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ALZHEIMER IMMUNOTHERAPY
Debarge ValentinFontaine Quentin
Olivier Jérôme
$1,5 billion : a good investment?
02-2009
Summary
I/ The dealI/ The deal
II/ Mechanism of Alzheimer’s diseaseII/ Mechanism of Alzheimer’s disease
III/ Active immunisationIII/ Active immunisation
V/ Our opinionV/ Our opinion
IV/ Passive immunisationIV/ Passive immunisation
2
I/ The Deal
3
www.jnj.comJULY 2, 2009
I/ The Deal
4
• Alzheimer Immunotherapy Program (AIP) :
= Elan’s interest in a collaboration with Wyeth (now Pfizer) to research, develop and commercialize selective products for the treatment and/or prevention of neurodegenerative conditions, including Alzheimer’s disease
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
www.elan.com
NATURE BIOTECHNOLOGY VOLUME 27 NUMBER 8 AUGUST 2009
I/ The Deal
5
Summer 2008 : two more patients taking the multiple sclerosis drug Tysabri (natalizumab) had contracted a potentially fatal brain disease : progressive multifocal leukoencephalopathy
The J&J deal solves both problems
These events combined to drive down Elan’s stock from more than 23€ to less than 10€
http://fr.finance.yahoo.com/
I/ The Deal
6
« 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
* bapineuzumabBioCentury, the Berstein report on biobusiness July 6, 2009 Page A22 of 37
What did J&J want ?
7
BioCentury, the Berstein report on biobusiness July 6, 2009 Page A22 of 37
Transaction
I/ The Deal
$885 M
18,4% Elan's capital
IP Elan (AIP)Estimated at $500 M
$ 500 M
49,9% Janssen AI's capital
RoyaltiesUnder conditions
BioCentury, the Berstein report on biobusiness July 6, 2009 Page A22 of 37
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
The program will remain partnered with Wyeth, which was acquired by Pfizer Inc (01/2009, $68 billion)
I/ The Deal
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 %
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.
NATURE BIOTECHNOLOGY VOLUME 27 NUMBER 8 AUGUST 2009
Bapineuzumab
What’s the level risk for J&J ?
10
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
NATURE BIOTECHNOLOGY VOLUME 27 NUMBER 8 AUGUST 2009
Active immunotherapy
Fail of AN 1792
Only in phase 2 today
If immunotherapy fails …
Empty pipeline ! No γ-secretase inhibitorNo Abeta aggregation inhibitorTau protein way non explorated
What’s the level risk for J&J ?
12
Alzheimer's disease : background
Leerink Swann analysis. Extrapolated from UN census and prevalence data from 2008 US Alzheimer's facts and figures
13
$ 6.0 billion in 2008
$ 7.8 billion expected in 2011
NATURE MEDECINE VOLUME 12 NUMBER 7 JULY 2006
Alzheimer's disease drugs market
14
Alzheimer's disease costs
NATURE MEDECINE VOLUME 12 NUMBER 7 JULY 2006
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
15
Type of immunization Compagny Product Description Status
Active 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 Phase I
Passive Eli Lilly and Co 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
Vaccine against Aβ
Solanezumab (LY2062430)
Solanezumab is the main competitor of bapineuzumab
but the overall trial is anticipated to be completed in mid 2012
Are they alone on the target ?
16
II/ Mechanism of Alzheimer’s disease
17
La maladie d’Alzheimer : aspects moléculaires, diagnostiques et thérapeutiquesMécanismes Moléculaires dans les Démences Neurodégénératives Inserm-UM2-EPHE U710
Octobre 2009
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
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La maladie d’Alzheimer : aspects moléculaires, diagnostiques et thérapeutiquesMécanismes Moléculaires dans les Démences Neurodégénératives Inserm-UM2-EPHE U710
Octobre 2009
Histological signsWe 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)
19
La maladie d’Alzheimer : aspects moléculaires, diagnostiques et thérapeutiquesMécanismes Moléculaires dans les Démences Neurodégénératives Inserm-UM2-EPHE U710
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
20
Synthesis of Aß peptide
From APP to Beta Amyloid (Aβ)
1 ) Amyloid precursor protein (APP)
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
Alzheimer's disease by Frank Lee adapted from the National Institute on Aging (NIA)
Amyloid cascade hypothesis
neurons grow
neurons survive
21
Alzheimer's disease by Frank Lee adapted from the National Institute on Aging (NIA)
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
Synthesis of Aß peptide
Amyloid cascade hypothesis
22
3 ) Fragments clump together and are mixed with other molecules,neurons and non-nerve cells
Senile plaques
Alzheimer's disease by Frank Lee adapted from the National Institute on Aging (NIA)
Synthesis of Aß peptide
Amyloid cascade hypothesis
23
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)
Amyloid cascade hypothesis
24
The amyloid cascade theory
JOURNAL OF NEUROCHEMISTRY | 2009 | 110 | 1129–1134
Acknowledgments at the time of the deal
Genes involved in AD
La maladie d’Alzheimer : aspects moléculaires, diagnostiques et thérapeutiquesMécanismes Moléculaires dans les Démences Neurodégénératives Inserm-UM2-EPHE U710
Octobre 2009
Can we unclutter plaques of Alzheimer’s Disease?
27
III/ Active Immunisation
28
Source:http://www.gensuisse.ch/gentech/mediz04_f.html
ACTIVE: Injection of an antigen
Production of antibodies
PASSIVE: injection of antibodies directly
Generalities of immunotherapy
29
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
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 brain-region-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 AD-like neuropathologies. Our results raise the possibility that immunization with amyloid-b may be effective in preventing and treatingAlzheimer disease.
Immunization with amyloid-β attenuates Alzheimer disease-like pathology in the PDAPP mouse
Source:Nature 1999
Beginning of Aβ42 immunisation
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Human Mutation APP717
Source:http://www.gnis-pedagogie.org/pages/docbio/chap4/4.htm
Production of Beta amyloid plaques
Principle
Beginning of Aβ42 immunisation
31
Transgenic Mouse with PBS
Mouse immunised with Abeta 42
Human synthetic
Results:
Beginning of Aβ42 immunisation
32
•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
Source:http://www.ncbi.nlm.nih.gov/pubmed/15883316?itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum&ordinalpos=1
Elan pharmaceutical was the first in Active Immunotherapy on Alzheimer disease with AN1792
http://www.neurology.org/cgi/content/abstract/64/1/94
•Results: - One meningoencephalitis - Good immune response
First human trial: AN1792
33
Principal
Objectif
Patients
Structure of immunisation
Eligibility of inclusion
Duration
AN1792:phase IIa
Randomized, multicenter, placebo controlled, double-blind IM
Evaluation of safety and tolerance
300 patients : 225μg of AN1792+ 50μg of QS21
72 patients : NaCl
Immunisation: 0, 1, 3, 6, 9 & 12 months
Patients with Alzheimer DiseaseMMSE 16 to 26Age: 50 – 85 years
12 months rather than 15 as originally planned
First human trial: AN1792
34
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
Reading
• 30 : normal subject• 20-26 : mild AD• 15-19 : moderate AD
Alzheimer’s tests on memory
35
Results of AN1792
IMMUNOGENIC RESULTS
COGNITIVE EVALUATION
OTHER EVALUATIONS
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
6% of meningoencephalitis13/59 of responders
5/241 of low responders
-No significant differences were found between antibody responder and placebo groups on battery of tests.
-Only NTB test which revealed differences favoring antibody responders
-CSF tau was decreased in antibody responders vs placebo subjects
36
Neuropsychological Test Battery
Short-term & Long-term visual memory
Short-term & Long-term auditive memory
Verbal fluency language test
Verbal learning test
Long-term reminder memory test
Memory span test
Acquisition test
40’
Alzheimer’s tests on memory
37
80 subjects enrolled into phase I study
80 subjects enrolled into phase I study
Phase I study completedPhase I study completed
44 patients dead or refusing consent for
clinical follow-up
44 patients dead or refusing consent for
clinical follow-up
12 patients treated
12 patients treated
12 patients with placebo12 patients
with placebo
36 patients and/or carers agree to clinical follow-up and/or post
mortem
36 patients and/or carers agree to clinical follow-up and/or post
mortem
10 patients died
(10 treated)
10 patients died
(10 treated)
26 patients alive(20 treated and
6 placebo)
26 patients alive(20 treated and
6 placebo)
-Aβ42 immune response-degree of plaque removal-long-term clinical outcomes
Follow of AN1792AN1792 stops in 2002, 1 year later, start « follow-up study » for 3 years.
Obj: assess
38
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)
Follow of AN1792
39
40
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.
Follow of AN1792
41
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?
Conclusion for first immunotherapy tests
42
Principle
Nature of Ag: injection 7 amino acid fragment Abeta N-terminal
Supply:CRM197 (nontoxic variant diphteria toxin)
Adjuvant:QS21 (to stimulate immune response)
Story continues with ACC-001
43
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.
Story continus with ACC-001
44
Arm Assigned Interventions
1: Active Comparator arm 1: ACC-001 + QS-21
2: Active Comparatorarm 2: ACC-001
3: Placebo Comparatorarm 3: QS-21
4: Placebo Comparatorarm 4: Phosphate Buffered Saline
Objectif
Criteria of inclusion
Scheme of phase II
Evaluating Safety, Tolerability, and Immunogenicity of ACC-001 in Subjects With Alzheimer's Disease
Age: 50 – 85 yearsMMSE 16 to 26
ACC-001 + QS21
QS-21 is fixed at 50 micrograms.
IM injection, dose 3-30micrograms, frequency: Day 1, month 1, 3, 6, &12.
ACC-001IM injection, dose 3-30microgramsfrequency: Day 1, month 1, 3, 6, &12.
QS-21: IM injection 50μg
Drug: Phosphate buffered saline
Story continus with ACC-001
45
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
46
IV/ Passive Immunisation
47
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
What is Bapineuzumab ?
48http://www.alzforum.org/
Three mechanisms postulated:
Direct effect of antibody on amyloid β
Dissolution
Neutralization of Aβ oligomers
Microglial cells with Fc domain
Plaques with Fab domain
Phagocytosis
Hypothesis on bapineuzumab’s activity
49
Amyloid β specific antibodies lead to
Neurology 73 15 december,2009
• 54 patients • 50 to 85 years• MMSE 14-26• Diagnosis of AD
The phase 1 study
One single ascending dose placebo controlled double blind studyPrimary outcome measures: safety-tolerabilitySecondary outcome measure: to characterize the pharmacokinetic
Study’s design :
0,15 mg/kg or placebo
5,00 mg/kg or placebo
ResultsSafety 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
Development of Bapineuzumab
50
http://www.clinicaltrials.gov
The phase 2 studyA 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
2,00 mg/kg of bapineuzumab or placebo once every 13 weeks
234 patients6 infusions of 1HRatio 8B:7P
SerumSerum
Cerebral Spinal FluidCerebral Spinal Fluid
Primary objectives: Safety & ToleranceSecondary objective: Efficacy
Measurement PK/PD of Bapineuzumab
Dosage of anti bapineuzumab antibodies51
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
52
http://www.slideshare.net/finance12/wyeth-phase-2-clinical-trial-of-bapineuzumab-icad-july-2008
Development of Bapineuzumab
Hachinski Ischemic score
Defines dementia nature
The lower the score, the degenerative dementia
Clinical criteria evaluated by doctor
Depression ?
Ischemia start Ischemia evolution
Nocturnal confusion ? …
Degenerative dementia: 04
Vascular dementia: ≥4
Alzheimer’s tests
53
Objectives: linear decline and compared treatment differences within dose cohorts
54Neurology 73 15 december,2009
Development of Bapineuzumab
Alzheimer’s tests on memoryAlzheimer’s Disease Assessment Scale-Cognitive subscale
Estimates severity and development of cognitive disordersReferential scale in all countriesUnvarying method used at every visits
Bad evaluation of attention fonctions & executive fonctions
11 advance sheets
Scale fuller than MMSE
No differences between kind of memory
55
Alzheimer’s tests
Started action
Carried out action
Planned action
Disability Assessment of Dementia
Estimates 5 entry level activities and 5 instrumental activities in daily life
For each activity three answers
56
Started action
Carried out action
Planned action
Disability Assessment of Dementia
Estimates 5 entry level activities and 5 instrumental activities in daily life
For each activity three answers1
POINT1
POINT
Alzheimer’s tests
57
Neuropsychological Test Battery
Short-term & Long-term visual memory
Short-term & Long-term auditive memory
Verbal fluency language test
Verbal learning test
Long-term reminder memory test
Memory span test
Acquisition test
40’
Alzheimer’s tests on memory
Sensibility NTB > Sensibility ADAS- Cog for dimly affected
58
Clinical Dementia Rating –Sum of Boxes
A 5 points scale to characterize six domains
Cognitive and functional performance
• 0=Normal
• 0,5=Very Mild Dementia
• 1=Mild Dementia
• 2=Moderate Dementia
• 3=Severe Dementia
Memory
Orientation
Judgment and Problem Solving
Community
Affairs Home and Hobbies
Personal Care
Alzheimer’s tests evaluating daily life
59
60
http://www.slideshare.net/finance12/wyeth-phase-2-clinical-trial-of-bapineuzumab-icad-july-2008
Development of Bapineuzumab
• Subject disposition
• 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 61
Neurology 73 15 december,2009
Development of Bapineuzumab
One infusion every 13 weeksA dosage every 6 weeks One infusion every 13 weeksA dosage every 6 weeks
No anti-bapineuzumab antibodies
Bapineuzumab’s activity blotter mecanismBapineuzumab’s activity blotter mecanism
Bioavailability = 100 %
2 ‰ – 3 ‰ Bapineuzumab serum brain
Pharmacokinetic Results
Maximum concentrations 1 hour after each infusion
Bapineuzumab dosage
Small volume of distribution = 49-80 ml/KgSlow clearance 0,07-0,09 mL/h/KgLong t ½ = 20-33 days
CSF Bapineuzumab
62Neurology 73 15 december,2009
Development of Bapineuzumab
• Efficacy Results
Exploratory analyses suggest to split population between
ApoE4
Non ApoE4
63Neurology 73 15 december,2009
Development of Bapineuzumab
• 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
Carrier ApoE 4 allele AD
AD Carrier ApoE 4
Why does ApoE4 gene influence study design?
64
40 – 70 % patients with AD are ApoE4 carriers
Why does ApoE4 gene influence study design?
65
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
Why does ApoE4 gene influence study design?
66
• Efficacy Results
For the 79 ApoE4 non carriers
For the 146 ApoE4 carriers
No treatment differences were observed on any endpoint including the ADAS-Cog the DAD
47 Bapineuzumab
32 Placebo
Treatment differences were observed on the ADAS-Cog the NTB the MMSE the CDR-SB
72 Bapineuzumab
74 Placebo
67Neurology 73 15 december,2009
Development of Bapineuzumab
• Efficacy Results
ApoE 4 non carriers Mitt population
The development of the Bapineuzumab
68
http://www.slideshare.net/finance12/wyeth-phase-2-clinical-trial-of-bapineuzumab-icad-july-2008
• 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
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
70
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)
Bapineuzumab patients
In Total population no differences in brain volume & ventricular volume
In ApoE4 carriers • No significant change in brain volume• Significant increase in ventricular volume• Clinical relevance is unclear
In ApoE4 non carriers • Significant less brain volume decline than placebo
71Neurology 73 15 december,2009
Development of 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• Significant increase in ventricular volume compared with placebo• Clinical relevance is unclear
In ApoE4 non carriers significant less brain volume decline than placebo
ApoE4 Non carriersApoE4 Non carriers
The development of the Bapineuzumab
72
http://www.slideshare.net/finance12/wyeth-phase-2-clinical-trial-of-bapineuzumab-icad-july-2008
• Safety Results
Most patients reported Adverse Effects
94 % Bapineuzumab
90 % Placebo
90 % mild to moderate in severity
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%
Vomiting 9,7% vs 3,6%
Skin laceration 5,6 % vs 2,7%
Vasogenic Edema 9,7% vs 0% Gait disturbance 5,6% vs 1,8%
Hypertension 8,1% vs 3,6% Muscle spasms 5,6 % vs 0,9%
AEs occuring >2 times as often as placebo rate and seen in >5% of bapineuzumab patients
73Neurology 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
0/110 in Placebo groupafter the 1st or 2nd infusion12 VE detected by MRI
In symptomatic patients, the most common AEs reported were
6 VE reported no clinical symptoms
headacheconfusion
vomiting
gait disturbance
One patient required dexamethasone treatment
All these symptoms generally resolved over several weeks after cessation of dosing 74Neurology 73 15 december,2009
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 %
ApoE status VE rate
ApoE4 carriers 13,5 % (10/74)
Non ApoE4 carriers 4,3 % (2/47)
10 of 12 VE cases occured in ApoE4 carriers with a higher rate observed in ApoE4
VE rate increases with ApoE4 gene dose : 4,3% with 0 copy 33,3 % with 2 copies 75
Neurology 73 15 december,2009
Development of Bapineuzumab
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
ApoE 4 gene Vasogenic Edema
76
Positive benchmarks Negative Benchmarks
• Conlusion on Phase 2 study
Safety
Tolerability
Greater efficacy in completer subjects (Non ApoE4)
More advanced Aβ pathology in ApoE4 carriers may have affected the clinical
response
Efficacy not statistically demonstrated
No segmentation on ApoE4 status
Variable rate of decline in the treated & placebo groups
Low-level statistical power for safety
Inclusion of patients ever too ill
Small dose cohorts
77Neurology 73 15 december,2009
Development of Bapineuzumab
The phase 3 study design:
ApoE4 carrier
ApoE4 non carrier
800800
12501250
ADAS-CogADAS-Cog
DADDAD
1 000 Avril 2009
Multiple dose, double-blind, placebo controlled, randomized, outpatient study
• Influenced by phase 2 results
• Endpoints : Efficacy & Safety on
• 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 )
• 2 cohorts well identified
78
http://www.clinicaltrials.gov
Development of Bapineuzumab
The phase 3 stugy design:
Multiple dose, double-blind, placebo controlled, randomized, outpatient study
ApoE4ApoE4
Non ApoE4
Non ApoE4
0,5 mg/kg of Bapineuzumab
1,0 mg/kg of Bapineuzumab
0,5 mg/kg of Bapineuzumab
1,0 mg/kg of Bapineuzumab
2,0 mg/kg of Bapineuzumab
One infusion every 13 weeksA dosage every 6 weeks One infusion every 13 weeksA dosage every 6 weeks
The development of the Bapineuzumab
79
The phase 3 stugy design:
Multiple dose, double-blind, placebo controlled, randomized, outpatient study
ApoE4ApoE4
Non ApoE4
Non ApoE4
0,5 mg/kg of Bapineuzumab
1,0 mg/kg of Bapineuzumab
0,5 mg/kg of Bapineuzumab
1,0 mg/kg of Bapineuzumab
2,0 mg/kg of Bapineuzumab
To decrease VE risk
To decrease VE risk
To decrease VE risk
To decrease VE risk
The development of the Bapineuzumab
80
• Efficacy statistically showed in phase 3
Non ApoE4
Non ApoE4
0,5 mg/kg
1,0 mg/kg
Marketing for Non ApoE4 carriers
Non ApoE4
Non ApoE4
Marketing for Non ApoE4 carriers
First-in-class
diagnosis test
diagnosis test
What’s next for Bapineuzumab?
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• Efficacy statistically showed in phase 3
ApoE4ApoE4 Marketing for ApoE4 carriers
0,5 mg/kg
ApoE4ApoE4 Non ApoE4
Non ApoE4
0,5 mg/kg
Marketing for overall population
First-in-class
diagnosis test
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What’s next for Bapineuzumab?
Critical reappraisal of amyloid hypothesis
JOURNAL OF NEUROCHEMISTRY | 2009 | 110 | 1129–1134
Hypothesis Status Comments
Other causes of AD would relate to Aβ production and
clearance:
PS I&II mutations γ secretase Aβ 42
ApoE4 Aβ deposition increased
Validated
Validated
By the cloning of PS I&II
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
SWOTStrengths Weaknesses
Proof of concept for immunotherapyActive immunotherapy: disappointing
results/meningoencephalitis
MAB most advancedDisappointing 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 pipelineOthers companies on Alzheimer’s disease
immunotherapy and others targets
First in Alzheimer’s immunotherapy market Solanezumab (Lilly) on phase III
Market of $ 6 billion Early diagnostic is a problem
BSP:forbetaben (phase III)
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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