ALZHEIMER IMMUNOTHERAPY
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ALZHEIMER IMMUNOTHERAPY. $1,5 billion : a good investment?. Debarge Valentin Fontaine Quentin Olivier Jérôme. 02-2009. Summary. I/ The deal. II/ Mechanism of Alzheimer’s disease. III/ Active immunisation. IV/ Passive immunisation. V/ Our opinion. I/ The Deal. I/ The Deal.

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Alzheimer immunotherapy

ALZHEIMER IMMUNOTHERAPY

$1,5 billion : a good investment?

Debarge Valentin

Fontaine Quentin

Olivier Jérôme

02-2009


Summary

Summary

I/ The deal

II/ Mechanism of Alzheimer’s disease

III/ Active immunisation

IV/ Passive immunisation

V/ Our opinion


I the deal

I/ The Deal


Alzheimer immunotherapy

I/ The Deal

JULY 2, 2009

www.jnj.com


Alzheimer immunotherapy

I/ The Deal

  • 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

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 BIOTECHNOLOGYVOLUME 27NUMBER 8AUGUST 2009


Alzheimer immunotherapy

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/


Alzheimer immunotherapy

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 Page A22 of 37


Alzheimer immunotherapy

I/ The Deal

Transaction

$885 M

18,4% Elan's capital

$ 500 M

IP Elan (AIP)

Estimated at $500 M

49,9% Janssen AI's capital

Royalties

Under conditions

BioCentury, the Berstein report on biobusiness July 6, 2009 Page A22 of 37


Alzheimer immunotherapy

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

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


Alzheimer immunotherapy

What’s the level risk for J&J ?

Bapineuzumab

IanSanderson, analyst at Cowen, New York, gives bapineuzumab a 50% likelihood of reaching the market, based on clinician surveys conducted by the investment bank.

NATURE BIOTECHNOLOGYVOLUME 27NUMBER 8AUGUST 2009


Alzheimer immunotherapy

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


Alzheimer immunotherapy

What’s the level risk for J&J ?

Active immunotherapy

Fail of AN 1792

Only in phase 2 today

If immunotherapy fails …

No γ-secretase inhibitor

No Abeta aggregation inhibitor

Tau protein way non explorated

Empty pipeline !

NATURE BIOTECHNOLOGYVOLUME 27NUMBER 8AUGUST 2009


Alzheimer immunotherapy

Alzheimer's disease : background

Leerink Swann analysis. Extrapolated from UN census and prevalence data from 2008 US Alzheimer's facts and figures


Alzheimer immunotherapy

Alzheimer's disease drugs market

  • $ 6.0 billion in 2008

  • $ 7.8 billion expected in 2011

NATURE MEDECINE VOLUME 12NUMBER 7JULY 2006


Alzheimer immunotherapy

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

NATURE MEDECINE VOLUME 12NUMBER 7JULY 2006


Alzheimer immunotherapy

Are they alone on the target ?

Solanezumab is the main competitor of bapineuzumab

but the overall trial is anticipated to be completed in mid 2012


Alzheimer immunotherapy

II/ Mechanism of Alzheimer’s disease


Alzheimer immunotherapy

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

Octobre 2009


Alzheimer immunotherapy

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

Octobre 2009


Alzheimer immunotherapy

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


Alzheimer immunotherapy

Amyloid cascade hypothesis

Synthesis of Aß peptide

From APP to Beta Amyloid (Aβ)

neurons grow

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

neurons survive

Alzheimer's disease by Frank Lee adapted from the National Institute on Aging (NIA)


Alzheimer immunotherapy

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

Alzheimer's disease by Frank Lee adapted from the National Institute on Aging (NIA)


Alzheimer immunotherapy

Amyloid cascade hypothesis

Synthesis of Aß peptide

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)


Alzheimer immunotherapy

Amyloid cascade hypothesis

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)


Alzheimer immunotherapy

The amyloid cascade theory

Acknowledgments at the time of the deal

JOURNAL OF NEUROCHEMISTRY|2009|110|1129–1134


Alzheimer immunotherapy

Genes involved in AD

Mécanismes Moléculaires dans les Démences Neurodégénératives Inserm-UM2-EPHE U710

La maladie d’Alzheimer : aspects moléculaires, diagnostiques et thérapeutiques

Octobre 2009


Alzheimer immunotherapy

Can we unclutter plaques of Alzheimer’s Disease?


Iii active immunisation

III/ Active Immunisation


Alzheimer immunotherapy

Generalities of immunotherapy

ACTIVE: Injection of an antigen

Production of antibodies

PASSIVE: injection of antibodies directly

Source:http://www.gensuisse.ch/gentech/mediz04_f.html


Alzheimer immunotherapy

  • 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

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 treating

Alzheimer disease.

Source:Nature 1999


Alzheimer immunotherapy

  • Beginning of Aβ42 immunisation

Principle

Human Mutation APP717

Production of Beta amyloid plaques

Source:http://www.gnis-pedagogie.org/pages/docbio/chap4/4.htm


Alzheimer immunotherapy

  • Beginning of Aβ42 immunisation

Results:

Mouse immunised with Abeta 42

Human synthetic

Transgenic Mouse with PBS


Alzheimer immunotherapy

  • 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 225µg) with QS-21 adjuvant (50 or 100 µg)

      • Or QS-21only (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&ordinalpos=1

http://www.neurology.org/cgi/content/abstract/64/1/94


Alzheimer immunotherapy

  • First human trial: AN1792

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 Disease

MMSE 16 to 26

Age: 50 – 85 years

12 months rather than 15 as originally planned


Alzheimer s tests on memory

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

?

  • 30 : normal subject

  • 20-26 : mild AD

  • 15-19 : moderate AD

Registration

Reading

Where are we ?

Whatis the date today?


Results of an1792

Results of AN1792

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.

-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


Alzheimer s tests on memory1

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

40’

Short-term & Long-term auditive memory

Verbal learning test

Acquisition test


Alzheimer immunotherapy

Follow of AN1792

AN1792 stops in 2002, 1 year later, start « follow-up study » for 3 years.

-Aβ42 immune response

-degree of plaque removal

-long-term clinical outcomes

Obj: assess

80 subjects enrolled into phase I study

Phase I study completed

44 patients dead or refusing consent for clinical follow-up

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)

12 patients

treated

12 patients with placebo


Alzheimer immunotherapy

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 theAβ load andinthe 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)


Alzheimer immunotherapy

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.


Alzheimer immunotherapy

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?


Alzheimer immunotherapy

  • 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)


First results

  • 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.


Alzheimer immunotherapy

  • Story continus with ACC-001

Scheme of phase II

Evaluating Safety, Tolerability, and Immunogenicity of ACC-001 in Subjects With Alzheimer's Disease

Age: 50 – 85 years

MMSE 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-001

IM injection, dose 3-30micrograms

frequency: Day 1, month 1, 3, 6, &12.

QS-21: IM injection 50μg

Drug: Phosphate buffered saline


Alzheimer immunotherapy

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


Alzheimer immunotherapy

IV/ Passive Immunisation


Alzheimer immunotherapy

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/


Alzheimer immunotherapy

Hypothesis on bapineuzumab’s activity

Three mechanisms postulated:

Direct effect of antibody on amyloid β

Dissolution

Neutralization of Aβ oligomers

Amyloid β specific antibodies lead to

Plaques with Fab domain

Phagocytosis

Microglial cells with Fc domain

  • The peripheralsinkhypothesis : Administration of amyloidβspecificantibodies

  • Efflux of Amyloidβfrombrain to blood

Neurology 73 15 december,2009


Alzheimer immunotherapy

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

http://www.clinicaltrials.gov


Alzheimer immunotherapy

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

234 patients

6 infusions of 1H

Ratio 8B:7P

1,00 mg/kg of bapineuzumab or placebo once every 13 weeks

2,00 mg/kg of bapineuzumab or placebo once every 13 weeks

Primary objectives:Safety & Tolerance

Secondary objective:Efficacy

Measurement PK/PD of Bapineuzumab

Dosage of anti bapineuzumab antibodies

Serum

Cerebral Spinal Fluid

http://www.clinicaltrials.gov


Alzheimer immunotherapy

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

http://www.slideshare.net/finance12/wyeth-phase-2-clinical-trial-of-bapineuzumab-icad-july-2008


Alzheimer s tests

Alzheimer’s tests

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: 04

Vascular dementia: ≥4


Alzheimer immunotherapy

Development of Bapineuzumab

Objectives: linear decline and compared treatment differences within dose cohorts

Neurology 73 15 december,2009


Alzheimer s tests on memory2

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 : Can you copy out thispicture?

11 advance sheets

Elocution : Can youread us thiswordlist?

Movements : Can yousend a letter?

Scale fuller than MMSE

No differences between kind of memory

Bad evaluation of attention fonctions & executive fonctions


Alzheimer s tests1

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 ?


Alzheimer s tests2

Alzheimer’s tests

Disability Assessment of Dementia

Estimates 5 entry level activities and 5 instrumental activities in daily life

For each activity three answers

Started action

Planned action

1 POINT

Carried out action

The higher the score

The lowerevolutionAlzheimer’sdisease


Alzheimer s tests on memory3

Alzheimer’s tests on memory

Neuropsychological Test Battery

Long-term reminder memory test

Memory span test

Short-term & Long-term visual memory

40’

Verbal fluency language test

Short-term & Long-term auditive memory

Verbal learning test

Acquisition test

Sensibility NTB > Sensibility ADAS- Cog for dimly affected


Alzheimer immunotherapy

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

  • Cognitive and functional performance

  • 0=Normal

  • 0,5=Very Mild Dementia

  • 1=Mild Dementia

  • 2=Moderate Dementia

  • 3=Severe Dementia

Orientation

?

Personal Care

Community

Judgment and Problem Solving


Alzheimer immunotherapy

Development of Bapineuzumab

http://www.slideshare.net/finance12/wyeth-phase-2-clinical-trial-of-bapineuzumab-icad-july-2008


Alzheimer immunotherapy

Development of Bapineuzumab

  • Subject disposition

  • Efficacy Results

In the mITT population: Onlytrends 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

Neurology 73 15 december,2009


Alzheimer immunotherapy

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

Bapineuzumab dosage

CSF Bapineuzumab

2 ‰ – 3 ‰ Bapineuzumab serum

brain

Bapineuzumab’s activity

blotter mecanism

Bioavailability = 100 %

Neurology 73 15 december,2009


Alzheimer immunotherapy

Development of Bapineuzumab

  • Efficacy Results

  • Exploratory analyses suggest to split population between

ApoE4

Non ApoE4

Neurology 73 15 december,2009


Alzheimer immunotherapy

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


Alzheimer immunotherapy

Why does ApoE4 gene influence study design?


Alzheimer immunotherapy

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


Alzheimer immunotherapy

Development of Bapineuzumab

  • Efficacy Results

  • For the 79 ApoE4 non carriers

  • For the 146 ApoE4 carriers

47 Bapineuzumab

32 Placebo

Treatment differences were observed on the ADAS-Cog

the NTB

the MMSE

the CDR-SB

72 Bapineuzumab

74 Placebo

No treatment differences were observed on any endpoint including

the ADAS-Cog

the DAD

Neurology 73 15 december,2009


Alzheimer immunotherapy

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


Alzheimer immunotherapy

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


Alzheimer immunotherapy

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

http://www.slideshare.net/finance12/wyeth-phase-2-clinical-trial-of-bapineuzumab-icad-july-2008


Alzheimer immunotherapy

Development of Bapineuzumab

  • Efficacy Results

  • MRI volumetric analyses through Week 71 (Mitt)

In Total populationno differences in brain volume & ventricular volume

  • In ApoE4 non carriers

  • Significant less brain volume decline than placebo

  • In ApoE4 carriers

  • No significant change in brain volume

  • Significant increase in ventricular volume

  • Clinical relevance is unclear

Bapineuzumab patients

Neurology 73 15 december,2009


Alzheimer immunotherapy

The development of the Bapineuzumab

  • Efficacy Results

  • MRI volumetric analyses through Week 71 (Mitt)

  • In Total populationno 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 carriers

http://www.slideshare.net/finance12/wyeth-phase-2-clinical-trial-of-bapineuzumab-icad-july-2008


Alzheimer immunotherapy

Development of Bapineuzumab

  • Safety Results

  • Most patients reported Adverse Effects

94 % Bapineuzumab

90 % mild to moderate in severity

90 % Placebo

AEs occuring >2 times as often as placebo rate and seen in >5% of bapineuzumab patients

Neurology 73 15 december,2009


Alzheimer immunotherapy

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

after the 1st or 2nd infusion

0/110 in Placebo group

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


Alzheimer immunotherapy

Development of Bapineuzumab

  • Safety Results

  • VE increase with increase of bapineuzumab dose

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

Neurology 73 15 december,2009


Apoe 4 gene vasogenic edema

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


Alzheimer immunotherapy

Development of Bapineuzumab

  • Conlusion on Phase 2 study

Safety

Efficacy not statistically demonstrated

No segmentation on ApoE4 status

Tolerability

Greater efficacy in completer subjects (Non ApoE4)

Variable rate of decline in the treated & placebo groups

More advanced Aβ pathology in ApoE4 carriers may have affected the clinical response

Low-level statistical power for safety

Inclusion of patients ever too ill

Small dose cohorts

Neurology 73 15 december,2009


Alzheimer immunotherapy

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

  • Treatment period : 18 mois

DAD

  • 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 )

800

ApoE4 carrier

  • 2 cohorts well identified

1250

1 000 Avril 2009

ApoE4 non carrier

http://www.clinicaltrials.gov


Alzheimer immunotherapy

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

One infusion every 13 weeks

A dosage every 6 weeks

0,5 mg/kg of Bapineuzumab

Non ApoE4

1,0 mg/kg of Bapineuzumab

2,0 mg/kg of Bapineuzumab


Alzheimer immunotherapy

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

To decrease VE risk

1,0 mg/kg of Bapineuzumab

0,5 mg/kg of Bapineuzumab

Non ApoE4

1,0 mg/kg of Bapineuzumab

To decrease VE risk

2,0 mg/kg of Bapineuzumab


Alzheimer immunotherapy

What’s next for Bapineuzumab?

First-in-class

  • Efficacy statistically showed in phase 3

Marketing for Non ApoE4 carriers

Non ApoE4

diagnosis test

0,5 mg/kg

Marketing for Non ApoE4 carriers

Non ApoE4

diagnosis test

1,0 mg/kg


Alzheimer immunotherapy

What’s next for Bapineuzumab?

First-in-class

  • Efficacy statistically showed in phase 3

Marketing for ApoE4 carriers

ApoE4

diagnosis test

0,5 mg/kg

ApoE4

Non ApoE4

Marketing for overall population

0,5 mg/kg


Alzheimer immunotherapy

Critical reappraisal of amyloid hypothesis

JOURNAL OF NEUROCHEMISTRY|2009|110|1129–1134


Alzheimer immunotherapy

SWOT


Alzheimer immunotherapy

Our opinion about this deal !!


Alzheimer immunotherapy

Thanks for your attention!


Alzheimer immunotherapy

Any questions?


Special thanks

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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