ALZHEIMER IMMUNOTHERAPY

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.


Bapineuzumab

What’s the level risk for J&J ?

10


Bapineuzumab

Probability of success estimated

= 50 % < 80 %

Why ?

AN 1792 fail

Disappointing phase II results « first in class » in CNS therapeutic area


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


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

18


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


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


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



22

3 ) Fragments clump together and are mixed with other molecules,neurons and non-nerve cells

Senile plaques




23

Normal brain = Aβ40 production > Aβ42 production

However, the amyloid plaque in Alzheimer's disease = Aβ42

Aβ42 aggregation faster than Aβ40



24

The amyloid cascade theory

JOURNAL OF NEUROCHEMISTRY | 2009 | 110 | 1129–1134

Acknowledgments at the time of the deal

Genes involved in AD


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


31

Transgenic Mouse with PBS

Mouse immunised with Abeta 42

Human synthetic

Results:


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’


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




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



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


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


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’


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



• 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



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




Exploratory analyses suggest to split population between

ApoE4

Non ApoE4



• 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


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


66


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




ApoE 4 non carriers Mitt population

The development of the Bapineuzumab

68



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



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




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




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


72


• 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



• 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


• 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



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



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



The phase 3 stugy design:


ApoE4ApoE4

Non ApoE4

Non ApoE4

0,5 mg/kg of Bapineuzumab





One infusion every 13 weeksA dosage every 6 weeks One infusion every 13 weeksA dosage every 6 weeks


79

The phase 3 stugy design:


ApoE4ApoE4

Non ApoE4

Non ApoE4






To decrease VE risk

To decrease VE risk

To decrease VE risk

To decrease VE risk


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?

81

• 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

82

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 !!

85

Thanks for your attention!

86

Any questions?

87

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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ALZHEIMER IMMUNOTHERAPY