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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 = 252)

  • 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 = 252)

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 = 252)

  • 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: = 252)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 = 252)

  • 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: trialsTrial Design Issues

  • Regulatory issues

    • Randomized start/withdrawal

    • Slope change

    • Use of biomarkers


Cognitive decline in ad treatment trials

Symptomatic+dis mod trials

Symptomatic

Disease-modifying

Placebo

Cog

0

3

6

9

12

15

18

Cognitive Decline in AD Treatment Trials

Months


Randomized start design symptomatic

Symptomatic trials

Placebo

Randomized Start Design:Symptomatic

Cog

0

3

6

9

12

15

18

21

24

27

30

33

36

Months


Randomized start design disease modifying drug

Disease-modifying trials

Placebo

Randomized Start Design: Disease Modifying Drug

Cog

0

3

6

9

12

15

18

21

24

27

30

33

36

Months


Difficulties with long trials
Difficulties with long trials trials

  • Cumulative informative drop-outs

  • Site variance (Alzhemed)

  • Changes to background therapy


Biomarkers
Biomarkers trials

  • Plasma amyloid

  • CSF amyloid, tau

  • Oxidative, inflammatory markers

  • Imaging: structural, functional, amyloid


  • 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 (Alzhemed efficacy at 3-6 months), long term efficacy TM)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 efficacy at 3-6 months), long term efficacy

  • 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 efficacy at 3-6 months), long term efficacy

  • 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 efficacy at 3-6 months), long term efficacy

  • 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 efficacy at 3-6 months), long term efficacy

  • 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 efficacy at 3-6 months), long term efficacy 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


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