Transcript Alzheimer`s vaccine Merzougui Mehdi, Mylle

Alzheimer’s vaccine
Janvier 2009
Mehdi MERZOUGUI Alexandre MYLLE
1
DEMENTIA
• Dementia is a progressive
and largely irreversible
syndrome that is
characterised by a
widespread impairment
of mental function.
Source : http://www.nice.org.uk/Guidance/TA111/SlideSet/ppt/English
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ALZHEIMER’S DISEASE :
Neurodegenerative disease of the central nervous system
Period
Stage asymptomatic
About 20-30 years
Stage premature
Lost of memorization, langage’s disorder and orientation’s
disorder, anxiety
Stage
Symptomatic
Stage moderate
Memory’s disorder, difficulty to understand and use word
Period
About 10
years
disorientation, halluciantion and/or delirium
Stage tardive
Physical faintness, opportunist infection,
Disapperance of memory on the long range, limitation of oral expression,
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difficulty to move, incontinence
EPIDEMIOLOGY
Very common disease:
50–60% of all dementia
Prevalence of AD:
60–64 years : < 1% in individuals
85 years or older : 24- 33% in the Western world
In 2001, more than 24 million people had AD.
This number is expected to double every 20 years up to 81 million in 2040
because of the anticipated increase in life expectancy
Source : CP Ferri, M Prince and C Brayne et al., Global prevalence of dementia: a Delphi consensus study, Lancet 366 (2005), pp. 2112–2117.
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RISK FACTORS & GENETICS
Risk factors :
•Ageing
•Decreased reserve capacity of the brain,
•Head trauma
•Vascular diseases: (e.g. hypertension, atherosclerosis…)
Genes & familial disease :
(rare disease, prevalence < 0·1%)
•Amyloid precursor protein (APP) gene
• Presenilin 1 (PSEN1) and presenilin 2 (PSEN2) genes
Genes & sporadic disease:
The APOE  4 allele :  risk by 3 times in heterozygotes
by 15 times in homozygotes
Each allele copy lowers the age at onset by almost 10 years.
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MECHANISM
Language’s zone
Source :Finelli, A. Kelkar, HJ. Song, H. Yang, M. Konsolaki ; Molecular and cellular neuroscience, 2004
Memory’s zone
ALZHEIMER’S PATHOGENESIS
γ-secretase
γ-secretase
α-secretase
β-secretase
Αβ generation
Aß
Tau
Oxidation Excitotoxicity aggregationInflammation
Hyperphosphorylation
Senile plaque
Neurofribrillary Tangles
Cognitive and
behavioral
abnormalities
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Robertson & Mucke, Science 2006
ALZHEIMER’S PATHOGENESIS
« amyloid-cascade hypothesis »: neuronal poisoning due to Aß
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AMYLOID PRECURSEUR PROTEIN (APP)
CATABOLISM
NH2
Ab
COOH
b-secretase
a-secretase
g-secretase
p3
g-secretase
Ab
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HOW TO MESURE COGNITIVE FUNCTION ?
ADAS-cog
.
.
.
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S : ADAS-cog (Alzheimer’s Disease Assessment Scale – cognitive) validation of the Slovak version : Kolibas E, Kornikova V, Novotny V, Vajdickova K, Hunakova D
DRUG INTERVENTION
Costs / patient / year: > 40,000 €
Drug costs in 2005: ca. 3.9 B €
Treatments that stop or at least effectively modify disease course do not
yet exist
Source :http://www.boursorama.com/forum/message.phtml?file=370722545&pageForum=1
HAS santé.fr : reévalutation des medicaments anti-Alzheimer (septembre 2007)
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DRUG INTERVENTION
Age ( in years)
Number of treated
patient
Number of
Alzheimer’s patient
Proportion of treated patient
Any drug that can modify or reverse the course of
Alzheimer's disease will generate billions of dollars in
sales.
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Source : Assemble-nationale.fr, n° 2454 (juillet 2005)
Amyloid-ß immunisation
for Alzheimer’s disease
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TYPES OF VACCINATION
αβ peptide with
adjuvant
Anti- αβ antibody
A) Active immunization
Anti- αβ Antibody
B) Passive immunization
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PART 1
Active immunization
The first concept used in Alzheimer’s vaccination
αβ peptide with
adjuvant
Anti- αβ antibody
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Once upon a time...
...1999, Schenk et al...
...a Anti-alzheimer’s
vaccine
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IMMUNIZATION WITH Aβ42 IN THE PDAPP
MOUSE
0
Immunization with Aβ42 attenuates Alzheimer-disease-like pathology
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Source :B. Schenk D, Barbour R, Dunn W, et al. (1999) Immunization with amyloid-β attenuates Alzheimer-disease-like pathology in the
PDAPP mouse. Nature
VACCINE STUDIES IN TRANSGENIC MOUSE MODELS OF AD
Model
TgCRND8
Treatment (age)
Activepassive
(route)
Treatment
schedule
Prophylactic (6 wk)
Active
Chronic (19wk)
Prophylactic (6 wk)
Active
Chronic (11mo)
Treatment (11 wk)
Active
Chronic (8mo)
PDAPP
Prophylactic (5 mo)
Active (nasal) Chronic (7 mo)
Prophylactic (8-20 mo)
Passive
Chronic (6 mo)
Prophylactic (7-8 mo)
Active
Chronic
Treatment (18 mo)
Passive
Acute
6-8 wk
Active
Acute
Tg2576
C57BL-6
Source :Gelinas et al. Immunotherapy for Alzheimer’s disease, October 5, 2004, vol. 101 suppl. 2 14657–14662
Furlan, R., et al (2003) Brain 126, 285–291.
Effect
Aß levels,
Pathology
+ Behaviour
Aß levels
Pathology
Aß levels
Pathology
Aß levels,
Pathology
Aß levels,
Pathology
Aß levels,
Pathology
+ Behaviour
Aß levels,
Pathology
Autoimmune
encephalomyelitis*
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Potential mechanisms of immunomodulation for
amyloid-β related pathology
: periferal sink
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Thomas Wisniewski, Uwe Konietzko, The Lancet, September 08
TOWARDS Aß VACCINATION IN HUMAN BEINGS
In transgenic mice:
• Striking biological effect
• apparent lack of side-effects
=>Treatments that prevents or remove Aβ aggregates have a genuine
effect on the Alzheimer disease process in animals: « validation » (in
animals) of the amyloid-cascade hypothesis
launch of clinical trials with AN1792, that contained preaggregated
Aβ1–42 and QS21
Because QS21 strongly induces Th1 lymphocytes, this vaccine
design aimed to induce a strong cell-mediated immune response
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AN-1792
DAEFRHDSGYEVHHQKLVFFAEDVGSNKGAIIGLMVGGVVIA
1
42
+Adjuvant QS-21
Aß1-42
+PS-80
Precinical studies :
Good safety and tolerability of combinaison AN-1792 + QS-21
Phase I :
April 2000 – June 2002
80 subjects : 20 % Responders after 4 injections
5 deaths during the study period
The optimal antibody reponse : 225μg of AN-1792 + 50 μg of QS-21 (+ 0,4% PS-80)
Source : Bayer AJ, Bullock R, Jones RW, et al. Evaluation of the safety and immunogenicity of synthetic Aß42 (AN1792) in patients with AD.
Neurology 2005;64:94–101
David A, et al, Neurology 64,January 2005 94-129
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Phase IIa
The beginning in September 2001…
Phase IIa
Patient
Term
Objectif
double-blind, placebo-controlled
372 subjects (300 AN-1792, 72 placebo)
Immunization: 0, 1, 3, 6, 9 & 12 months
15 Months
safety, tolerability, and pilot efficacy of AN1792(QS-21) in patients
with mild to moderate AD
Specificity Adverse events
Primary measures
Elisa (IgG and IgM in serum and CSF samples)
MRI = the change in whole brain volume
Secondary measures
Cognitive function (antibody reponse vs placebo)
CSF = CerebroSpinal fluid
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Source :Masliah E, Hansen L, Adame A, et al. Aß vaccination effects on plaque pathology in the absence of encephalitis in Alzheimer’s disease.
Neurology 2004;64:129–131
Fox et al. 2004,
AN-1792 : OUTCOMES
Immunologic findings:

There is 19.7 % (59 patients) treated with
AN1792 were antibody responders (the majority
after the Second injection)

Total IgG titers were higher than found in the
phase I trial
CSF tau
Cognitive function:
Placebo

There were no differences between treatment
groups responder versus placebo

The results of the NTB revealed that antibody
responders had an improvement compared with
placebo
Responders
CSF Aß42
CSF tau and Aß42:

there was a significant decline of tau and no
change in Aß levels compared with placebo
Placebo
Responders
CSF = CerebroSpinal Fluid
NTB = Neuropsychological Test Battery
Source :M. Grundman et al Neurology 71 , correspondance August 26, 2008
S. Gildman et al, neurology Clinical effects of A immunization (AN1792) in patients with AD in an interrupted trial , 2005
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AN-1792 : MENINGOENCEPHALITIS
The study was suspended in January 2002…..
….after four patients developed meningoencephalitis
+1 Patient (phase I)
18 Patients : 6%
13 Responders
5 Non Responders
13 Survivors (6 with residual deficits)
+
5 Deaths
Parietal neocortex of the immunized case, with persistent vascular
amyloid (CAA)
Meningoencephalitis
Macrophages in White
Matter
CD 3+-Tcell infiltatres in
leptomeninges
Source : David A, et al, Neurology 64,January 2005 94-129
Masliah E, Hansen L, Adame A, et al. Aß vaccination effects on plaque pathology in the absence of encephalitis in Alzheimer’s disease.
Neurology 2004;64:129–131
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DEAD BUT WITHOUT AMYLOID PLAQUES
A :The brain was grossly normal
B: Aß-immunoreactivity was only
detected as aggregate structures
within cells
C.D.E: aggregates were within
CD68-immunoreactive
macrophages/microglia
FRONTAL CORTEX
F.G: Minimal perivascular
lymphocytic infiltration was
observed, consisting of T and B
cells
LEPTOMENINGES
H: abundant amyloid plaques
I.J.K: Macrophages/ microglia
were identified among these
plaques
L: Neurofibrillary tangles and
neuropilthreads were abundant
throughout the neocortex and
hippocampus, consistent with a
Braak stage VI.
M: Luxol fast blue analysis showed
that the white matter was well
myelinated and no macrophage
infiltration was observed
WHITE MATTER
PARIETAL CORTEX
Source : Masliah et al, A vaccination effects on plaque pathology in the absence of encephalitis in Alzheimer disease, Neurology 2005;64:129–131
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DEAD BUT WITHOUT AMYLOID PLAQUES
Mean plaque density (Plaques/mm²)
Cingulate Medial
frontal
Inferior Middle Superior
Temporal
Aß load (%)
Cingulate Medial
frontal
Inferior Middle Superior
Temporal
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Source : J Nicoll et al, Neuropathology of human Alzheimer disease after immunization with amyloid-ß peptide, Nature 2003
LONG-TERM EFFECTS OF Aß42
IMMUNISATION
The come back in Juny 2003…..
80 subjects into phase I study
June 2002,
Phase I study completed
Study completed
36 patients agree to clinical follow-up
and/or post mortem
June 2003,
Follow-up study
10 patients dead (treated)
26 patients alive : 20 treated and 6 placebo
commenced
September 2006,
Follow-up study
completed
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Source :Holmès. C, Long-term eff ects of Aβ42 immunisation in Alzheimer’s disease: follow-up of a randomised, placebo-controlled phase I trial,
Lancet 2008; 372: 216–23
LONG-TERM EFFECTS OF Aß42
IMMUNISATION
Persistent elevated Antibody titers
No further cases of encephalitis
Histological patterns of Aβ in the temporal lobe
neocortex after immunisation with AN1792
Aβ load
 lower than in the unimmunised controls

was considerable variation both in the Aβ load
and in the degree of plaque removal among the
immunised participants
There is no evidence of differences :
(the treated versus placebo groups)
in survival time
In time to severe dementia
In decline over the 6 year follow-up period for any
measures
No correlation :
Between anti-Aβ antibody titres at long-term followup and rate of decline as measured by at 6-year
follow-up (ADAS-Cog;MMSE, or DAD)
Source :Holmès. C, Long-term eff ects of Aβ42 immunisation in Alzheimer’s disease: follow-up of a randomised, placebo-controlled phase I
trial, Lancet 2008; 372: 216–23
IS THE AMYLOID HYPOTHESIS DEAD
FOR A VACCINE ?
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FROM AN1792 TO ACC001
NH2-
DAEFRHDSGYEVHHQKLVFFAEDVGSNKGAIIGLMVGGVVIA
1
Humoral reponse
(Lc B)
Source : Schenk D, Nature 2002
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-COOH
Aß1-42
Excessif reponse
(Lc T)
ACC-001
Idendity card
Nature: 7-amino acid of Aß42
peptide : N-Terminal
+
CRM197 Conjugate : a nontoxic
Variant of Diphtheria Toxin
CRM197 :

An excellent carrier for B-cell
epitopes.

Carrier protein inside vaccines:
Prevnar®,
Tetramune®,
Clinical trial : Phase II
Meningitec®
ACC-001
Study
Pharmaceutical companies Wyeth and Elan Corp. suspended dosing at a Phase II trial for
Alzheimer's vaccine ACC-001 after….
…..One patient was hospitalized with skin lesions (rash)
Cause : vasculitis, an inflammation of blood vessels
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Source: Biocentury , april 21 2008 , page 21
PART 2
Passive immunization
Monoclonal antibodies
How to avoid meningoencephalitis symptoms ?
Anti- αβ Antibody
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BAPINEUZUMAB : ABB-001
Structure
WHAT IS A –ZUMAB ?
of mouse 1975
humans 1994-1999
…momab
…mumab
chimerics 1984
humanized 1988-1991
…ximab
…zumab
HUMANIZATION
Immunogenic +++
less immunogenics
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BAPINEUZUMAB : ABB-001
Identity card
NH2-
DAEFRHDSGYEVHHQKLVFFAEDVGSNKGAIIGLMVGGVVIA
1
42
Aß1-42
Humoral reponse
(Lc B)
-COOH
BAPINEUZUMAB : ABB-001
Identity card
•
•
•
•
•
•
•
•
•
Name: AAB-001
Other Name: Bapineuzumab
Class: Humanized monoclonal antibody
Therapeutic Applications: Mild to moderate AD
Therapy Types: Protein : humanized monoclonal antibody against Aβ
Mechanisms: Designed to bind and remove the Aβ peptide that
accumulates in the brain
Development Status: Investigational in U.S
FDA Phase: Phase III
Side Effects:
– Passive immunotherapy will induce similar side effects is largely
unknown. One report has shown that frequency and severity of cerebral
microhemorrhage
– Vasogenic edema
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BAPINEUZUMAB : ABB-001
Clinical trials: Phase I
Design
Placebo-controlled, multiple ascending dose study
Safety objective
The safety, tolerability and pharmacokinetic
Serious adverse
events
Retinal vascular disorder
Cerebral vasogenic edema
More common in the highest dose group (5mg/kg)
Source : http://www.elan.com/Images/Bapineuzumab%20_AAB-001_%20Backgrounder%20Final_tcm3-20147.pdf
http://clinicaltrials.gov/ct2/show/NCT00397891?term=bapineuzumab&rank=7
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BAPINEUZUMAB : ABB-001
Clinical trials: Phase II
Design
Randomized, double-blind, placebo-controlled, multiple
ascending dose study
Safety Objective The safety and tolerability
Estimated study
Duration
Dosing
123 weeks :-6 for sceening period
-65 of dosing
-52 for follow up
5 groups : -0.15 mg/kg
-0.5 mg/kg
total of 6 doses over the
-1 mg/kg
course of the study
-2 mg/kg
-placebo
Source : http://www.elan.com/Images/Bapineuzumab%20_AAB-001_%20Backgrounder%20Final_tcm3-20147.pdf
http://clinicaltrials.gov/ct2/show/NCT00606476?term=bapineuzumab&rank=2
http://clinicaltrials.gov/ct2/show?term=bapineuzumab&rank=3
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BAPINEUZUMAB : ABB-001
Clinical trials: Phase II
ADAS-cog : Total population - All doses combined
N = 234
18 mos
6 doses
q 13 wks
4 dose
groups
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BAPINEUZUMAB : ABB-001
Clinical trials: Phase II
ADAS-cog : ApoE4 non carriers - All doses combined
http://www.elan.com/News/full.asp?ID=1180940
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BAPINEUZUMAB : ABB-001
Clinical trials: Phase II
Vasogenic edema on MRI
Cohort : 1.0mg/kg; ApoE4 carrier (asymptomatic)
Pre-dose
7 weeks
13 weeks
19 weeks
More likely to occur in E4 carriers at higher doses
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BAPINEUZUMAB : ABB-001
Clinical trials: Phase III
Design
Randomized, double-blind, placebo-controlled, parallelgroup, studies
4 studies : 2 with ApoE4 (+) & 2 withApo E4 (-)
Safety Objective
The safety and tolerability
Estimated study
Duration
83 weeks : -5 for sceening period
-65 of dosing
-13 for follow up
Dosing
5 groups :0.5 mg/kg
1 mg/kg
2 mg/kg
0.5 mg/kg
in noncarriers
in ApoE4 carriers
Source : http://www.elan.com/Images/Bapineuzumab%20_AAB-001_%20Backgrounder%20Final_tcm3-20147.pdf
http://clinicaltrials.gov/ct2/show/NCT00574132?term=bapineuzumab&rank=1
http://clinicaltrials.gov/ct2/show?term=bapineuzumab&rank=4
total of 6
infusion
over the
course of
the study
42
BAPINEUZUMAB : ABB-001
Conclusion
It's still very risky, with serious side effects !
43
AD immunotherapies:
competition
Most current programs are focused on passive immunization
44
CONCLUSION
No amyloid hypothesis is not dead for a vaccine

Biological effect exist

Lot of research about it
It won’t be miracle drug

Percentage of responder about 20 %

Problem of side effect
Discussion :
There is not just a mecanism in Alzheimer’s disease
Protein Aß inside senile plaque is toxic ?
When begins it to administrate the vacccine ?
Thank you for your attention
QUESTIONS ?
46
AN-1792 : ADVERSE EVENTS
Adverse events
The study was suspended in January 2002…..
59
…. Study remained blinded for 12 months rather than 15 as
originally planned.
Placebo
(n=72)
Responder
(n=59)
51
Treatment-related Adverse Events:
Non
Responder
(n=241)
215
 AN1792(QS-21) > placebo
60
50
 were generally of mild to
moderate intensity.
40
30
20
10
0
Why to suspend ?
Placebo (n=72)
Responder (n=59)
Non Responder (n=241)
Treatment-related
Mild
Moderate
Severe
SAD Non-fatal
SAD Treatment-related
SAD Death
Clinically important abnormal laboratory values
Source : S. Gildman et al, neurology Clinical effects of A immunization (AN1792) in patients with AD in an interrupted trial , 2005
BAPINEUZUMAB : ABB-001
Clinical trials: Phase II
ADAS-cog : ApoE4 carriers – All doses combined
MITT
http://www.elan.com/News/full.asp?ID=1180940
Completers