Clinical trials in alzheimer s disease
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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

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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


Clinical trials in alzheimer s disease

  • Symptomatic 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 trials

Comparison between Tramiprosate and Tarenflurbil Phase II trials


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


Randomized start design disease modifying drug

Disease-modifying

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

  • 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


Clinical trials in alzheimer s disease

  • 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


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