024 *.015 *.004 3.5 4 4.5 5 Memantine Placebo196 196 196 n = 194 197 197 197 n = 197 Intention-to-treat (ITT) population; last observation carried forward (LOCF); *P value for LS mean difference (memantine vs placebo)

22. Memantine/Rivastigmine Combination Therapy in Mild to Moderate AD* Design ► Multicenter (20), open-label, single-arm, historically controlled Population ► 95 outpatients with mild to moderate AD (MMSE, 10-29) on stable rivastigmine Treatment ► Memantine 20 mg/d (10 mg bid) 4-week titration (5 10 15 20 mg) Duration: 12 weeks Assessments - Primary: ADAS-Cog *Memantine is not indicated for the treatment of mild AD. ADAS-Cog = Alzheimer’s Disease Assessment Scale–Cognitive Subscale. Source: Riepe MW, et al. 17th U.S. Psychiatric and Mental Health Congress Research Abstract Presentation Book; Volume 1, #74, page 20; November 17-20, 2004; San Diego, Calif.   0 5 10 15 20 25 30 -12-8-40+4+8 Change in ADAS-Cog Memory Score Number of Patients 

23. Memantine Adverse Events ► No clinically relevant differences between memantine- and placebo-treated groups were observed in: l Adverse event profile l Vital signs values l Laboratory parameters l ECG values ► Memantine at a dosage of 20 mg/d l Exhibits a safety profile similar to that of placebo l Is well tolerated and safe for the treatment of patients with AD

24. Memantine: Drug-Drug and Drug-Disease Interactions ► Pharmacokinetic l Clearance via filtration and secretion—decreased renal clearance at alkaline urine pH Potential for decreased renal clearance drugs that undergo tubular secretion, eg, amantadine, cimetidine, ranitidine, etc. l Reduced bioavailability of hydrochlorothiazide (↓20%) ► Pharmacodynamic l Avoid use with other NMDA antagonists: amantadine, ketamine, dextromethorphan l No interactions with ChEIs ► Renal Impairment l Consider decreased dose in moderate renal impairment; memantine is not recommended in severe renal impairment Sources: Guay D. The Consultant Pharmacist. 2003;18:625-634; Hartmann S, Mobius HJ. Int Clin Psychopharmacol. 2003;18:81-85; Namenda (memantine) package insert. Forest Laboratories, Inc.

25. Behavioral Symptoms in AD ► Common ► Occur early in the disease ► May be part of the disease prodrome ► Symptoms emerge as disease progresses ► Once present, symptoms tend to persist ► Multiple types of symptoms that may occur simultaneously (eg, hallucinations, delusions, depression, euphoria, agitation, aggression, abnormal vocalization, wandering, overactivity, sexual disinhibition, sleep disturbances, and apathy)

26. Interventions for Dementia-Related Behavioral Symptoms Nonpharmacologic ► Remove trigger ► Caregiver/family education ► Caregiver support ► Increase staffing ratio ► Activity programs ► Adult day care Pharmacologic ► Antidepressants ► Mood stabilizers ► Antipsychotics* ► Cholinesterase inhibitors ► NMDA-receptor antagonist (memantine) *Public health advisory from FDA (April 2005): Clinical trials of antipsychotic drugs to treat behavioral disorders in elderly patients with dementia have shown a higher death rate compared to placebo. Specific causes of death were primarily due to heart-related events (eg, heart failure, sudden death) or infections (mostly pneumonia)

27. Peak Frequency of Behavioral Symptoms as AD Progresses Jost BC, Grossberg GT. J Am Geriatr Soc. 1996;44:1078-1081 Months Before/After Diagnosis -40 -30 -20 -10 0 10 20 30 Frequency (% of Patients) 100 80 60 40 20 0 Agitation Diurnal Rhythm Irritability Wandering Aggression Hallucinations Mood Change Socially Unacc. Delusions Sexually Inappropriate Accusatory Suicidal Ideation Paranoia Depression Anxiety Social Withdrawal

28. Effects of Galantamine on Behaviors *p<0.05 vs. placebo; N=978 Tariot PN, Solomon PR, Morris JC, et al. Neurology. 2000(June 27); 54(12):2269-2276 Change in NPI Score Mean (± SEM) from Baseline Improvement Deterioration Baseline 1 2 3 4 5 -2 0 1 2 3 4 5 Time (Weeks) * Placebo Galantamine 8 mg/day Galantamine 16 mg/day Galantamine 24 mg/day

29. Pharmacotherapy for Moderate to Severe Alzheimer’s Disease FDA Approved: ► Memantine l Monotherapy l Combination Therapy New Developments in Severe AD: ► ChEIs l Monotherapy l Combination Therapy

30. Memantine Monotherapy in Moderate to Severe AD: Efficacy *Data on file. SIB = Severe Impairment Battery. Source: Reisberg B,et al. N Engl J Med. 2003;348:1333-1341. Data on file, Forest Laboratories. Difference in score -12 -10 -8 -6 -4 -2 0 2 41228 Week Memantine Placebo 0 End Point (LOCF) P=.002P<.001*P<.001*P=.068 Cognition: SIB 41228 Week 0 End Point (LOCF) -7 -5 -4 -3 -2 0 1 -6 Memantine Placebo P=.003P=.02*P=.106*P=.145 Function: ADCS- ADL 19 Percentage of Patients CIBIC-Plus Global Score Improvement Decline No Change Memantine Placebo 0 5 10 15 20 25 30 35 40 45 1234567 Global: CIBIC- Plus *

31. Donepezil Monotherapy in Moderate to Severe AD*: Efficacy †P<.01; ‡P<.001. *Cholinesterase inhibitors (ChEIs) are not indicated for treatment of severe AD; †P<.01; ‡P<.001. DAD = Disability Assessment in Dementia; LOCF = last observation carried forward. Source: Feldman H, et al. Neurology. 2001;57:613-620. (134) (140) Week n = 134 n = 140 2412LOCF0 -12 -10 -8-8 -6-6 -4-4 -2-2 2 4 LS Mean Change From Baseline ±SE 0 Donepezil Placebo 125 129 121 126 Improvement Decline Function: DAD ‡ ‡ †

32. Increased Probability of Institutionalization by Disease Severity 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

33. Effects of Donepezil on Behaviors in Nursing Home Patients at Week 24 Improvement Placebo (N=105) Donepezil (N=103) 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 Nighttime Behavior Appetite/Eating * Baseline Decline -3 -2 0 1 2 3 4 *p<0.05 vs. placebo, secondary analysis ITT, LOCF analysis Tariot PN, Cummings JL, Katz IR, et al. J Am Geriatr Soc. 2001;49:1590-1599

34. * * * ** * * * Behavioral Improvement with Rivastigmine: NPI-Mean Change from Baseline -3.5 -3.0 -2.5 -2.0 -1.5 -0.5 0 Agitation Irritability Anxiety Aberr. Motor Behavior Apathy Depression Delusions Disinhibition Hallucinations Euphoria Nighttime Behavior Appetite Mean Change from Baseline *p<0.05 vs. baseline; **p<0.001 vs. baseline; Baseline MMSE = 9.2; OC analysis; N=98; Anand R, Kourmaras B, Hartman RD. Neurobiol Aging. 2000;21:S220; Cummings J. Presented at the American Academy of Neurology. San Diego, Calif; April 26- May 6, 2000 (Poster presentation ) Improvement 26-Week U.S. Nursing Home Study

35. Memantine/Donepezil Combination Therapy in Moderate to Severe AD: Efficacy Source: Tariot P, et al. JAMA. 2004;291:317-324. n = Placebo + Donepezil Memantine + Donepezil Treatment Week Mean Change From Baseline in SIB Score Improvement Decline P<.001 P=.006 P<.001 P=.03 P=.06 198197190185181171198 n = 197194180169164153 196 Design US phase 3, multicenter (37), randomized, double-blind, placebo- controlled study Population 404 outpatients with moderate to severe AD on stable donepezil MMSE range, 5-14 Treatment Memantine 20 mg/d (10 mg bid) 4-week titration (5  10  15  20 mg) Duration 24 weeks Cognition—SIB -4 -3 -2 0 1 2 3 4 0 481218 24End Point (LOCF)

36. *P=.03; LOCF analysis; n=394 Source: Tariot P, et al. JAMA. 2004;291:317-324. Function—ADCS-ADL 19 Global Change—CIBIC-Plus* Mean Change From Baseline in ADCS-ADL 19 Score Decline n = 198198190185181172198 197195182170163152197 P=.03P=.02P=.03P=.02P=.01P=.03 Improvement -4.0 -3.5 -3.0 -2.5 -2.0 -1.5 -0.5 0.0 0.5 1.0 Memantine Placebo Percentage of Patients ImprovementDecline CIBIC-Plus Global Score Placebo + Donepezil (n=196) Memantine + Donepezil (n=198) 0 5 10 15 20 25 30 35 40 45 1 234567 No Change 0 481218 24End Point (LOCF) Treatment Week Memantine/Donepezil Combination Therapy in Moderate to Severe AD: Efficacy

37. LOCF analysis; *P=.045; **P=.005; ***P=.001 Source: Cummings J, et al. Presented at: 56th Annual Meeting of the American Academy of Neurology; April 24– May 1, 2004; San Francisco, Calif. Memantine in Patients Receiving Ongoing Donepezil: Behavior Delusions Hallucinations Agitation/ Aggression Depression/ Dysphoria Anxiety Elation/Euphoria Apathy/Indifference Disinhibition Irritability/Lability Aberrant Motor Behavior Nighttime Behavior Appetite/ Eating Change Improvement Decline LS Mean Change (SE) 1.0 0.8 0.6 0.4 0.2 0 -0.2 -0.4 *** ** * Memantine Placebo NPI Single-Item Domains

38. Memantine + Donepezil: Significant Improvements in Behavior Compared to Donepezil Alone Treatment Week LS Mean Change (SE) in Total NPI Score n =198186171 n =197175152 Decline Improvement 01224End Point -4 -2 0 2 4 *P<.001 *P=.010 † P=.002 193 189 Results: Behavior—NPI Placebo + Donepezil Memantine + Donepezil *OC analysis; † LOCF analysis. Sources: Tariot P, et al. JAMA. 2004;291:317-324. Cummings JL, et al. Presented at: American Association for Geriatric Psychiatry Annual Meeting; March 3-6, 2005; San Diego, Calif.

39. Tolerability of Memantine/Donepezil Combination Therapy *Adverse events reported in  5% of either treatment group. Source: Tariot P, et al. JAMA. 2004;291:317-324. Placebo + Donepezil (n=201) n (%) 17 (8.5) 8 (4.0) 8 (4.0) 14 (7.0) 13 (6.5) 4 (2.0) 4 (2.0) 6 (3.0) 6 (3.0) 16 (8.0) 10 (5.0) 13 (6.5) 5 (2.5) 5 (2.5) 16 (8.0) 24 (11.9) 24 (11.9) Diarrhea Peripheral edema Fall Influenza-like symptoms Confusion Urinary incontinence Accidental injury Fecal incontinence Urinary tract infection Upper respiratory tract infection Headache Dizziness Memantine + Donepezil (n=202) n (%) 9 (4.5) 9 (4.5) 10 (5.0) 15 (7.4) 16 (7.9) 11 (5.4) 10 (5.0) 4 (2.0) 4 (2.0) 12 (5.9) 10 (5.0) 13 (6.4) 14 (6.9) 19 (9.4) Agitation Adverse Event*

40. Evaluating Response ► Assess: l At baseline l After reaching maximal tolerated dose l Every 6 – 12 months l If change in status ► Family/Patient/Nursing interview ► Documentation in medical record l Cooperation in activities, tolerance of groups l ADL abilities & tolerance with assistance Eating, toileting, dressing, showering, etc. l Routine and psychotropic medication usage

41. Summary ► AD is an expensive illness in human and economic terms for patients, their caregivers, and society. ► Diagnosis is often not made, especially in early and mild AD; clinical nihilism can interfere with initiating or sustaining treatment. The long term setting brings additional clinical challenges. ► Cholinesterase inhibitors and NMDA receptor antagonists attenuate symptomatic decline and may modify disease progression. ► Early treatment pays off; delaying treatment has long-term consequences.

42. ► ChEls (mild to moderate AD) and memantine (moderate to severe AD) monotherapies are associated with less decline (vs placebo) in cognition and function ► Although not indicated, newer data support a role for memantine in mild AD and ChEIs in severe AD ► In moderate to severe AD, patients treated with combination therapy (ie, memantine + ChEIs) exhibited improved cognitive outcomes and delayed functional decline (vs patients treated with ChEI only) Summary