Long Term Outcomes in Alzheimers Disease

1
Long Term Outcomes in Alzheimers Disease
ASENT National Meeting Washington, DC March 7,
2008

• Steven T. DeKosky, MDChair, Department of
  NeurologyDirector, Alzheimers Disease Research
  CenterUniversity of PittsburghPittsburgh, PA USA

2
Disease modification Will we know it when we
see it?

• Eric Siemers, MD
• International Conference on Alzheimers disease
• Chicago, Illinois
• July 28, 2008

3
Why is the concept disease-modification important?
Cognitive measures after 21 months of treatment
Months after initiating treatment
4
Overview

• Alzheimers Disease has a long prodrome of
  pathological change prior to symptom emergence
• Treatments can be characterized as symptomatic or
  disease-modifying, 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

5
Alzheimers Disease Course, Treatment, and
Prevention
Secondary Prevention
Treatment
Primary Prevention
Intervention
Normal
AD
Pre-symptomatic AD
Mild Cognitive Impairment
Clinical State
Early Brain Changes NoSymptoms
AD Brain Changes Mild Symptoms
Moderate to Severe Impairment
Brain Pathologic State
No Disease No Symptoms
Disease Progression
National Institute on Aging, USA.
6
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

7
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

8
Current Symptomatic Drugs for Alzheimers
Disease all studies took 6 months or less to
show effect
9
Trial Length in Possible Future Symptomatic
Therapies

• Ketasyn (3 months)
• Dimebon (12 months)

10
Amyloid Metabolism
soluble APP?
Amyloid plaques, Inflammation Neuron loss
soluble APP?
Amyloid Precursor Protein (APP)
N
Aggregation
?
?
?
Monomers ? Dimers ? Oligomers
? ? cleavage
(BACE-1) ? site
g
Soluble Ab (1-40, 1-42)
? site
A? domain
CELL MEMBRANE

• -cleavage site Presenilin 1/2

C
11
Anti-Amyloid Strategies and Mechanisms
12
NINCDS/ADRDA Criteria for Probable Alzheimers
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 198434939-944
13
Adding Biomarkers to Clinical Findings
Research criteria for the diagnosis of
Alzheimers disease revising the NINCDSADRDA
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 OBrien,
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?

14
CSF in Alzheimers Disease Low Aß and High Tau
Concentration (pg/mL)
Aß
Tau
Sunderland T, et al. JAMA. 20032892094-2103.
15
CSF Clinical Test ß-Amyloid and Phospho-Tau
(P-Tau)
47
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
60
90
120
150
P-Tau (pg/mL)
Indicates position of patient result.
16
CSF in MCI has elevated tau, decreased ß-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 177, p00001). The
association between pathological CSF and
progression to Alzheimers 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
17
Evolution of Neuroimaging in AD
39

• Computed Tomography
• MRI
• Volumetric MRI
• Co-registration of MRI
• Functional MRI
• FDG Glucose PET
• PiB PET

FDG Glucose PET
Helmuth L. Science. 20022971260-1262.
Alzheimer Disease Forum. http//www.alzforum.org/n
ew/detail.asp?id948.
Lab of Neuro Imaging UCLA School of Medicine.
www.loni.ucla.edu/thompson/AD_4D/dynamic.html.
18
Seeking Biomarkers to Speed Research

• Alzheimers Disease Neuroimaging Initiative
  (ADNI) 3 year study of MRI FDG-PET, CSF for
  ß-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)

19
Mean Cortical PIB Binding in Nondemented Controls
and AD (N41) a way to identify at-risk subjects
to shorten trials?
1.200
1.000
0.800
0.600
scBP
0.400
0.200
0.000
-0.200
Subject AGE
Mintun et al. Neurology. 2006.
20
AD Prevention Trials

• Opportunities for major public health gains
• Large (power calculations based on incidence
  rates require 3,000 subjects)
• Expensive (40 - 50 million US)
• 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?

21
Effects of Delay of Onset of Disease on
Prevalence of Dementia
Delay (years)
U.S. Prevalence of AD (millions)
5 years of delay of onset equals a 50 decrease
in prevalence
Brookheimer et al. Am J Pub Health.
1998881337-1342.
22
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

23
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

24
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

25
Currently Prevention Postponement
Level of function
Dementia
Death
8-12 years
26
Prevention Trials Discontinued(because of
toxicity of the drug)
27
Current Prevention Trials
28
New Technologies for Prevention
TrialsHome-Based Assessment of Elderly at Risk
for Cognitive Decline, MCI and AD
ALZHEIMERS DISEASE COOPERATIVE STUDY

• AKA
• Partners in Prevention

29
Study Design
Subjects
Randomized to Technologies
Procedures
30
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

31
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
32
Alzheimers Disease Course, Treatment, and
Prevention
Secondary Prevention
Treatment
Primary Prevention
Intervention
Normal
AD
Pre-symptomatic AD
Mild Cognitive Impairment
Clinical State
Early Brain Changes NoSymptoms
AD Brain Changes Mild Symptoms
Moderate to Severe Impairment
Brain Pathologic State
No Disease No Symptoms
Disease Progression
National Institute on Aging, USA.
33

• Thanks from Steve and Eric

34
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
• Estrogen
• Statins
• Vitamin E
• 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
• Agent -- Design
• Dose --Duration
• Population --Clinical Research Team

35
Probability of Progressing to AD for ApoE4
Positive Participants (4 years study)
Probability of not converting to AD
Donepezil
Vitamin E
Placebo
Time in MCI study (days)
36
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?

37
Blood tests for Alzheimers DiseaseAD, MCIthen
pre-symptomatic cases?
A GENE EXPRESSION SIGNATURE IN BLOOD TO
ACCURATELY DETECT ALZHEIMERS 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
38
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

39
Clinical Trials in DementiaHow many, How Long
40
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

41
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
• 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

42
Alzheimers Disease as a Continuum of
Pathological and Behavioral/Cognitive Change
Normal
AD
Pre-symptomatic AD
Mild Cognitive Impairment
Clinical State
Disease Progression
43
Linking Clinical Symptoms With Degree of
Pathology
Normal
AD
Pre-symptomatic AD
Mild Cognitive Impairment
Clinical State
Early Brain Changes No Symptoms
AD Brain Changes Mild Symptoms
Mild, Moderate, or Severe Impairment
Brain Pathologic State
No Disease No Symptoms
Disease Progression
44
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.
45
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

46
Prevention of Alzheimers 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

47
Dynamics of Amyloid Formation CSF
(TIMES APPROXIMATE)
So HIGH tau and LOW Aßare the CSF signature in
AD
With plaque deposition, soluble amyloid drops
to lower than normal levels
Synapse Loss
48
Natural history of dementia
Level of function
dementia
Death
8-12 years
49
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