1. Clinical Update: Full Spectrum Treatment of Alzheimers Disease

2. Alzheimers Disease Economic Consequences Third most expensive disease in the U.S. Third most expensive disease in the U.S. Costs over $100 billion/year Costs over $100 billion/year Further $33 billion in lost productivity and other employer costs Further $33 billion in lost productivity and other employer costs 3/4 of patients admitted to residential care within 5 years of diagnosis 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; Alzheimers Association, 2002

3. Growth of the Problem Alzheimers 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 Diagnostic interview: Both the patient and a reliable informant Office-based clinical assessment 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 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 Neuropsychologic testing or functional scan (PET) if diagnosis is unclear Alva, Clin Geriatr Med 19 (2003)763-776

5. The Stages of Alzheimers 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 T. 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 Alzheimers 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 Maintain quality of life Maximize function Maximize function Stabilize cognition Stabilize cognition Treat mood and behavior problems Treat mood and behavior problems Ease caregiver burden 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 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 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 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 ChA T Noncholinergic Action MR NR MR NR MR

14. Pharmacotherapy for Mild to Moderate Alzheimers Disease FDA Approved: Cholinesterase inhibitors (ChEIs) 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) NMDA-receptor antagonist (memantine) – Monotherapy l Combination Therapy

15. Important Considerations in Alzheimers 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.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 Improvement Decline 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 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 Pharmacokinetic l None rivastigmine l Minimal donepezil l Moderate galantamine + CYP450 inhibitors (2D6, 3A4) Renal impairment 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 Dose escalation may need to be slower than suggested in Physicians Desk Reference Side effects to treatment are justifiable reasons to switch Side effects to treatment are justifiable reasons to switch Typically, switching ChEIs can be done without washout period and with shorter titration periods 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 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 May not tolerate cholinergic side effects despite slow and careful escalation When medication is prescribed, give it time to work; gauge different domains When medication is prescribed, give it time to work; gauge different domains Establishing benefit in an individual patient may be influenced by their staging 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 Studies suggest that most subjects benefit and that long-term treatment is useful May see some deterioration when medication is stopped 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 Multicenter (20), open-label, single-arm, historically controlledPopulation 95 outpatients with mild to moderate AD (MMSE, 10-29) on stable rivastigmine 95 outpatients with mild to moderate AD (MMSE, 10-29) on stable rivastigmineTreatment Memantine 20 mg/d (10 mg bid) 4-week titration (5 10 15 20 mg) 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 = Alzheimers 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: 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 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 Pharmacokinetic l Clearance via filtration and secretiondecreased 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 Pharmacodynamic l Avoid use with other NMDA antagonists: amantadine, ketamine, dextromethorphan l No interactions with ChEIs Renal Impairment 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 Common Occur early in the disease Occur early in the disease May be part of the disease prodrome May be part of the disease prodrome Symptoms emerge as disease progresses Symptoms emerge as disease progresses Once present, symptoms tend to persist 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) 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 Remove trigger Caregiver/family education Caregiver/family education Caregiver support Caregiver support Increase staffing ratio Increase staffing ratio Activity programs Activity programs Adult day care Adult day care Pharmacologic Antidepressants Antidepressants Mood stabilizers Mood stabilizers Antipsychotics* Antipsychotics* Cholinesterase inhibitors Cholinesterase inhibitors NMDA-receptor antagonist (memantine) 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. 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

28. Pharmacotherapy for Moderate to Severe Alzheimers Disease FDA Approved: Memantine Memantine l Monotherapy l Combination Therapy New Developments in Severe AD: ChEIs ChEIs l Monotherapy l Combination Therapy

29. 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 *

30. 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

31. 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

32. 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

33. * * * ** * * * 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

34. 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 CognitionSIB -4 -3 -2 0 1 2 3 4 0 481218 24End Point (LOCF)

35. 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

36. 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*

37. Evaluating Response Assess: Assess: l At baseline l After reaching maximal tolerated dose l Every 6 – 12 months l If change in status Family/Patient/Nursing interview Family/Patient/Nursing interview Documentation in medical record 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

38. Summary AD is an expensive illness in human and economic terms for patients, their caregivers, and society. 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. 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. Cholinesterase inhibitors and NMDA receptor antagonists attenuate symptomatic decline and may modify disease progression. Early treatment pays off; delaying treatment has long-term consequences. Early treatment pays off; delaying treatment has long-term consequences.

39. ChEls (mild to moderate AD) and memantine (moderate to severe AD) monotherapies are associated with less decline (vs placebo) in cognition and function 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 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) 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