Transcript Presentation

ASENT National Meeting
Washington, DC
March 7, 2008
Long Term Outcomes in
Alzheimer’s Disease
Steven T. DeKosky, MD
Chair, Department of Neurology
Director, Alzheimer’s Disease Research Center
University of Pittsburgh
Pittsburgh, PA USA
Disease modification: Will we know it
when we see it?
Eric Siemers, MD
International Conference on Alzheimer’s disease
Chicago, Illinois
July 28, 2008
Why is the concept disease-modification important?
10
5
Cognitive measures after 21
months of treatment
placebo
change in ADAS-cog
0
-5 0
12
24
36
48
60
72
84
96
AChE inhib
-10
-15
-20
disease
progression
-25
-30
AChE inhib +
disease
progression
-35
-40
-45
Months afterMonths
initiating treatment
Overview

Alzheimer’s Disease has a long prodrome of pathological change
prior to symptom emergence

Treatments can be characterized as symptomatic or diseasemodifying, depending largely on the mechanism of action of the
intervention

Designs for treatment can focus on slope of change or incidence
of events

Biomarkers may aid as surrogates, initially as proof of mechanism
and potentially as evidence of drug effectiveness

Technical developments may make long term follow-up of large
populations (in prevention trials) easier and less expensive,
although not necessarily shorter
Alzheimer’s Disease Course,
Treatment, and Prevention
Primary
Prevention
Intervention
Clinical
State
Brain
Pathologic
State
Normal
No Disease
No Symptoms
Presymptomatic
AD
Early Brain
Changes
No
Symptoms
Secondary
Prevention
Treatment
Mild
Cognitive
Impairment
AD
AD Brain
Changes
Mild Symptoms
Disease Progression
National Institute on Aging, USA.
Moderate to
Severe
Impairment
Therapeutic Strategies and Timing

Symptomatic improvement (cognitive and behavioral)
 Trials lasted from 12 to 24 weeks

Disease Modifying Therapies in AD
 Trials last 12-24 months
 Non-specific therapies
 Antioxidants, Anti-inflammatory agents, Estrogen, others
 Specific therapies: Anti-amyloid therapy, Anti-neurofibrillary
tangle strategies

Prevention Trials:
 Trials last 5-9 years
 Lifestyle Therapies (e.g., exercise, cognitive therapies)
 Decades
Trial Designs for
Symptomatic Treatments of AD


Assess effect over brief intervals: 3 to 6 months
Rely on change score for efficacy:
 Compare change in treated group with change in placebo
Current Symptomatic Drugs for
Alzheimer’s Disease: all studies took 6
months or less to show effect
Tacrine
Cognex
Cholinesterase Not used due to
inhibition
toxicity
Donepezil
Aricept
Cholinesterase Approved 1997
inhibition
Rivastigmine
Exelon
Cholinesterase Approved in US in
inhibition
2000
Galantamine
Reminyl
Cholinesterase Released Spring
inhibition
2001
Memantine
Namenda
Glutamate
receptor
modulation
Approved 2004
Trial Length in Possible Future
Symptomatic Therapies
 Ketasyn (3 months)
 Dimebon (12 months)
Amyloid Metabolism
soluble
APP
soluble
APP
N
Amyloid Precursor Protein (APP)


Amyloid plaques,
Inflammation
Neuron loss

&
cleavage
(BACE-1)  site
 site
Monomers  Dimers  Oligomers
g
A domain
CELL MEMBRANE
C
-cleavage site
Presenilin 1/2
Soluble Ab (1-40, 1-42)
Anti-Amyloid Strategies and Mechanisms
Strategy
Examples
Mechanism
Preclinical
Active immunotherapy
Fragments of A used as
vaccines
Stimulate specific A antibodies
-Secretase inhibitor
Many in development
Directly reduces Aβ cleavage from APP
-Secretase activator
Bryostatin 1, others
Protein kinase C activator
Peripheral sink
Gelsolin
Sequestration of Aβ in periphery
Many in development
Directly reduces Aβ cleavage from APP
Many in development
Monoclonal antibodies; IgG
Anti-polymerization
Tramiprosate (Alzhemed)
Glycosaminoglycan mimetic (study
failed)
-Secretase modulator
R-Flurbiprofen (Flurizan)
NSAID enantiomer reduces A
fragment size
Phase I
-Secretase inhibitor
Phase I and II
Passive immunotherapy
Phase III
NINCDS/ADRDA Criteria for Probable
Alzheimer’s Disease

DEMENTIA established by clinical examination; confirmed by
cognitive screening test (MMSE, Blessed)





Deficits in TWO or MORE areas of cognition
Progressive worsening of memory and other cognitive functions
No disturbance of consciousness
Onset between 40 and 90, most often after 65
Absence of systemic disorders or other brain diseases that could
account for the deficits and progression
McKhann et al. Neurology 1984;34:939-944
Adding Biomarkers to Clinical Findings:
Research criteria for the diagnosis of Alzheimer’s disease:
revising the NINCDS–ADRDA criteria
Bruno Dubois*, Howard H Feldman*, Claudia Jacova, Steven T DeKosky, Pascale Barberger-Gateau,
Jeffrey Cummings, André Delacourte, Douglas Galasko, Serge Gauthier, Gregory Jicha, Kenichi Meguro,
John O’Brien, Florence Pasquier, Philippe Robert, Martin Rossor, Steven Salloway, Yaakov Stern, Pieter J
Visser, Philip Scheltens
Lancet Neurology 2007; 6: 734-46
• In the future, biomarkers combined with very early
changes in cognition will likely lead to more definitive
early diagnosis and initiation of medical intervention
• This will then extend to pre-symptomatic stages
• Can use of biomarker as surrogate shorten time needed
for studies?
CSF in Alzheimer’s Disease:
Low Aβ and High Tau
Concentration (pg/mL)
AD Patients
Control Patients
700
600
500
400
300
200
100
0
Sunderland T, et al. JAMA. 2003;289:2094-2103.
Aβ
Tau
47
CSF Clinical Test:
β-Amyloid and Phospho-Tau (P-Tau)
ATI vs P-Tau
2.8
2.4
2.0
Not consistent with AD
1.6
1.2
0.8
0.4
Consistent with AD
0.0
0
30
*Indicates position of patient result.
60
P-Tau (pg/mL)
90
*
120
150
CSF in MCI has
elevated tau,
decreased β-amyloid
A combination of CSF T-tau and A42 at
baseline yielded a sensitivity of 95% and a
specificity of 83% for detection of incipient
AD inpatients with MCI. (hazard ratio 17·7,
p0·0001).
The association between pathological CSF
and progression to Alzheimer’s disease was
much stronger than, and independent of,
established risk factors including age, sex,
education, APOE genotype, and plasma
homocysteine.
Hansson et al., Lancet Neurology 2006
39
Evolution of Neuroimaging in AD







Computed Tomography
FDG Glucose PET
MRI
Volumetric MRI
Co-registration of MRI
Functional MRI
FDG Glucose PET
Helmuth L. Science. 2002;297:1260-1262.
PiB PET
Alzheimer Disease Forum.
http://www.alzforum.org/new/detail.a
sp?id=948.
Lab of Neuro Imaging UCLA School of Medicine. www.loni.ucla.edu/~thompson/AD_4D/dynamic.html.
Seeking Biomarkers to Speed Research
 Alzheimer’s Disease Neuroimaging
Initiative (ADNI):
3 year study of MRI; FDG-PET,
CSF for β-amyloid, tau,
isoprostanes
 MRI volumetric techniques
 CSF: in addition to above: ADDLs
by DNA Barcode techniques?
 Cell or serum markers?
 Use genetic markers (eg, apoE4) to
increase risk in study cohort?
 Amyloid imaging PET agents:
Pittsburgh Compound B (PIB)
Mean Cortical PIB Binding in Nondemented
Controls and AD (N=41): a way to identify atrisk subjects to shorten trials?
1.200
1.000
scBP
0.800
0.600
0.400
0.200
0.000
-0.200
20 22 23 49 49 51 56 57 58 58 59 59 59 60 60 60 61 61 62 64 64 66 71 72 72 74 75 75 75 76 77 77 77 79 80 81 83 83 84 85 86 86 72 73 73 79 79 81 84 85 86
Subject AGE
Mintun et al. Neurology. 2006.
AD Prevention Trials


Opportunities for major public health gains





Expensive ($40 - $50 million US)
Large (power calculations based on incidence rates require
>3,000 subjects)
Long duration (5 years minimum)
Must have double-blind, placebo-controlled design
First efforts: safe, inexpensive compounds
New designs: computerized testing, group decline rather than
incident dementia
 Less expensive, but as useful?
Effects of Delay of Onset of Disease on Prevalence of
Dementia
0
8
6
.5
1
2
5
4
2
U.S. Prevalence of
AD (millions)
Delay
(years)
0
2047
2037
2027
2017
Year
1997 2007
5 years of delay of onset equals a 50% decrease in prevalence
Brookheimer et al. Am J Pub Health. 1998;88:1337-1342.
Considerations
•
•
While pathologies for AD are potential targets for
interventions they are likely to be associated with
a range of adverse effects
If these agents are to be preventive a very low
tolerance for risk can be expected unless
biomarkers indicate a very high risk of disease
development
Issues in Dementia Prevention

No reliable ways (e.g., biomarkers) to identify most
presymptomatic people- YET.

Current suggestions, e.g. exercise, control of vascular
risk factors, not widely used

Expense and risks of using costly preventive
medications which may have associated side effects

Long time needed to ‘prove’ that preventive treatments
work

Difficult to keep an elderly population in a multi-year
study, as well as a proxy who provides information
about the subject
Trial Designs for Slowing Progression/ Prevention

Assess treatments over extended time period:
one or more years


Compare slope of performance over time
Survival analysis:
 Requires discrete events
 Compares the time to reach events in treatment
and placebo group
 Example of events: reach a certain level of
severity, or be diagnosed with AD
Level of function
Currently: Prevention = Postponement
Dementia
Death
8-12 years
Prevention Trials Discontinued
(because of toxicity of the drug)
Study
WHIMS
Women’s Health Initiative
Memory Study
PREPARE
Post-menopausal Memory
Loss and Alzheimer’s
Disease with Replacement
Estrogens
ADAPT
Alzheimer’s Disease Antiinflammatory Prevention Trial
Agent(s)
Comment
Estrogen/
Progesterone or
>age 65
Estrogen
Stopped; Study neg.
Estrogen/
Progesterone or
>age 65
Estrogen
>7500 women
Requires affected family
member
Stopped
Naproxen or Celecoxib
>age 70
>2600 subjects; + Family Hx
Stopped
Current Prevention Trials
Study
GEM
Agent(s)
Ginkgo biloba
Ginkgo biloba in Evaluation of
Memory
PreADVISE
>3000 subjects
Recruitment complete
Vitamin E, selenium
Add-on to SELECT prostate
cancer prevention trial
GUIDAGE
14 sites in France
PHSII
Physicians’ Health Study
Comment
>age 75; MCI or normal
Results in mid-2008
Mean age 62
10,000 males:
Ginkgo biloba
Recruiting
>age 70
2600 subjects
beta-carotene, folic acid,
vitamin E
Subjective memory complaint
>age 65
>10,000 subjects
Cognitive assessments by
telephone; meds by mail
ALZHEIMER’S DISEASE COOPERATIVE STUDY
New Technologies for Prevention Trials:
Home-Based Assessment of Elderly at Risk for
Cognitive Decline, MCI and AD
AKA
Partners in Prevention
Study Design
Subjects
Randomized to
Technologies
600 Non-Demented Community dwelling
“real world” Elderly (>=75 yo) 20%
minority In-Person Baseline Evaluation
Mail-in and Telephone
Cognitive Battery
Written Med diary
(N=200)
Automated Telephone
Asse ssment
Phone Med diary
(N=200)
4-Year Follow-Up Period
Procedures
25% Receive an In-Person E valuation
In-P erson Diagnostic Evaluation Upon
Cognitive Trigger
All Receive In-P erson E valuations
at 4-Year Endpoint
Computerized
Asse ssment
Medtracker
(N=200)
Proposed Technologies and Domains



Mail In Administration &
“tester administered”
phone-based cognitive
assessment
Telephonic Assessment
with automated
presentation and vocal
and key pad response
Computerized
Assessment for
presentation and
response capture


Cognitive
Functional
 IADL
 Performance Based
Medication Compliance




Global
Behavioral
QOL
Pharmacoeconomic
Pilot Study to Evaluate Home Based Assessment of Elders for
Dementia Prevention Trials

Lessons so far:
 Elders were not eager to
have people or computer
in home
 Many “too busy”
 Did not want vitamin
 20% drop out
 Most drop from computer
arm
Courtesy of Mary Sano
Alzheimer’s Disease Course,
Treatment, and Prevention
Primary
Prevention
Intervention
Clinical
State
Brain
Pathologic
State
Normal
No Disease
No Symptoms
Presymptomatic
AD
Early Brain
Changes
No
Symptoms
Secondary
Prevention
Treatment
Mild
Cognitive
Impairment
AD
AD Brain
Changes
Mild Symptoms
Disease Progression
National Institute on Aging, USA.
Moderate to
Severe
Impairment
Thanks from Steve and Eric
“Add-On” Trial

A study in with a primary purpose to assess one outcome
“adds-on” another domain of assessment

Examples of such studies in which cognition was “added on”

Most long term studies are added onto the symptomatic AD
drugs because they are regarded as standard of care

Study features are selected for one purpose may or may not
be ideal for another
 Estrogen
 Statins
 Vitamin E
 Agent
 Dose
 Population
-- Design
--Duration
--Clinical Research Team
Probability of Progressing to AD for ApoE4 Positive
Participants (4 years study)
1.0
0.8
Probability of
not
converting to
AD
0.6
0.4
Donepezil
Vitamin E
Placebo
0.2
0.0
0
200
400
600
800
Time in MCI study (days)
1,000
1,200
Strategies for Prevention or Slowing of Disease
Progression

Use medicines that delay clinical manifestations or
slow entry into symptomatic state (delay onset)

Use medications that slow biological and clinical
progression (disease-modifying)

How would this affect current projections for
growth in dementia prevalence?
Blood tests for Alzheimer’s Disease:
AD, MCI…then pre-symptomatic cases?
A GENE EXPRESSION SIGNATURE IN BLOOD TO ACCURATELY DETECT
ALZHEIMER’S DISEASE
Anders Lönneborg*, Birgitte Booij*, Nina Hagen*,Ken Bårdsen*, Marianne Jensen*, Lena
Kristiansen*, Guri Feten**,Torbjørn Lindahl*, Bengt Winblad1, Praveen Sharma*
[Abstract number: 162960 2005 12th IPA Stockholm, Sweden].
Nature
Medicine 2007
Effectiveness/Duration of Therapy

Pathological changes begin years prior to any
clinical symptoms

Better chance for success if intervention is earlier
 MCI or presymptomatic detection of AD pathology
such as with amyloid-imaging compounds, LP,
other markers

Early identification and use of disease-modifying
drugs may become as common as the combinations
of anti-hypertensives, lipid-lowering agents, and
beta-blockers in use today for cardiac disease
prevention and treatment
Clinical Trials in Dementia
How many, How Long
Group
Outcome
Sample Size Duration
AD Patients Symptom change 200-300
Slow Progression
MCI
Dementia
700-1000
6 months
1-2 years
3-4 years
Healthy
Elders
5-7 years
Dementia
2000-4000
Summary

In diagnosis of dementia and AD, morphologic imaging will
likely serve as a powerful adjunct to clinical measures for
diagnostic purposes

Identification/prognostic evaluation of MCI
 Aid case selection for AD interdiction and prevention therapies

Functional imaging with disease-specific markers
 Promising for staging disease in vivo
 Monitoring therapeutic interventions more quickly than just
cognitive/behavioral outcomes

Screening for prevention studies, to decrease N and speed
incidence studies
How Many Subjects? How long to study?
•
•
Sample size is determined by the frequency of the
outcome measure in a given population
In general sample size need increases as disease or
symptoms decrease, i.e.:
• # Patient < # MCI < # Healthy Elders
•
•
Those with disease and symptoms are likely to
progress rapidly; consequently shorter trial periods
Those with disease or early symptoms have more
pathology, therefore more difficult disease to treat
Alzheimer’s Disease as a Continuum of
Pathological and Behavioral/Cognitive Change
Clinical
State
Normal
Presymptomatic
AD
Mild
Cognitive
Impairment
Disease Progression
AD
Linking Clinical Symptoms With
Degree of Pathology
Clinical
State
Brain
Pathologic
State
Normal
No Disease
No Symptoms
Presymptomatic
AD
Mild
Cognitive
Impairment
Early Brain
Changes
No
Symptoms
AD Brain
Changes
Mild
Symptoms
Disease Progression
AD
Mild,
Moderate, or
Severe
Impairment
NFT and Plaque Progression in AD
Rates of time over which this
accumulation occurs, and how
long it would take to show that
it had decreased or regressed, is
not known.
Braak & Braak. Acta Neuropathol. 1991.
Delacourte et al. 1999.
Thal et al. 2002.
Issues in Dementia Prevention

No reliable ways (eg, biomarkers) to identify most
presymptomatic people

Current suggestions, eg, exercise, control of
vascular risk factors, not widely used

Expense and risks of using costly preventive
medications which may have associated side effects
potential

Long time needed to ‘prove’ that preventive
treatments work

Drugs that work in one stage of the disease may not
work in other stages
Prevention of Alzheimer’s Disease

Primary: targets induction phase
 a larger number of people are treated
 low tolerance for adverse effects
 risk - benefit HAS to favor very low risk
Dynamics of Amyloid
Formation: CSF
Molecular AD
(TIMES APPROXIMATE)
SoPathological
HIGH tau andAD
LOW Aβ
are the CSF signature in AD
Clinical AD
NP
NFT
Soluble A
With plaque deposition,
soluble amyloid
drops to
A Oligomers
lower than normal levels
Syn
NP
Sx
Synapse Loss
NFT
10
20
30
40
50
AGE
60
Sub-clinical Sx
Sx
70
80
Level of function
Natural history of dementia
dementia
Death
8-12 years
Clinical Trials Design: How Should We
Proceed in the Future?
 Symptomatic Treatment vs. Disease Modification
 Pragmatic or theoretical?

Either must prevent or slow cognitive decline, and show
another clinically meaningful effect (e.g., preserve
ADLs, ‘maintain’ behavior)

Delay onset of some symptom or attainment of some
‘endpoint’, e.g., delay to NH placement

What is most meaningful to AD pts? family?
Public health?

Other possibility beside endpoint designs
 Randomized start; randomized withdrawal