CHOLINESTERASE INHIBITORS AND NEW TREATMENTS IN DEMENTIA

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CHOLINESTERASE INHIBITORS AND NEW TREATMENTS IN
DEMENTIA

• Serge Gauthier, MD, FRCPC
• McGill Centre for Studies in Aging

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OUTLINE

• Natural history and pathophysiology of AD
• Therapeutic objectives
• Cholinesterase inhibitors for AD, mixed AD/VaD,
  VaD
• Disease-modifying strategies for AD

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DIAGNOSTIC CRITERIA FOR PROBABLE AD

• Dementia established clinically, e.g. deficit in
  two or more areas or cognition, interfering with
  daily life, progressing gradually.
• No disturbance of consciousness.
• Onset between age 40 and 90 (below 65 early
  onset).
• Absence of other brain or systemic disease that
  could account for the dementia.

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NATURAL HISTORY OF AD

• Presymptomatic stage (ex. mutation carrier)
• Very early symptoms (MCI, CDR 0.5, incipient
  dementia)
• Mild to moderate stages (MMSE 10-26)
• Severe stage (MMSE lt 10)

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CLINICAL MILESTONES IN AD

• Emergence of cognitive symptoms
• Conversion from MCI to dementia
• Emergence of neuropsychiatric symptoms
• Nursing home placement
• Loss of self-care ADL
• Death

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PATHOPHYSIOLOGY OF AD

• Deposition of insoluble amyloid
• Formation of neuritic plaques
• Formation of tangles with hyperphosphorylated tau
  protein
• Inflammatory response
• Cholinergic deficit

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RISK FACTORS FOR AD

• Age
• Gender
• Low education
• Family history of AD
• Apolipoprotein E 4/4 genotype
• Systolic arterial hypertension

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PROTECTIVE FACTORS FOR AD

• High education
• NSAIDS
• Statins
• Red wine, ? Beer
• Intellectual leisure activities, socialization
• ? Post menopausal hormonal replacement therapy

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THERAPEUTIC OBJECTIVES

• Control of existing symptoms by restoring
  cholinergic activity
• Delay progression of disease after diagnosis by
  modifying pathophysiology
• Delay emergence of symptoms in persons at risk

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TRIAL DESIGNS TO TEST SYMPTOMATIC BENEFIT

• Parallel groups over 3, 6 or 12 months
• Extended open-label observations
• Measure all relevant symptomatic domains
  cognition, ADL, behavior, global impression of
  change.

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COGNITIVE OUTCOMES

• Mini Mental State Examination (MMSE)
• Alzheimer Disease Assessment Scale cognitive
  section (ADAS-cog)
• Severe Impairment Battery (SIB)

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Mini-Mental State Examination (MMSE)
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Reminyl maintains cognitive benefits in AD over
12 months (Raskind GAL-USA-1/3)
Open-Extension
Double-blind
Improvement
4
3
2
1
Mean ( SE)Change From Baseline inADAS-cogScore
0
1
2
3
4
5
6
7
Deterioration
0
3
6
9
12
Months
Placebo/Reminyl 24 mg
P lt0 .05 vs Placebo/Reminyl and not
statistically different from baseline.
Reminyl 24 mg/Reminyl 24 mg
Historical placebo group
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Cognition Severe Impairment Battery(SIB)
plt0.0001
p0.0051
plt0.0009
plt0.0001
p0.0001
p0.0078
Clinical improvement
Baseline
Clinical decline
24
18
12
8
4
ITT LOCF
0
Study week
Donepezil n139 130 115 123
119 120 (139) Placebo n145 139 119 128
128 126 (145)
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FUNCTIONAL OUTCOMES

• Disability Assessment in Dementia (DAD)

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Functional autonomy Disability assessmentfor
dementia (DAD)
Clinical improvement
p0.0037
plt0.0001
plt0.0001
Baseline
Clinical decline
24
ITT LOCF
12
0
Study week
Donepezil n134 125 121 (134) Placebo n140 129 12
6 (140)
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BEHAVIOR OUTCOMES

• NeuroPsychiatric Inventory (NPI)
• Behave AD

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Reminyl delays the emergence of behavioral
symptoms (Tariot GAL-USA-10)
Improvement
Dose Increment
Dose Increment
3
2
1

0
Mean ( SE)Change From Baseline InNPI
1
2
3
4
5
6
Deterioration
Months
Placebo
Reminyl 16 mg/d
P lt 0.05 vs placebo.
Reminyl 24 mg/d
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Behavior Neuropsychiatric Inventory (NPI)
12-item total
p0.0083
p0.0005
p0.0618
p0.0303
Clinical improvement
Baseline
Clinical decline
24
18
12
8
4
ITT LOCF
0
Study week
Donepezil n138 130 114 124 118 119
(138) Placebo n144 138 116 128 128 125
(144)
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GLOBAL OUTCOMES

• Clinical Global Impression of Change (CGIC)
• Clinical Interview Based Impression of Change
  (CIBIC) with caregiver input (CIBIC)
• Clinical Dementia Rating (CDR)

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CHOLINESTERASE INHIBITORS FOR AD RECOMMENDATIONS

• Patients in mild to moderately severe stages of
  AD should be offered a trial of a CI of at least
  6 months.
• Baseline and follow-up assessments should include
  mood, cognition, functional autonomy and
  behavior.
• Continue if improvement or stabilization of
  symptoms.

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ISSUES IN CLINICAL PRACTICE CLINICAL ASSESSMENT
OF RESPONSE TO CI

• Global impression of change based on interview
  with patient and caregiver.
• MMSE
• Targeted symptoms to resolve or to emerge.

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ISSUES IN CLINICAL PRACTICEWHEN IS IT TIME TO
STOP A CI?

• Intolerable side-effects (ex. insomnia,
  nausea/vomiting/diarrhea, muscle cramps).
• Clear deterioration of symptoms over the first 6
  months.
• Loss of response over time.
• -gt consider switching to another CI.

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SWITCHING BETWEEN CI (Morris et al, Clin Ther
23 Suppl A, A31-A39, 2001)

• No wash out required unless unresolved side
  -effects from first CI
• Monthly titration of second CI
• Monitor for efficacy and tolerability monthly for
  3 months
• Combinations of CI are not recommended

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DIAGNOSTIC CRITERIA FOR VASCULAR DEMENTIA

• Decline in intellectual function interfering with
  daily life not due to physical effects of
  stroke(s) alone.
• Evidence by Hx, physical and/or brain imaging of
  stroke(s).
• Temporal relationship between dementia and
  cerebrovascular disease.

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Donepezil in VaD LS Mean Change in ADAS-cog
4
3







2

Clinical improvement
LS mean change from baseline ADAS-cog score
1
0
Baseline
Donepezil 10 mg/day Donepezil 5 mg/day Placebo
1
Clinical decline
2
12
0
6
18
24
ITT LOCF
Study week
Donepezil 10 mg n 194 188 172 163 155 194 Donep
ezil 5 mg n 201 193 183 173 164 199 Placebo n
181 180 167 160 150 180
p lt 0.01 p lt 0.001 versus placebo.
Statistical analyses were conducted on the
observed cases at Weeks 6, 12, 18, and 24, and at
endpoint (Week 24 LOCF) by ANCOVA.
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Donepezil in VaD LS Mean Change in MMSE
p lt 0.05 p ? 0.01 p lt 0.001 versus
placebo. Statistical analyses were conducted on
the observed cases at Weeks 6, 12, 18, and 24,
and at endpoint (Week 24 LOCF) by ANCOVA.
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Erkinjuntti Trial Change in
ADAS-cog
Placebo/Reminyl Reminyl/Reminyl
3
Improvement
2
1
Mean (? SE) change in ADAS-cog from baseline
0
1
2
Double-blind phase
Open-label phase
Month 12
Baseline
Week 6
Month 3
Month 6
PLA/GAL (n) (194) (183) (173) (158) (146) (116) GA
L/GAL (n) (388) (354) (319) (285) (275) (239)
p lt 0.001 vs placebo.
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Galantamine maintains Disability Assessment for
Dementia (DAD) scores
Improvement

Mean (? SE) change in DAD from baseline
p ? 0.002 vs placebo
Deterioration
2
4
6
Baseline
Time (months)
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Galantamine improves Neuro-Psychiatric Inventory
(NPI) scores over 6 months
Improvement

Mean (? SE) change in NPI from baseline
p 0.016 vs placebo
Time (months)
Deterioration
Baseline
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CI FOR VASCULAR DEMENTIA

• EVIDENCE three RCT with donepezil and with
  galantamine showing efficacy in patients with AD
  CVD or probable VaD
• CONTROVERSY are CI acting on the AD component of
  VaD?
• RECOMMENDATION treat vascular risk factors in
  all patients with dementia, consider a CI in
  mixed AD-VaD need for more RCT in probable VaD

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DISEASE-MODIFYING STRATEGIES STUDY DESIGNS

• Parallel groups with survival to a clinically
  meaningful endpoint (ex. conversion from MCI to
  AD).
• Addition of novel treatment or placebo to
  standard care.

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Hypothetical MCI Trial with Delay to AD as
Primary Endpoint
100
Symptomatic or Disease Modifying Agent
Percent without AD diagnosis
50
Placebo
0
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Time in Months
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Add-On Design
Cholinesterase Inhibitor Disease Modifying
Agent
Stable Dose of Cholinesterase Inhibitor
Performance
Cholinesterase Inhibitor Placebo
-3
0
12
Time
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DISEASE MODIFYING STRATEGIES FOR AD TREATMENT
OPTIONS

• Control of vascular risk factors
• Anti-inflammatory drugs
• Post-menopausal hormonal therapy
• Inhibition of beta secretase
• Immunotherapy (vaccine)
• Inhibition of fibrillogenesis
• Anti-oxidants
• Statins

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CONCLUSIONS

• CI offer useful benefit in AD and mixed AD/VaD.
• Treatment expectations should be a stabilization
  of decline of cognition, functional autonomy and
  behavior over time.
• Switching between CI is possible.
• Future improvements will be in modifying disease
  progression.