Transcript Why ApoE4 gene influences study design?

ALZHEIMER IMMUNOTHERAPY
$1,5 billion : a good investment?
02-2009
Debarge Valentin
Fontaine Quentin
Olivier Jérôme
Summary
I/ The deal
II/ Mechanism of Alzheimer’s disease
III/ Active immunisation
IV/ Passive immunisation
V/ Our opinion
1
I/ The Deal
2
I/ The Deal
JULY 2, 2009
www.jnj.com
3
I/ The Deal
• Alzheimer Immunotherapy Program (AIP) :
www.elan.com
In 2008, Elan spent $113 million on AIP, partnered with Wyeth (now Pfizer), and estimated
it would spend as much as $500 million on bapineuzumab and the rest of the portfolio
over the next 3 or 4 years.
Impossible for Elan
NATURE BIOTECHNOLOGY VOLUME 27
NUMBER 8
4
AUGUST 2009
I/ The Deal
Summer 2008 : two more patients taking the multiple sclerosis drug Tysabri (natalizumab)
had contracted a potentially fatal brain disease : progressive multifocal
leukoencephalopathy
These events combined to drive down Elan’s stock from more than 23€ to less than 10€
The J&J deal solves both problems
http://fr.finance.yahoo.com/
5
What did J&J want ?
« As of April 2009, J&J did not list any
neurodegenerative programs in its pipeline.
We believe that AIP gives us a significant
opportunity to build a position in Alzheimer’s
disease by getting access to a late- stage
molecule* that has potential in delaying
progression of Alzheimer’s disease.”
J&J spokesman Srikant Ramaswami
* bapineuzumab
BioCentury, the Berstein report on biobusiness
July 6, 2009
6
Page A22 of
I/ The Deal
Transaction
$885 M
18,4% Elan's capital
$ 500 M
IP Elan (AIP)
49,9% Janssen AI's capital
Estimated at $500 M
Royalties
Under conditions
BioCentury, the Berstein report on biobusiness
July 6, 2009
Page A22 of 37
I/ The Deal
Transaction
J&J purchased 107.3 million Elan's shares at $8,241/share
J&J also agreed not to acquire any more shares for the next five years
Royalties : ONLY after J&J has earned profits from the AIP equal to its $500 M
Janssen AI: all annual in-market
sales
Royalties for Elan
$2 billion - $4 billion
5%
$4 billion - $ 10 billion
7%
> 10 billion
9%
The program will remain partnered with Wyeth, which was acquired by Pfizer Inc
(01/2009, $68 billion)
BioCentury, the Berstein report on biobusiness
July 6, 2009
Page A22 of 37
What’s the level risk for J&J ?
Bapineuzumab
Ian Sanderson, analyst at Cowen, New York, gives bapineuzumab a 50% likelihood of
reaching the market, based on clinician surveys conducted by the investment bank.
9
NATURE BIOTECHNOLOGY VOLUME 27
NUMBER 8
AUGUST 2009
What’s the level risk for J&J ?
Bapineuzumab
Probability of success estimated
= 50 % < 80 %
Why ?

AN 1792 fail
Disappointing phase II
results

« first in class » in CNS
therapeutic area

What’s the level risk for J&J ?
Active immunotherapy
Fail of AN 1792
Only in phase 2 today
If immunotherapy fails …
Empty pipeline !
No γ-secretase inhibitor
No Abeta aggregation inhibitor
Tau protein way non explorated
11
NATURE BIOTECHNOLOGY VOLUME 27
NUMBER 8
AUGUST 2009
Alzheimer's disease : background
12
Leerink Swann analysis. Extrapolated from UN census and prevalence data from 2008 US Alzheimer's facts and figures
Alzheimer's disease drugs market

$ 6.0 billion in 2008

$ 7.8 billion expected in 2011
NATURE MEDECINE VOLUME 12 NUMBER 7
JULY 2006
13
Alzheimer's disease costs
The current direct and indirect cost of caring for the 4,5 million Americans with AD was
at least $100 billion annually in 2006 and estimated at $160 billion in 2010
Medicare costs
Medicaid costs
14
NATURE MEDECINE VOLUME 12 NUMBER 7
JULY 2006
Are they alone on the target ?
Type of immunization
Active
Passive
Compagny
Product
Description
Status
Cytos Biotechnology AG/Novartis AG
CAD106
Vaccine whith a fragment of Aβ protein
Phase II
Affiris GmbH/GlaxoSmithKline plc
Affitope AD01 and AD02
Vaccine against Aβ
Phase I
Merck&Co
V950
Vaccine against Aβ
Phase I
United Biomedical Inc
UBITh AD
Vaccine against Aβ
Phase I
Eli Lilly and Co
Solanezumab (LY2062430)
Ab against soluble Aβ
Phase III
Pfizer Inc.
PF-4360365
Humanized mAb against Aβ
Phase II
GlaxoSmithKline plc
GSK-933776A
mAb against Aβ
Phase I
MorphoSys AG/Roche
Gantenerumab (RG1450)
HuCAl-derived human mAb against Aβ
Phase I
Roche (Genentech)
RG7412
mAb against Aβ
Phase I
Solanezumab is the main competitor of bapineuzumab
but the overall trial is anticipated to be completed in mid 2012
15
II/ Mechanism of Alzheimer’s disease
16
Alzheimer’s disease
Disease or neurodegenerative progressive appearance of mnemonic disorders evolving
towards: a syndrome aphaso-apraxo-agnosic syndrome
progressive loss of nerve cells in the brain
death
Mécanismes Moléculaires dans les Démences Neurodégénératives Inserm-UM2-EPHE U710
La maladie d’Alzheimer : aspects moléculaires, diagnostiques et thérapeutiques
17
Octobre 2009
Histological signs
We observe two types of damage in the neocortex :
Tau protein and neurofibrillary tangles=NFTs
(intra-neuronal)
Beta amyloid protein (Aß) and senile plaques
(extra-cellular)
Mécanismes Moléculaires dans les Démences Neurodégénératives Inserm-UM2-EPHE U710
La maladie d’Alzheimer : aspects moléculaires, diagnostiques et thérapeutiques
18
Octobre 2009
Senile plaques
= insoluble substance (Aß) which settles slowly and gradually +++ in the grey matter of the
cerebral cortex
This substance seems to be neurotoxic in particular for neurones involved in the intellectual
functions (memory, reading, writing, language, visual recognition …)
Amyloid cascade hypothesis
Synthesis of Aß peptide
Mécanismes Moléculaires dans les Démences Neurodégénératives Inserm-UM2-EPHE U710
La maladie d’Alzheimer : aspects moléculaires, diagnostiques et thérapeutiques
Octobre 2009
19
Amyloid cascade hypothesis
Synthesis of Aß peptide
From APP to Beta Amyloid (Aβ)
neurons grow
1 ) Amyloid precursor protein (APP)
neurons survive
APP may help damaged neurons to repair themselves and may help parts of neurons to grow
after brain injury
APP sticks through the neuron's membrane
20
Alzheimer's disease by Frank Lee adapted from the National Institute on Aging (NIA)
Amyloid cascade hypothesis
Synthesis of Aß peptide
2 ) Aβ is generated from APP :
β-secretase cuts APP at an outside position of the cell
γ-secretase cuts APP at an inside position of the cell membrane
21
Alzheimer's disease by Frank Lee adapted from the National Institute on Aging (NIA)
Amyloid cascade hypothesis
Synthesis of Aß peptide
3 ) Fragments clump together and are mixed
with other molecules,neurons and
non-nerve cells
Senile plaques
22
Alzheimer's disease by Frank Lee adapted from the National Institute on Aging (NIA)
Amyloid cascade hypothesis
Non
amyloidogenic
way
Normal
brain
+++
AD brain
++
Amyloidogenic
Aβ
way
peptide
(AA)
-
40
42
Normal brain = Aβ40 production > Aβ42 production
However, the amyloid plaque in Alzheimer's disease = Aβ42
Aβ42 aggregation faster than Aβ40
Alzheimer's disease by Frank Lee adapted from the National Institute on Aging (NIA)
23
The amyloid cascade theory
Acknowledgments at the time of the deal
JOURNAL OF NEUROCHEMISTRY |
2009
|
110
|
1129–1134
Genes involved in AD
Chromosome
Gene
14
PS1
Comments
γ-secretase
1
PS2
21
APP
19
ApoE4
Aβ (trisomy 21
AD)
Major risk factor
Mécanismes Moléculaires dans les Démences Neurodégénératives Inserm-UM2-EPHE U710
La maladie d’Alzheimer : aspects moléculaires, diagnostiques et thérapeutiques
Octobre 2009
Can we unclutter plaques of
Alzheimer’s Disease?
26
III/ Active Immunisation
27
Generalities of immunotherapy
ACTIVE: Injection of an antigen
Production of antibodies
PASSIVE: injection of antibodies
directly
28
Source:http://www.gensuisse.ch/gentech/mediz04_f.html
Beginning of Aβ42 immunisation
Immunization with amyloid-β
attenuates Alzheimer disease-like
pathology in the PDAPP mouse
Dale Schenk, Robin Barbour, Whitney Dunn, Grace
Gordon,Henry Grajeda, Teresa Guido, Kang Hu,
Jiping Huang,Kelly Johnson-Wood, Karen Khan,
Dora Kholodenko,Mike Lee, Zhenmei Liao, Ivan
Lieberburg, Ruth Motter,Linda Mutter, Ferdie
Soriano, George Shopp, Nicki Vasquez,Christopher
Vandevert, Shannan Walker, Mark Wogulis,Ted
Yednock, Dora Games & Peter SeubertElan
Pharmaceuticals, 800 Gateway Boulevard, South
San Francisco,
Amyloid-b peptide (Ab) seems to have a central role
in theneuropathology of Alzheimer’s disease (AD).
Familial forms ofthe disease have been linked to
mutations in the amyloid precursorprotein (APP)
and the presenilin genes. Disease-linkedmutations
in these genes result inincreased production of
the42-amino-acid form of the peptide (Ab42), which
is the predominantform found in the amyloid
plaques of Alzheimer’sdisease. The PDAPP
transgenic mouse, which
Source:Nature 1999
overexpressesmutant human APP (in which the
amino acid at position 717 is phenylalanine
instead of the normal valine), progressively
develops many of the neuropathological hallmarks
of Alzheimer’s disease in an age- and brainregion-dependent manner. In the present study,
transgenic animals were immunized with Ab42,
either
before
the
onset
of
AD-type
neuropathologies (at 6 weeks of age) or at an
older age (11 months), when amyloid-b déposition
and several of the subsequent neuropathological
changes were well established. We report that
immunization of the Young animals essentially
prevented the development of b-amyloidplaque
formation, neuritic dystrophy and astrogliosis.
Treatment of the older animals also markedly
reduced the extent and progression of these ADlike neuropathologies. Our results raise the
possibility that immunization with amyloid-b may
be effective in preventing and treating
Alzheimer disease.
29
Beginning of Aβ42 immunisation
Principle
Human Mutation APP717
Source:http://www.gnis-pedagogie.org/pages/docbio/chap4/4.htm
Production of Beta amyloid plaques
30
Beginning of Aβ42 immunisation
Results:
Transgenic Mouse
with PBS
Mouse immunised
with Abeta 42
Human synthetic
31
First human trial: AN1792
Elan pharmaceutical was the first in Active Immunotherapy on
Alzheimer disease with AN1792
•PHASE I: 2000-2002
•80 patients: 64 treated+16 placebo
•4 groups: 4 differentes formulations
•AN1792 (50 or 225 µg) with QS-21 adjuvant (50 or 100 µg)
•Or QS-21 only (control) in a 4:1
•Results: - One meningoencephalitis
- Good immune response
Source:http://www.ncbi.nlm.nih.gov/pubmed/15883316?itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum&o
http://www.neurology.org/cgi/content/abstract/64/1/94
rdinalpos=1
32
First human trial: AN1792
AN1792:phase IIa
Principal
Randomized, multicenter, placebo controlled,
double-blind IM
Objectif
Evaluation of safety and tolerance
Patients
300 patients : 225μg of AN1792+ 50μg of
QS21
72 patients : NaCl
Structure of immunisation
Immunisation: 0, 1, 3, 6, 9 & 12 months
Eligibility of inclusion
Patients with Alzheimer Disease
MMSE 16 to 26
Age: 50 – 85 years
Duration
12 months rather than 15 as originally planned
33
Alzheimer’s tests on memory
Mini Mental State Examination
Referential test for inclusions
The lower the score, the more sever the disease
Only If people have equal access to treatment
Orientation to time
?
Naming
Registration
• 30 : normal subject
• 20-26 : mild AD
• 15-19 : moderate AD
Reading
34
Results of AN1792
IMMUNOGENIC
RESULTS
13/59 of responders
6% of meningoencephalitis
5/241 of low responders
-No significant differences were found between
antibody responder and placebo groups on battery of tests.
COGNITIVE
EVALUATION
OTHER EVALUATIONS
-Only NTB test which revealed differences favoring
antibody responders
-CSF tau was decreased in antibody responders
vs placebo subjects
Source:-www.ncbi.nlm.nih.gov:80/pmc/articles/PMC2615484
-Neurology.2005 May 10;64(9):1553-62.Clinical effects of Abeta immunization (AN1792) in patients with AD in an interrupted trial
35
Alzheimer’s tests on memory
Neuropsychological Test Battery
Long-term reminder memory test
Memory span test
Short-term & Long-term visual memory
Verbal fluency language test
Verbal learning test
40
’
Short-term & Long-term auditive memory
Acquisition test
36
Follow of AN1792
AN1792 stops in 2002, 1 year later, start « follow-up study » for 3 years.
-Aβ42 immune response
Obj: assess
-degree of plaque removal
-long-term clinical outcomes
80 subjects enrolled into
phase I study
Phase I study completed
44 patients dead or
refusing consent for
clinical follow-up
12 patients
treated
12 patients
with placebo
36 patients and/or
carers agree to clinical
follow-up and/or post
mortem
10 patients died
(10 treated)
26 patients alive
(20 treated and
6 placebo)
37
Follow of AN1792
Persistent elevated Antibody titers
No further cases of encephalitis
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
No correlation :
Between anti-Aβ antibody titres at long-term follow-up and rate of decline as measured
by at 6-year follow-up (ADAS-Cog;MMSE, or DAD)
38
39
Follow of AN1792
There is no significant amelioration of survival or evolution to severe dementia
between AN1792 and placebo groups.
However , the small numbers of participants enrolled in the initial study greatly
limit the power of this study and a larger trial might have shown some small
benefits that could not be detected with the cohort size examined here.
40
Conclusion for first immunotherapy tests
Although immunisation with Aβ42 resulted in clearance of amyloid
plaques in patients with Alzheimer’s disease, this clearance did
not prevent progressive neurodegeneration.
IMMUNOTHERAPY CAN BE ALWAYS A GOOD WAY FOR TREATMENT OF
ALZHEIMER DISEASE?
41
Story continues with ACC-001
Principle
Nature of Ag: injection 7 amino acid fragment Abeta N-terminal
Supply:CRM197 (nontoxic variant diphteria toxin)
Adjuvant:QS21 (to stimulate immune response)
42
Story continus with ACC-001
First results
In April 2008 the ACC 001 phase II study was suspended because one patient
developed a vascularitis resulting in skin lesions.
The cause is currently unknown
Actually, this study is currently recruiting participants.
43
Story continus with ACC-001
Scheme of phase II
Objectif
Evaluating Safety, Tolerability, and Immunogenicity of
ACC-001 in Subjects With Alzheimer's Disease
Criteria of inclusion
Age: 50 – 85 years
MMSE 16 to 26
Arm
Assigned Interventions
1: Active Comparator
arm 1: ACC-001 + QS-21
ACC-001 + QS21
QS-21 is fixed at 50 micrograms.
IM injection, dose 3-30micrograms,
frequency: Day 1, month 1, 3, 6, &12.
2: Active Comparator
arm 2: ACC-001
ACC-001
IM injection, dose 3-30micrograms
frequency: Day 1, month 1, 3, 6, &12.
3: Placebo Comparator
arm 3: QS-21
QS-21: IM injection 50μg
4: Placebo Comparator
arm 4: Phosphate Buffered Saline
Drug: Phosphate buffered saline
44
Limits of Active immunisation approach:
-The light immune response in older people
-Trigger of chronic immune reaction and neurotoxic by T cell in the brain
Also an other approach can be envisaged:
PASSIVE IMMUNISATION
45
IV/ Passive Immunisation
46
What is Bapineuzumab ?
1st humanized monoclonal candidate for AD
Humanized version of the 3D6 murine monoclonal antibody
Disulfide dimer between heavy and light chain of humanised mouse’s antibody
AAB 001 IV  phase III
AAB 001 SC  phase II
Monoclonal Antibody Ig G1
Passive immunotherapie approach
Target: the N-terminal 1-5 amino acids of Aβ peptides in amyloid plaques
Goal: to bind to Aβ in the brain and facilitate its removal, yielding beneficial clinical effects
http://www.alzforum.org/
47
Hypothesis on bapineuzumab’s activity
Three mechanisms postulated:
Dissolution
Direct effect of antibody on amyloid β
Neutralization of Aβ oligomers
Plaques with Fab domain
Amyloid β specific antibodies lead to
Phagocytosis
Microglial cells with Fc domain
The peripheral sink hypothesis : Administration of amyloid β specific antibodies
Efflux of Amyloid β from brain to blood
48
Neurology 73 15 december,2009
Development of Bapineuzumab
The phase 1 study
One single ascending dose placebo controlled double blind study
Primary outcome measures: safety-tolerability
Secondary outcome measure: to characterize the pharmacokinetic
Study’s design :
0,15 mg/kg or placebo
5,00 mg/kg or placebo
• 54 patients
• 50 to 85 years
• MMSE 14-26
• Diagnosis of AD
Results
Safety and Tolerance
1,5 mg/kg dose demonstrated a significant increase in MMSE score
The dose of 5,00 mg/kg was associated with MRI abnormalities in 3 out of 10 patients
49
http://www.clinicaltrials.gov
Development of Bapineuzumab
The phase 2 study
A randomized, multicenter, double blind, placebo-controlled study in patients
with mild to moderate AD
0,15 mg/kg of bapineuzumab or placebo once every 13 weeks
0,50 mg/kg of bapineuzumab or placebo once every 13 weeks
1,00 mg/kg of bapineuzumab or placebo once every 13 weeks
234 patients
6 infusions of 1H
Ratio 8B:7P
2,00 mg/kg of bapineuzumab or placebo once every 13 weeks
Primary objectives: Safety & Tolerance
Secondary objective: Efficacy
Serum
Measurement PK/PD of Bapineuzumab
Cerebral Spinal Fluid
Dosage of anti bapineuzumab antibodies
50
http://www.clinicaltrials.gov
Development of Bapineuzumab
Inclusion Criteria
• Diagnosis of probable AD
• Age from 50 to 85 years
• 16<MMSE<26
• Rosen Modified Hachinski Ischemic score < or = 4
• MRI scan consistent with the diagnosis of AD
• Fluency language
• Stable doses of medication
51
http://www.slideshare.net/finance12/wyeth-phase-2-clinical-trial-of-bapineuzumab-icad-july-2008
Alzheimer’s tests
Hachinski Ischemic score
Defines dementia nature
The lower the score, the degenerative dementia
Clinical criteria evaluated by doctor
Depression ?
Ischemia start
Degenerative dementia: 04
Ischemia evolution
Vascular dementia: ≥4
Nocturnal confusion ?
…
52
Development of Bapineuzumab
Objectives: linear decline and compared treatment differences within dose cohorts
Scr
J1
W
6
W
12
W
18
W
24
W
30
W
36
W
42
W
48
Adas
cog
X
X
X
X
X
X
X
X
X
DAD
X
X
X
X
X
X
X
X
NTB
X
X
X
X
X
X
X
Mms
e
X
X
X
X
X
X
X
CDR
sb
X
X
W
54
W
60
W
66
W
72
W
78
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
CSF
X
X
W
52
X
X
MRI
Safet
y
Vol.
X
X
X
X
X
X
X
X
53
Neurology 73 15 december,2009
Alzheimer’s tests on memory
Alzheimer’s Disease Assessment Scale-Cognitive subscale
Estimates severity and development of cognitive disorders
Referential scale in all countries
Unvarying method used at every visits
Memory :
11 advance sheets
Elocution :
Movements :
Scale fuller than MMSE
No differences between kind of memory
Bad evaluation of attention fonctions & executive fonctions
54
Alzheimer’s tests
Disability Assessment of Dementia
Estimates 5 entry level activities and 5 instrumental activities in daily life
Started action
For each activity
three answers
Planned action
Carried out action
The clothing ?
The lunches ?
Daily wash ?
55
Alzheimer’s tests
Disability Assessment of Dementia
Estimates 5 entry level activities and 5 instrumental activities in daily life
Started action
For each activity
three answers
Planned action
1
POINT
Carried out action
The higher the score
The lower evolution Alzheimer’s disease
56
Alzheimer’s tests on memory
Neuropsychological Test Battery
Long-term reminder memory test
Memory span test
Verbal fluency language test
Short-term & Long-term visual memory
40
’
Short-term & Long-term auditive memory
Verbal learning test
Acquisition test
Sensibility NTB > Sensibility ADAS- Cog for dimly affected
57
Alzheimer’s tests evaluating daily life
Clinical Dementia Rating –Sum of Boxes
A 5 points scale to characterize six domains
Affairs Home and Hobbies
Memory
Orientation
Cognitive and functional performance
• 0=Normal
• 0,5=Very Mild Dementia
?
• 1=Mild Dementia
Personal Care
• 2=Moderate Dementia
• 3=Severe Dementia
Community
Judgment and Problem Solving
58
Development of Bapineuzumab
59
http://www.slideshare.net/finance12/wyeth-phase-2-clinical-trial-of-bapineuzumab-icad-july-2008
Development of Bapineuzumab
• Subject disposition
Subjects
Bapineuzumab
group
Placebo group
mITT
35 %
29 %
Completer
65 %
71 %
• Efficacy Results
In the mITT population: Only trends on the ADAS –Cog
the NTB
In the Completer population: treatment differences were observed on the ADAS-Cog
the DAD
the NTB
& only a trend on the MMSE
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Neurology 73 15 december,2009
Development of Bapineuzumab
Pharmacokinetic Results
Maximum concentrations 1 hour after each infusion
Small volume of distribution = 49-80 ml/Kg
Slow clearance 0,07-0,09 mL/h/Kg
Long t ½ = 20-33 days
One infusion every 13 weeks
A dosage every 6 weeks
No anti-bapineuzumab antibodies
CSF Bapineuzumab
Bapineuzumab dosage
2 ‰ – 3 ‰ Bapineuzumab serum
brain
Bapineuzumab’s activity
blotter mecanism
Bioavailability = 100 %
61
Neurology 73 15 december,2009
Development of Bapineuzumab
•
Efficacy Results
ApoE4
Exploratory analyses suggest to split population between
Non ApoE4
Subjects
Bapineuzumab
group
Placebo group
mITT
• ApoE4
• Non ApoE4
35 %
42 %
23 %
29 %
Completer
• ApoE4
• Non ApoE4
65 %
58 %
77 %
71 %
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Neurology 73 15 december,2009
Why does ApoE4 gene influence study design?
• ApoE gene  apolipoprotein E
= component of VLDL lipoprotein responsible for removing excess cholesterol
from the blood to the liver for processing
Three alleles
ε3: 65%
ε2 :20%
ε4 :15% = risk factor for AD
Inherited from one parent: × 3 AD risk
two parents: × 10 AD risk
40 – 70 % patients with AD are ApoE4 carriers
Carrier ApoE 4 allele
AD
AD
Carrier ApoE 4
63
Why does ApoE4 gene influence study design?
64
Why does ApoE4 gene influence study design?
Deleterious action of ApoE4 in the brain
Fixation ApoE4 + specific receptor  link between receptor and APP  Phagocytosis
Proteases attack APP  agregation of fragments  cell death, memory loss and
neurological dysfunction = Alzheimer’s disease
65
Development of Bapineuzumab
• Efficacy Results
47 Bapineuzumab
For the 79 ApoE4 non carriers
32 Placebo
Treatment differences were observed on the ADAS-Cog
the NTB
the MMSE
the CDR-SB
72 Bapineuzumab
For the 146 ApoE4 carriers
74 Placebo
No treatment differences were observed on any endpoint including
the ADAS-Cog
the DAD
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Neurology 73 15 december,2009
The development of the Bapineuzumab
• Efficacy Results
ApoE 4 non carriers Mitt population
http://www.slideshare.net/finance12/wyeth-phase-2-clinical-trial-of-bapineuzumab-icad-july-2008
67
Development of Bapineuzumab
• Efficacy Results
The change in CSF biomarkers from baseline to Week 52
No differences in CSF Aβ or total τ
Phospho-τ levels trend lower in Bapineuzumab-treated patients
68
Development of Bapineuzumab
• Efficacy Results
The change in CSF biomarkers from baseline to Week 52
No differences in CSF Aβ or total τ
Phospho-τ levels trend lower in Bapineuzumab-treated
patients
69
http://www.slideshare.net/finance12/wyeth-phase-2-clinical-trial-of-bapineuzumab-icad-july-2008
Development of Bapineuzumab
• Efficacy Results
MRI volumetric analyses through Week 71 (Mitt)
In Total population no differences in brain volume & ventricular volume
In ApoE4 non carriers
• Significant less brain volume decline than placebo
In ApoE4 carriers
Bapineuzumab patients
• No significant change in brain volume
• Significant increase in ventricular volume
• Clinical relevance is unclear
70
Neurology 73 15 december,2009
The development of the Bapineuzumab
• Efficacy Results
MRI volumetric analyses through Week 71 (Mitt)
In Total population no differences in brain volume & ventricular volume
In ApoE4 carriers
• No significant change in brain volume
ApoE4 Non carriers
• Significant increase in ventricular volume compared with placebo
• Clinical relevance is unclear
In ApoE4 non carriers significant less brain volume decline than placebo
71
http://www.slideshare.net/finance12/wyeth-phase-2-clinical-trial-of-bapineuzumab-icad-july-2008
Development of Bapineuzumab
• Safety Results
94 % Bapineuzumab
90 % mild to
moderate in severity
Most patients reported Adverse Effects
90 % Placebo
AEs occuring >2 times as often as placebo rate and seen in >5% of bapineuzumab patients
Back pain
12,1% vs 5,5%
Weight loss
6,5% vs 1,8%
Anxiety
11,3% vs 3,6%
Paranoia
6,5% vs 0,9%
Skin laceration
5,6 % vs 2,7%
Vomiting
9,7% vs 3,6%
Vasogenic Edema 9,7% vs 0%
Gait disturbance 5,6% vs 1,8%
Hypertension
Muscle spasms 5,6 % vs 0,9%
8,1% vs 3,6%
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Neurology 73 15 december,2009
Development of Bapineuzumab
• Safety Results
Vasogenic Edema
VE appeares with high signal intensity in the white matter
12/124 in Bapineuzumab group
12 VE detected by MRI
0/110 in Placebo group
after the 1st or 2nd
infusion
6 VE reported no clinical symptoms
In symptomatic patients, the most common AEs reported were vomiting
gait disturbance
confusion
headache
One patient required dexamethasone treatment
All these symptoms generally resolved over several weeks after cessation of dosing
Neurology 73 15 december,2009
73
Development of Bapineuzumab
• Safety Results
VE increase with increase of bapineuzumab dose
Bapineuzumab dose
cohort
VE rate
0,15 mg/kg
3,2 %
0,50 mg/kg
0%
1,00 mg/kg
10,0 %
2,00 mg/kg
26,7 %
10 of 12 VE cases occured in ApoE4 carriers with a higher rate observed in ApoE4
ApoE status
VE rate
ApoE4 carriers
13,5 % (10/74)
Non ApoE4 carriers
4,3 % (2/47)
VE rate increases with ApoE4 gene dose : 4,3% with 0 copy  33,3 % with 2 copies
Neurology 73 15 december,2009
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ApoE 4 gene
Vasogenic Edema
Apolipoprotein E4 enhances brain inflammation:
• better activation for NF-κB
• enriched in NF-κB response elements
• microglial and NF-κB activation more pronounced
• brain inflammation in apoE4 related to disregulation
of NF-κB signaling pathway
Growth of cerebral vasogenic edema
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Development of Bapineuzumab
• Conlusion on Phase 2 study
Positive benchmarks
Safety
Negative Benchmarks
Efficacy not statistically demonstrated
No segmentation on ApoE4 status
Tolerability
Greater efficacy in completer subjects
(Non ApoE4)
More advanced Aβ pathology in ApoE4
carriers may have affected the clinical
response
Variable rate of decline in the treated &
placebo groups
Low-level statistical power for safety
Inclusion of patients ever too ill
Small dose cohorts
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Neurology 73 15 december,2009
Development of Bapineuzumab
The phase 3 study design:
Multiple dose, double-blind, placebo controlled, randomized, outpatient study
• Influenced by phase 2 results
ADAS-Cog
• Endpoints : Efficacy & Safety on
DAD
• Treatment period : 18 mois
Inclusion criteria
• Diagnosis of probable AD
• Age: 50  89 years
• 16 < MMSE score < 26
• MRI scan consistent with the diagnosis of AD
• Stable doses of medications (cholinesterase inhibitors and memantine allowed )
ApoE4 carrier
800
• 2 cohorts well identified
ApoE4 non carrier
1250
1 000 Avril 2009
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http://www.clinicaltrials.gov
The development of the Bapineuzumab
The phase 3 stugy design:
Multiple dose, double-blind, placebo controlled, randomized, outpatient study
0,5 mg/kg of Bapineuzumab
ApoE4
1,0 mg/kg of Bapineuzumab
Non
ApoE4
0,5 mg/kg of Bapineuzumab
One infusion every 13 weeks
A dosage every 6 weeks
1,0 mg/kg of Bapineuzumab
2,0 mg/kg of Bapineuzumab
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The development of the Bapineuzumab
The phase 3 stugy design:
Multiple dose, double-blind, placebo controlled, randomized, outpatient study
0,5 mg/kg of Bapineuzumab
ApoE4
1,0 mg/kg of Bapineuzumab
To
decrease
VE risk
0,5 mg/kg of Bapineuzumab
Non
ApoE4
1,0 mg/kg of Bapineuzumab
2,0 mg/kg of Bapineuzumab
To
decrease
VE risk
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What’s next for Bapineuzumab?
• Efficacy statistically showed in phase 3
Non
ApoE4
First-in-class
Marketing for Non ApoE4 carriers
diagnosis test
0,5 mg/kg
Non
ApoE4
1,0 mg/kg
Marketing for Non ApoE4 carriers
diagnosis test
80
What’s next for Bapineuzumab?
• Efficacy statistically showed in phase 3
First-in-class
Marketing for ApoE4 carriers
ApoE4
diagnosis test
0,5 mg/kg
ApoE4
Non
ApoE4
Marketing for overall population
0,5 mg/kg
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Critical reappraisal of amyloid hypothesis
Hypothesis
Status
Comments
Validated
By the cloning of PS I&II
Other causes of AD would
relate to Aβ production and
clearance:
PS I&II mutations
γ
secretase
Aβ 42
ApoE4
Aβ deposition
increased
Validated
Aβ shoul be toxic
+/- Validated
Aβ oligomers have a synaptic
effect but << massive cell loose
Aβ induces tangle disfunction
Validated
Link unknown
Reducing Aβ & plaques
would ameliorate AD
symptoms
Non validated
Not seen in clinical trials
JOURNAL OF NEUROCHEMISTRY |
2009
|
110
|
1129–1134
SWOT
Strengths
Weaknesses
Proof of concept for immunotherapy
Active immunotherapy: disappointing
results/meningoencephalitis
MAB most advanced
Disappointing clinicals results of phase II for
bapineuzumab
Buyback of AIP: several products and
experience
phase III of Bapineuzumab not much
conclusive currently
If Abeta theory fails not γ secretase inhibitor, or
products against Tau
Opportunities
Threats
Before buyback nothing in pipeline
Others companies on Alzheimer’s disease
immunotherapy and others targets
First in Alzheimer’s immunotherapy market
Solanezumab (Lilly) on phase III
Market of $ 6 billion
BSP:forbetaben (phase III)
Early diagnostic is a problem
Our opinion about this deal !!
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Thanks for your attention!
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Any questions?
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Special thanks
Dr Mackowiak Marie-Anne (department of neurology CHRU Lille
Mr Bertin Benjamin (laboratory of immunology)
Mr Carnoy Christophe (laboratory of immunology)
Mr Tartar André (organic laboratory chemistry)
Mrs Gras Hélène (laboratory of therapeutic chemistry)
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