Current dementia research: a local perspective€¦ · The amyloid cascade hypothesis Amyloid...

Current dementia research: a local perspective

Clive HolmesUniversity of Southampton

The amyloid cascade hypothesis

Amyloid plaques/ dimers

Tangles

Microglia

Environment and

Genetic variation

Neuronal cell lossNeurotransmitter

changesClive Holmes - BGS Spring 2009

Plaque preventionAnti-aggregants

Metallopeptidases

Vaccination

Secretase inhibition/ promotion

Clive Holmes - BGS Spring 2009

Immunization with amyloid-β attenuates Alzheimer-disease-like pathology in the PDAPP mouse SCHENK et al. Nature, 1999

control Aβ42

immunized at 6 weeks

Aged 13 months

immunized at 11 months

Aged 18 months

control Aβ42


Phase I Human trials• First study entrant April 2000 and last entrant Aug 2000

• Undertaken to test the safety, tolerability andimmunogenicity of aggregated human Aβ42 (AN-1792) plus QS-21

• Four study sites in UK (including Southampton) recruited 80 subjects

– Randomisation 4:1 active : placebo

• Neuropsychological testing– ADAS-cog, MMSE, ADCS-CGIC, DAD– Screening (-3 weeks), 32; 64; 84 weeks


Phase II study

• Larger European study (n= 372) – started Sept 2001 (before end of phase I)– 225μg AN1792 + 50 μg QS-21 + 0. 4%

polysorbate

• Study halted Jan 2002– 6% meningoencephalitis

Orgogozo et al 2003 Clive Holmes - BGS Spring 2009

Neuropathology of human Alzheimer’s disease following immunization with amyloid β-peptide : phase I study

Nicoll et al Nature Medicine 2003Clive Holmes - BGS Spring 2009

Aβ immunotherapy approaches

AN 1792

Conjugate

HumanmAb

1

2

3

Aβ42

Aβ fragmentsActive

immunization

Passive immunization


Immunisation approaches

Aβ1-40Aβ1-40PfizerAnti-Aβ aa 33-40PF04360365

Elan Anti-Aβ aa 1-5Bapineuzumab

LillyAnti-Aβ aa 13-28LY2062430

Novartis Anti-Aβ aa 1-6 CAD106 9 (Active)

Intravenous immunoglobulin (IVIg) Clive Holmes - BGS Spring 2009

Immunisation Clinical outcomes

Efficacy


ADAS cog change by amyloid dose

-21

-18

-15

-12

-9

-6

-3

0

3

Baseline Week 32 Week 64/5 Week 84 Final visit

Mea

n ch

ange

in A

DA

S co

g fr

om b

asel

ine

QS-21 AN 1792 (+QS-21)

Bayer et al Neurology 2005

Phase I AN1792 study


Timeline and patient disposition of the long term clinical and post mortem follow up of patients entering the AN1792 phase I study.

80 subjects enrolledinto phase 1 study

Phase 1 study completed

24 patients and/or carers refused

consent for clinical follow up.

20 patients dead at baseline

(2 post mortems)

36 patients and/or carers agree to

clinical follow up and /or pm

12 patients dead 12 patients alive 10 patients dead (7 post mortems) 26 patients alive

September 2000Treatment study

commenced

June 2002Treatment study

completed

June 2003Follow up study

commenced

September 2006Follow up study

completed

Holmes et al Lancet 2008


Kaplan-Meier estimates of survival time to

severe dementia by treatment group.

806040200

Months

1.0

0.8

0.6

0.4

0.2Prob

abili

ty o

f non

pro

gres

sion

to s

ever

e de

men

tia Placebo group

AN1792 treatment group

Log rank p = 0.73



Histological patterns of Aβ in the temporal lobe

neocortex after immunization with AN1792.







Novartis Anti-Aβ aa1-6 CAD106 9 (Active)


Bapineuzumab• Passive immunisation study (N= 234)

– 18 month study

• Double-blind, placebo-controlled multiple ascending dose trial in mild-to-moderate Alzheimer’s disease

• In the total study population, statistical significance was not obtained on the pre-specified efficacy endpoints of ADAS-cog and DAD but – post-hoc efficacy analyses in ApoE4 Non-Carrier Population

· ADAS-cog treatment difference of 5.0; p=0.026· NTB treatment difference of 0.35; p=0.006· CDR-SB treatment difference of 1.5; p=0.040

– Phase III study (n ~ 4,100)

ICAD Unpublished data 2008


Elan share prices

2008Clive Holmes - BGS Spring 2009

Immunisation Clinical outcomes

Side effect profile


Neuropathology of human Alzheimer’s disease following immunization with amyloid β-peptide : phase I study

Nicoll et al Nature Medicine 2003Clive Holmes - BGS Spring 2009

Histological patterns of Aβ in the temporal lobe

neocortex after immunization with AN1792.



CasescAD iAD

CasescAD iAD

0

2

4

6

Aβ 4

2

cAD

immunised AD

Parenchymal Aβ42

Vascular Aβ42

Parenchymal Aβ42

Vascular Aβ42

Parenchymal Aβ42

Vascular Aβ42

Control AD

Distribution of Aβ42 in parenchyma vs vasculature

Boche et al Brain 2008


LiverKidney

BBBBlood Brain

Mechanism of Action


LiverKidney

BBBBlood Brain

Mechanism of Action


MSI

/ 5

0 fi

elds

*

0

2

4

6

AD iAD PSP 2 1 3 4 6 7 9 8

Mic

rova

scul

arle

sion

s /

50 f

ield

s

Cases

0.0

0.2

0.4

0.6

AD iAD PSP 2 1 3 4 6 7 9 8

*

Microvascular lesions

Quantification of microhaemorrhages /microvascular lesions

Haemorrhage severity(Perls staining)

11.24 clusters per 50 fields in the severe CAA case represent 0.35% of the parenchyma.

H&E GFAP CD68

P = 0.021

P = 0.033

Boche et al Brain 2008






Novartis

Anti-Aβ aa 1-6

CAD 106



Aβ1-40Aβ1-40Elan Anti-Aβ aa 1-5Bapineuzumab Vasogenic oedema in ~10% of ApoE e4

carriers


Will anti-amyloid therapies work?

• Prevention v.s. treatment?• What Aβ species is being targeted?• Is early onset AD different to late

onset AD?• Better understanding of the

molecular biology of Aβ immunisation


Acknowledgments• Delphine Boche • David Wilkinson • Ghasem Yadegarfar • Vivienne Hopkins • Anthony Bayer • Roy W Jones • Roger Bullock • Seth Love • James W Neal • Elina Zotova • Roy Weller• James AR Nicoll

• Alzheimer’s Research Trust and Medical Research Council for funding this study

• Thanks to: – all patients and carers taking part

in the study.– Elan Pharmaceuticals for access to

phase 1 AN1792 treatment study data

– J Gifford; Helen Cartwright; Carol Hall and other clinical research staff at Southampton, Cardiff, Swindon and Bath.

– Neuropathology laboratory staff; staff of the HistochemistryResearch Unit and Biomedical Imaging Unit at Southampton General Hospital.

– M Esiri and C Joachim at Oxford University.


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Current dementia research: a local perspective€¦ · The amyloid cascade hypothesis Amyloid...

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