Clinical Update: Full Spectrum Treatment of Alzheimers Disease

1
Clinical Update Full Spectrum Treatment of
Alzheimers Disease
2
Alzheimers DiseaseEconomic 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
Alzheimers Association, 2002
3
Growth of the Problem
Alzheimers Prevalencein the U.S. by Age (1997)
Projected Dementia Patients in the U.S. (in
Millions)
70 50 30 10
14.3
11.8
8.7
6.8
Percentage
5.8
4.0
0
45 55 65 75 85 90
2000 2010 2020 2030 2040 2050
Age (Years)
Year
Guttman R, Altman RD, Nielsen NH. Arch Fam Med.
1999(July-Aug)8(4)347-353
4
Suggested Diagnostic Workup for Dementia

• Diagnostic interview Both the patient and a
  reliable informant
• Office-based clinical assessment
• Comprehensive physical examination
• Neurologic and mental status evaluation
• Brief quantified cognitive function evaluation
  (MMSE)
• Laboratory evaluation and imaging CBC,
  chemistries, liver function, thyroid, vitamin
  B12 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 Alzheimers Disease
Mild Moderate Severe
Stage
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
Symptoms
ADL activities of daily living LTC long-term
care
6
Neuropathological ChangesCharacteristic of AD
AP amyloid plaques NFT neurofibrillary
tangles Courtesy of George Grossberg M.D. St.
Louis University
7
Model-Based Analysis ADAS-Cog Score Mean Change
from Baseline
-6
0
Improvement
ADAS-Cog Mean Change from Baseline
6
Decline in ADAS-Cog score based on the natural
history of untreated patients with moderate AD
12
18
0
6
12
14
26
38
50
62
74
85
98
Decline
N133
Rogers and Friedhoff, 1998 Stern et al, 1994
8
Cognitive Decline in AD Correlates with Rate of
Cerebral Atrophy
12 10 8 6 4 2 0
y 0.48x 0.34 r 0.8
Loss of Brain Volume ()
0 2 4 6
8 10 12 14
16 18
Fall in MMSE Score
Fox, DRG98
9
UCI Brain Imaging Center
Alzheimers Disease
Normal Control
DecreasedTemporoparietal
FrontalLobe
OccipitalLobe
Cerebellum
0.00
19.36
mg/100g/min
10
Management of the AD Patient
Treatment Goals

• 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.
11
Treatment ConsiderationWhen to Begin?

• Current guidelines (AAN) recommend that all
  patients with AD be treated at time of diagnosis
• Well established rationale for ChEI treatment in
  patients diagnosed with mild or moderate AD
• Well established rationale for treating patients
  diagnosed with moderate to severe AD with
  memantine
• Patients with severe AD have been shown to
  benefit from treatment1-3
• Establish realistic expectations of treatment

Sources1. Winblad B, et al. Int J Geriatr
Psychiatry. 199914135-146.
2. Reisberg B, et al. N Engl J Med.
20033481333-1341. 3.
Tariot P, et al. J Am Geriatr Soc.
200351(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
• Cholinergic neurons are lost in AD
• Theory increase available acetylcholine to
  improve or maintain cognitive function
• 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
Normal Cholinergic Function
ACh acetylcholine AChE acetylcholinesterase
BuChE butyrylcholinesterase ChAT choline
acetyltransferase CoA coenzyme A MR
muscarinic receptor NR nicotinic
receptor Adapted from Adem, 1992
14
Pharmacotherapy for Mild to ModerateAlzheimers
Disease

• FDA Approved
• Cholinesterase inhibitors (ChEIs)
• Tacrine
• Donepezil
• Galantamine
• Rivastigmine
• Monotherapy as standard treatment
• New Developments in Mild AD
• NMDA-receptor antagonist (memantine)
• Monotherapy
• Combination Therapy

15
Important Considerations in Alzheimers Disease
Treatment
Rivastigmine
Galantamine
Donepezil
Memantine
Plasma protein binding
40
96
18
45
Not Hepatic
Metabolism
CYP450
CYP450
Partially Hepatic
50 Kidney50 Liver
Kidney(inactive metabolite)
Elimination pathway
Liver
Kidney
No
None stated
Yes
Dosage adjustment required for renal/hepatic
impairment
Yes
ketoconazole, quinidine, and other drugs
metabolized by CYP2D6/3A4
amitriptyline, cimetidine, erythromycin,
fluoxetine, fluvoxamine, ketoconazole,
paroxetine, quinidine, and other drugs
metabolized by CYP2D6/3A4
carbonic anhydrase inhibitors, sodium bicarbonate
Listed drug-druginteractions
NoneKnown
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 Mildto Moderate AD Efficacy
Improvement
Mean Change From Baseline
Decline
(LS)
Plt.05 Plt.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. 200157489-495. (Data represent
change in least squares LS mean) 2.
Corey-Bloom J, et al. Int J Geriatr
Psychopharmacol. 1998155055-65 3.
Tariot PN, et al. Neurology. 2000542269-2276
17
ChEI Drug-Drug and Drug-Disease Interactions

• Pharmacodynamic
• Digoxin, ß blockers ChEIs may exert vagotonic
  effects on sinoatrial and atrioventricular nodes
• ChEIs may exaggerate succinylcholine-type muscle
  relaxation during anesthesia
• Concurrent anticholinergic or cholinergic
  pharmacotherapy
• Pharmacokinetic
• None rivastigmine
• Minimal donepezil
• Moderate galantamine CYP450 inhibitors (2D6,
  3A4)
• Renal impairment
• Clearance of galantamine decreased in renal
  insufficiency

Source Bentué-Ferrer D, et al. CNS Drugs.
200317947-963.
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 justifiablereasons
  to switch
• Typically, switching ChEIs can be donewithout
  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 ChEI1,2

Sources 1. Reisberg B, et al. N Engl J Med.
20033481333-1341. 2. Tariot P,
et al. JAMA. 2004291317-324.
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
• US 24-week trial
• Statistically significant advantage of memantine
  over placebo at end point on cognitive and global
  measures
• European 24-week trial
• Numerical advantage at end point for memantine
  (not statistically significant) over placebo for
  cognitive and global measures
• Combination Therapy Trials
• 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
Memantine Monotherapy in Mild to Moderate AD US
24-Week Trial Results
Cognition ADAS-Cog
Global Change CIBIC-Plus
3.5
-3
.009
.002
.003
Improvement
-2
.003
.021
.024
Improvement
.015
-1
4
Mean Score (SE)
.004
LS Mean Change From Baseline (SE)
0
Decline
1
4.5
Decline
Memantine
Memantine
2
Placebo
Placebo
3
5
18
4
8
12
24
0
4
8
12
18
24
Treatment Week
Treatment Week
Intention-to-treat (ITT) population last
observation carried forward (LOCF) P value for
LS mean difference (memantine vs placebo)
Source Peskind E, et al. Presented at the 8th
Congress of the European Federation of
Neurological Societies
September 4-7, 2004 Paris, France.
22
Memantine/Rivastigmine CombinationTherapy 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

30
25
20
15
Number of Patients
10
5
?
?
?
0
-12
-8
-4
0
4
8
Change in ADAS-Cog Memory Score
Memantine is not indicated for the treatment of
mild AD. ADAS-Cog Alzheimers Disease
Assessment ScaleCognitive 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.
23
Memantine Adverse Events

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

24
Memantine Drug-Drug and Drug-Disease
Interactions

• Pharmacokinetic
• 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.
• Reduced bioavailability of hydrochlorothiazide
  (?20)
• Pharmacodynamic
• Avoid use with other NMDA antagonists
  amantadine, ketamine, dextromethorphan
• No interactions with ChEIs
• Renal Impairment
• Consider decreased dose in moderate renal
  impairment memantine is not recommended in
  severe renal impairment

Sources Guay D. The Consultant Pharmacist.
200318625-634 Hartmann S, Mobius HJ. Int Clin
Psychopharmacol. 20031881-85 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/familyeducation
• Caregiver support
• Increase staffing ratio
• Activity programs
• Adult day care

• Pharmacologic
• Antidepressants
• Mood stabilizers
• Antipsychotics
• Cholinesteraseinhibitors
• 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
100
80
60
Frequency ( of Patients)
40
20
0
-40 -30 -20 -10
0 10 20 30
Months Before/After Diagnosis
Jost BC, Grossberg GT. J Am Geriatr Soc.
1996441078-1081
28
Effects of Galantamine on Behaviors
Improvement
-2 -1 0 1 2 3 4 5
Change in NPI Score Mean ( SEM) from Baseline
Placebo Galantamine 8 mg/day Galantamine 16
mg/day Galantamine 24 mg/day
Deterioration
Baseline 1 2 3
4 5
Time (Weeks)
plt0.05 vs. placebo N978 Tariot PN, Solomon
PR, Morris JC, et al. Neurology. 2000(June 27)
54(12)2269-2276
29
Pharmacotherapy for Moderateto Severe
Alzheimers Disease

• FDA Approved
• Memantine
• Monotherapy
• Combination Therapy
• New Developments in Severe AD
• ChEIs
• Monotherapy
• Combination Therapy

30
Memantine Monotherapy in Moderate to Severe AD
Efficacy
Difference in score
Data on file. SIB Severe Impairment
Battery. Source Reisberg B,et al. N Engl J
Med. 20033481333-1341. Data on
file, Forest Laboratories.
31
Donepezil Monotherapy in Moderate to Severe AD
Efficacy
(134) (140)
Cholinesterase inhibitors (ChEIs) are not
indicated for treatment of severe AD Plt.01
Plt.001. DAD Disability Assessment in Dementia
LOCF last observation carried forward. Source
Feldman H, et al. Neurology. 200157613-620.
32
Increased Probability of Institutionalization by
Disease Severity
1.0
0.8
0.6
Probability of Institutionalization
0.4
0.2
0.0
Mild(MMSE 21-30)
Moderate(MMSE 11-20)
Severe(MMSE 0-10)
Severity of AD
Hauber AB, Gnanasakthy, Snyder EH, et al.
Pharmacoeconomics. 2000(April)17(4)351-360
33
Effects of Donepezil on Behaviors in Nursing Home
Patients at Week 24
Placebo (N105) Donepezil (N103)
Improvement
-3
-2
-1

Baseline
0
Mean Change from Baseline NPI-NH Individual Item
Score at Week 24
1
Anxiety
Delusions
Disinhibition
Hallucinations
Elation/Euphoria
2
Irritability/Lability
Apathy/Indifference
Agitation/Aggression
Nighttime Behavior
Depression/Dysphoria
Aberrant Motor Behavior
Appetite/Eating
3
Decline
4
plt0.05 vs. placebo, secondary analysis ITT, LOCF
analysis Tariot PN, Cummings JL, Katz IR, et al.
J Am Geriatr Soc. 2001491590-1599
34
Behavioral Improvement with Rivastigmine
NPI-Mean Change from Baseline
26-Week U.S. Nursing Home Study
-3.5
-3.0
-2.5
-2.0
Improvement
Mean Change from Baseline
-1.5
-1.0
-0.5
0
Anxiety
Apathy
Irritability
Appetite
Agitation
Euphoria
Delusions
Depression
Disinhibition
Hallucinations
Nighttime Behavior
Aberr. Motor Behavior
plt0.05 vs. baseline plt0.001 vs. baseline
Baseline MMSE 9.2 OC analysis N98 Anand R,
Kourmaras B, Hartman RD. Neurobiol Aging.
200021S220 Cummings J. Presented at the
American Academy of Neurology. San Diego, Calif
April 26- May 6, 2000 (Poster presentation)
35
Memantine/Donepezil Combination Therapy in
Moderate to Severe AD Efficacy

• 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
Plt.001
P.03
3
P.006
P.06
Improvement
Plt.001
Plt.001
2
1
Mean Change From Baseline in SIB Score
0
-1
Decline
-2
Memantine Donepezil
-3
Placebo Donepezil
-4
Treatment Week
n
198
197
190
185
181
171
198
n
197
194
180
169
164
153
196
Source Tariot P, et al. JAMA. 2004291317-324.
36
Memantine/Donepezil Combination Therapy in
Moderate to Severe AD Efficacy
FunctionADCS-ADL19
Global ChangeCIBIC-Plus
No Change
1.0
P.03
P.02
P.03
P.02
P.01
P.03
45
Improvement
Decline
0.5
Improvement
40
0.0
35
-0.5
30
-1.0
Memantine Donepezil (n198)
Mean Change From Baseline in ADCS-ADL19 Score
-1.5
25
Percentage of Patients
-2.0
20
Placebo Donepezil (n196)
-2.5
15
Memantine
Decline
-3.0
10
Placebo
-3.5
5
-4.0
0
4
8
12
18
24
End Point (LOCF)
0
1
2
3
4
5
6
7
CIBIC-Plus Global Score
Treatment Week
n
198
198
190
185
181
172
198
n
197
195
182
170
163
152
197
P.03 LOCF analysis n394 Source Tariot
P, et al. JAMA. 2004291317-324.
37
Memantine in Patients Receiving Ongoing
Donepezil Behavior
NPI Single-Item Domains
Placebo
Memantine

Improvement

-0.4

-0.2
0
0.2
LS Mean Change (SE)
Decline
0.4
0.6
0.8
1.0
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 24May 1, 2004 San
Francisco, Calif.
38
Memantine Donepezil Significant
Improvementsin Behavior Compared to Donepezil
Alone
Results BehaviorNPI
Plt.001
-4
Improvement
-2
P.010
P.002
LS Mean Change (SE) in Total NPI Score
0
Decline
2
Memantine Donepezil
4
Placebo Donepezil
0
12
24
End Point
Treatment Week
n
198
186
171
193
n
197
175
152
189
OC analysis LOCF analysis. Sources Tariot P,
et al. JAMA. 2004291317-324. 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
Memantine Donepezil(n202) n ()
Placebo Donepezil(n201) n ()
Adverse Event
19 (9.4)
24 (11.9)
Agitation
16 (7.9)
4 (2.0)
Confusion
15 (7.4)
14 (7.0)
Fall
15 (7.4)
13 (6.5)
Influenza-like symptoms
14 (6.9)
16 (8.0)
Dizziness
13 (6.4)
5 (2.5)
Headache
12 (5.9)
10 (5.0)
Urinary tract infection
11 (5.4)
6 (3.0)
Urinary incontinence
10 (5.0)
16 (8.0)
Accidental injury
10 (5.0)
13 (6.5)
Upper respiratory tract infection
10 (5.0)
8 (4.0)
Peripheral edema
9 (4.5)
17 (8.5)
Diarrhea
4 (2.0)
10 (5.0)
Fecal incontinence
Adverse events reported in ?5 of either
treatment group. Source Tariot P, et al. JAMA.
2004291317-324.
40
Evaluating Response

• Assess
• At baseline
• After reaching maximal tolerated dose
• Every 6 12 months
• If change in status
• Family/Patient/Nursing interview
• Documentation in medical record
• Cooperation in activities, tolerance of groups
• ADL abilities tolerance with assistance
• Eating, toileting, dressing, showering, etc.
• 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
  earlyand 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
Summary

• 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)