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ASENT Symposium Neuroprotection and Disease Modification: Successes, Failures and Lessons Learned. Clinical Trials in Alzheimer’s Disease. Paul S. Aisen, MD Professor, Department of Neurosciences, UCSD Director, Alzheimer’s Disease Cooperative Study. AD Therapeutics.

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clinical trials in alzheimer s disease

ASENT Symposium

Neuroprotection and Disease Modification:

Successes, Failures and Lessons Learned

Clinical Trials in Alzheimer’s Disease

Paul S. Aisen, MD

Professor, Department of Neurosciences, UCSD

Director, Alzheimer’s Disease Cooperative Study

ad therapeutics
AD Therapeutics
  • 1906 Alzheimer’s description
  • 1970’s Cholinergic hypothesis
  • 1985 first THA trial
  • 1993 Tacrine approved
  • 1997 Vitamin E
  • 1997 Donepezil
  • 2000 Rivastigmine
  • 2001 Galantamine
  • 2003 Memantine
  • 2008-2015 Disease-modifying therapy
fda guidelines for ad trials
FDA Guidelines for AD Trials
  • Co-Primary outcome measures
  • Memory/cognition test, plus global or functional measure
therapeutic strategies for ad
Therapeutic Strategies for AD
  • Symptomatic treatment
  • Disease-modifying treatment
chei monotherapy in mild to moderate ad cognition n 286

1.0

0.5

0

–0.5

–1.0

–1.5

–2.0

–2.5

ChEI Monotherapy in Mild to Moderate AD: Cognition (N = 286)

Donepezil: MMSE

*

Improvement

*

LS Mean Change in Score From Baseline (±SE)

Decline

Donepezil

Placebo

0

12

24

36

52

LOCF

*P<.001.†P<.05.

‡P=.001.

Intent-to-treat population.

LS = least squares; SE = standard error; LOCF = last observation carried forward.

Source: Winblad B, et al. Neurology. 2001;57:489-495.

Week

memantine monotherapy in moderate to severe ad cognition n 252
Memantine Monotherapy in Moderate to Severe AD: Cognition (N = 252)

SIB

P<.001

2

0

-2

-4

Difference in SIB Score

-6

-8

Memantine

-10

Placebo

-12

0

4

12

28

End Point

(LOCF)

Week

126

119

n =

107

96

124

n =

126

117

106

83

123

SIB = Severe Impairment Battery.

Source: Reisberg B, et al. N Engl J Med. 2003;348:1333-1341.

disease modification
Disease-modification
  • Most important need
    • AD treatment- beyond symptomatic
    • MCI, primary prevention
  • Clear, specific targets
  • Methodologic problems may be the limiting issue
disease modifying strategies
Disease-Modifying Strategies

anti-inflammatories

antioxidants

neuroprotectants

immunotherapy

amyloid binders

secretase

modulators

inflammation

oxidative stress

β-secretase

Neuron death

APP

γ-secretase

excitotoxicity

direct toxicity

disease modifying drug development for ad
Disease-Modifying Drug Development for AD
  • May be no symptomatic effect
  • Goal is usually slowing the rate of decline
  • Implications:
    • Long trial
    • Many subjects
    • Slope analysis?
    • Still need co-primary outcome measures
  • If “disease-modifying” is to be specified in label:
    • May need two randomization steps in pivotal trials
    • Alternatively, need convincing biomarker evidence of disease modification
disease modifying rx phase ii problem
Disease-Modifying RX:Phase II problem
  • No short-term benefit expected, rather change in slope of decline
  • Placebo groups in mild AD studies don’t decline in 6 months; minimal in 12 months
  • To see effect on slope, need hundreds or thousands of subjects (1500?-Myriad; 4000?-Elan) followed for 18 months
  • CANNOT SEE PROOF OF EFFICACY IN

PHASE II-TYPE TRIAL

phase ii
Phase II
  • Aim for hints of clinical efficacy (Myriad)
  • Focus on biomarkers (Alzhemed, IgIV)
  • Or both
comparison between tramiprosate and tarenflurbil phase ii trials1
Comparison between Tramiprosate and Tarenflurbil Phase II trials

Tramiprosate: CSF-Aß Results

Tarenflurbil: Psychometric Results

Source:www.myriad.com

disease modification trial design issues
Disease-Modification:Trial Design Issues
  • Regulatory issues
    • Randomized start/withdrawal
    • Slope change
    • Use of biomarkers
cognitive decline in ad treatment trials

Symptomatic+dis mod

Symptomatic

Disease-modifying

Placebo

Cog

0

3

6

9

12

15

18

Cognitive Decline in AD Treatment Trials

Months

randomized start design symptomatic

Symptomatic

Placebo

Randomized Start Design:Symptomatic

Cog

0

3

6

9

12

15

18

21

24

27

30

33

36

Months

difficulties with long trials
Difficulties with long trials
  • Cumulative informative drop-outs
  • Site variance (Alzhemed)
  • Changes to background therapy
biomarkers
Biomarkers
  • Plasma amyloid
  • CSF amyloid, tau
  • Oxidative, inflammatory markers
  • Imaging: structural, functional, amyloid
slide21
In absence of symptomatic (ie, short-term) efficacy (no efficacy at 3-6 months), long term efficacy suggests disease modification
    • statistical evidence: growing group difference v. slope change by regression
  • Supported by mechanism, animal model data
  • Supported by biomarkers related to proposed mechanism (eg, for anti-amyloid rx, CSF Abeta or PET PIB; for anti-tangle, CSF tau), esp. if biomarker validated in animal studies
tramiprosate alzhemed tm phase iii study design
Tramiprosate (AlzhemedTM)Phase III Study Design

Placebo (n=315)

CL-758007

Study

entry

AlzhemedTM 150 mg BID

AlzhemedTM 100 mg BID (n=315)

+ AChEI

+/- NMDA

antagonist

AlzhemedTM 150 mg BID (n=315)

Titration

Period

Maintenance Dose

Period

Titration

Period

Maintenance Dose

Period

78 Week

Double - Blind

78 Week

Open – label Extension

efficacy endpoints
Efficacy Endpoints
  • Primary endpoint
    • Approval: Change from baseline to month 18 in both ADAS‑cog and CDR-SB scores
    • Disease Modification Claim: Rate of brain volume change as measured by MRI
  • Secondary endpoints
    • Changes from baseline in the MMSE, CIBIC-plus, NPI and DAD scores
    • Changes from baseline in plasma & CSF Aβ, CSF tau
tramiprosate phase iii summary
Tramiprosate Phase III Summary
  • Primary analysis of North American Phase III trial is inconclusive with respect to tramiprosate treatment effect
  • Some descriptive data show numerical differences on the primary clinical endpoints data in favor of tramiprosate.
  • Some descriptive data show numerical differences between groups on the primary disease modification endpoint (MRI).
prevention trials
Prevention Trials
  • MCI (secondary prevention?)
    • Subject selection
    • Operationalizing AD end-point
    • Significance of other end-points (cognition, function, global)
  • Primary Prevention
    • Enriching population; numbers required; duration
    • Operationalizing MCI/AD end-point
    • Significance of other end-points (cognition, function, global)
    • Simplifying trial design to allow large N
  • Biomarker targets
    • Treat plasma/CSF abeta? PIB? CSF tau?
ad trials current status
AD Trials: current status
  • FDA guidelines have remained consistent
  • ADAScog, SIB, CIBIC+ have performed adequately
  • 5 symptomatic drugs approved
  • But:
    • No successful MCI trials
    • No completed prevention trials
    • Disease-modification??
ad disease modifying trials in progress
AD Disease-Modifying Trials in Progress
  • Results soon:
    • Myriad Flurizan Phase III
    • Elan AAB-001 Phase II
  • Later:
    • Phase III: AAB-001, IgIV, Dimebon, Lilly gamma secretase inhibitor
    • Phase II: ELND005, ACC-001, Pfizer RAGE inhibitor, DHA
ad