Summary I/ The deal II/ Mechanism of Alzheimer’s disease

ALZHEIMER IMMUNOTHERAPY $1,5 billion : a good investment?
22/01/10 ALZHEIMER IMMUNOTHERAPY Lancer une intro: maladie peut toucher tout le monde On a beaucoup parlé de l’immuothérapie Est ce que un vaccin ctre la maladie d’alzheimer a 1,5 milliards de $ vaut le cout $1,5 billion : a good investment? 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

I/ The Deal

I/ The Deal Rachat programme JULY 2, 2009

NATURE BIOTECHNOLOGY VOLUME 27 NUMBER 8 AUGUST 2009
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  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 AUGUST 2009

The J&J deal solves both problems
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€ humanized mAb against integrin alpha(4) The J&J deal solves both problems

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, Page A22 of 37

I/ The Deal $885 M 18,4% Elan's capital 49,9% Janssen AI's capital
22/01/10 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, Page A22 of 37 7

Janssen AI: all annual in-market sales
22/01/10 I/ The Deal Transaction J&J purchased 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, Page A22 of 37 8

What’s the level risk for J&J ? Bapineuzumab 1 ère chose à dire:dire que le Bapineuzumab appartient à la classe des biologicals.Classe dont la chance d’être sur le marché est plus importante que les petites molécules. 2 ème chose:50 % plus pour des petites molécules 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

What’s the level risk for J&J ?
22/01/10 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 1 ère chose à dire:dire que le Bapineuzumab appartient à la classe des biologicals.Classe dont la chance d’être sur le marché est plus importante que les petites molécules. 2 ème chose:50 % plus pour des petites molécules 10

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 Risque important mais qui dit risque dit bénéfice important si ca fonctionne. NATURE BIOTECHNOLOGY VOLUME 27 NUMBER 8 AUGUST 2009

Alzheimer's disease : background
Avant cette diapo ok il y a un risque mais le marché est attirant 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

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 12 NUMBER 7 JULY 2006

Are they alone on the target ?
On est pas tout seul sur l’immunothérapie alzheimer.Parler des différents boites qui sont dessus mais pas parler des mécanismes. Solanezumab is the main competitor of bapineuzumab but the overall trial is anticipated to be completed in mid 2012

II/ Mechanism of Alzheimer’s disease

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

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

Synthesis of Aß peptide
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

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)

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 Précu=APP Faire diapo bonus sur possible cible thérapeutique des gamma secrétases AT= APP->maturation proteolytique->selon clivage on aura Abeta de 40 ou 42 AA. Alzheimer's disease by Frank Lee adapted from the National Institute on Aging (NIA)

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)

Amyloid cascade hypothesis
Non amyloidogenic way Amyloidogenic way Aβ peptide (AA) Normal brain +++ - 40 AD brain ++ 42 Normal brain = Aβ40 production > Aβ42 production However, the amyloid plaque in Alzheimer's disease = Aβ42 Aβ42 aggregation faster than Aβ40 Mais taux faible quand même de Aβ 40 Alzheimer's disease by Frank Lee adapted from the National Institute on Aging (NIA)

The amyloid cascade theory
22/01/10 The amyloid cascade theory Acknowledgments at the time of the deal Les personnes qui ont une trisomie 21 évoluent vers alzheimer car le gene codant le peptide Abeta 42 est sur le chromosome 21. JOURNAL OF NEUROCHEMISTRY | 2009 | 110 | 1129–1134 24

Genes involved in AD Chromosome Gene Comments 14 1 PS1 PS2 γ-secretase
22/01/10 Genes involved in AD Chromosome Gene Comments 14 1 PS1 PS2 γ-secretase 21 APP Aβ (trisomy AD) 19 ApoE4 Major risk factor bonus Mécanismes Moléculaires dans les Démences Neurodégénératives Inserm-UM2-EPHE U710 La maladie d’Alzheimer : aspects moléculaires, diagnostiques et thérapeutiques Octobre 2009 25

Can we unclutter plaques of Alzheimer’s Disease?

III/ Active Immunisation
Avant peut on agir sur la maladie d’alzheimer en nettoyant les plaques via la vaccination

Generalities of immunotherapy
ACTIVE: Injection of an antigen Production of antibodies L’immunisation active consiste en l’injection d’un antigene chez la personne activation par les cellules dendritiques des lymphocytes b production d’anticorps par la personne. L’immunisation passive consiste en l’injection directement des anticorps dirigé vers l’antigene voulu à la personne.les anticorps sont préparés chez la souris. Active immunizationMain article: Active immunityActive immunization entails the introduction of a foreign molecule into the body, which causes the body itself to generate immunity against the target. This immunity comes from the T cells and the B cells with their antibodies.Active immunization can occur naturally when a person comes in contact with, for example, a microbe. If the person has not yet come into contact with the microbe and has no pre-made antibodies for defense (like in passive immunization), the person becomes immunized. The immune system will eventually create antibodies and other defenses against the microbe. The next time, the immune response against this microbe can be very efficient; this is the case in many of the childhood infections that a person only contracts once, but then is immune.Artificial active immunization is where the microbe, or parts of it, are injected into the person before they are able to take it in naturally. If whole microbes are used, they are pre-treated, Attenuated vaccine. Depending on the type of disease, this technique also works with dead microbes, parts of the microbe, or treated toxins from the microbe.[edit ]Passive immunizationMain article: Passive immunityPassive immunization is where pre-synthesized elements of the immune system are transferred to a person so that the body does not need to produce these elements itself. Currently, antibodies can be used for passive immunization. This method of immunization begins to work very quickly, but it is short lasting, because the antibodies are naturally broken down, and if there are no B cells to produce more antibodies, they will disappear.Passive immunization occurs physiologically, when antibodies are transferred from mother to fetus during pregnancy, to protect the fetus before, as well as shortly after birth.Artificial passive immunization is normally administered by injection and is used if there has been a recent outbreak of a particular disease or as an emergency treatment for toxicity (for example, for tetanus). The antibodies can be produced in animals ("serum therapy") although there is a high chance of anaphylactic shock because of immunity against animal serum itself. Thus, humanized antibodies produced in vitro by cell culture are used instead if available. PASSIVE: injection of antibodies directly Source:

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. En 1999 le magasine Nature s’embale en publiant la possibilité de guérison de la maladie d’alzheimer chez des souris transgenique possedant un gene permettant de produire des peptide beta amyloide humain cependant meme si ce model est tout a fait exact il est un peu biaisé car le complement de ces souris n’est pas activé ce qui en fait model bcp moins comparable a l’homme. . Source:Nature 1999

Principle Human Mutation APP717 Production of Beta amyloid plaques En 1999 Schenk and al of elan pharmaceutical suggere que l’immunisation contre le peptide Abeta pourrait etre utilisé comme thérapeutique potentiel pour MA.Dans les etudes de Schenk montre que des souris PDAPP peuvent etre immunisées avec un peptide Abeta 42 avec un adjuvant pour des ages ou des depots amyloid sont présents.les souris ont été immunisées mensuellement et le taux de peptide amyloide a diminué. Fabrication de souris transgéniques qui font alzheimer car sinon absence de modèle Source:

Results: Mouse immunised with Abeta 42 Human synthetic Transgenic Mouse with PBS Sur la gauche on a des souris qui ont été traités par du PBS(Le tampon phosphate salin (souvent abrégé « PBS », venant de l'anglais phosphate buffered saline) est une solution tampon) chez ces souris les plaques se developpent de facon assez importante. Sur la droite on a injecté aux souris le peptide beta amyloid (42 acide amines) et l’on voit un net nettoyage des plaques amyloides. Des études par la suite ont montrées que les souris immunisées avaient un temps pour le test du labyrinthe diminués.Il en a donc été deduit que la vaccination améliorée l’apprentissage et la mémoire des souris.(cependant peut on vraiment affirmer qu’il y a une amélioration des capacités cognitives?et ces évolutions si il y a sont elles tranposable à l’homme?) En effet, cette experience est la preuve que l’immunisation est une voie thérapeutique interessante pour le traitement ou l’attenuation de la maladie d’alzheimer chez la souris mais ne prouve pas son efficacité chez l’homme

First human trial: AN1792 Elan pharmaceutical was the first in Active Immunotherapy on Alzheimer disease with AN1792 PHASE I: 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 -Explication diapo Phase1: 1 meningo encephalite en post mortem 5 morts pendant l’etude mais non relié a l’effet du traitement 64 recoivent le traitement 16 le placebo. 4 groupes:an1792 (50 ou 225 ug)+qs21 (50ou 100 ug) et par la suite 4 inj avec des doses croissantes de polysorbate 80 Bonne reponse immune avec 23,4% des patients traités avec un taux d’ac interessant >= 1:1,000 et ca augmenté jusque 58,8% lors de la modification de formulation. Résultat: test DAD (Disability Assessment for Dementia) montre un declin moins rapide pour les personnes traitées que les controles. effet clinique leger demontré par ce test. Methods: Twenty patients were enrolled into each of four dose groups and randomly assigned to receive IM AN1792 (50 or 225 µg) with QS-21 adjuvant (50 or 100 µg) or QS-21 only (control) in a 4:1 active:control ratio on day 0 and at weeks 4, 12, and 24. Patients could receive up to four additional injections of a polysorbate 80 modified formulation at weeks 36, 48, 60, and 72. Safety, tolerability, immunogenicity, and exploratory evidence of efficacy were evaluated. Results: Treatment-related adverse events were reported in 19 (23.8%) patients, but no relationship was observed between AN1792 dose and incidence. One patient developed meningoencephalitis that was diagnosed after death (not directly related to study treatment) and 219 days after discontinuing from the study. Five deaths occurred during the study follow-up, but none was considered to be directly related to study treatment. During the period of the first four injections, 23.4% of AN1792-treated patients had a positive anti-AN1792 antibody titer (an anti-AN1792 antibody titer of 1:1,000). This increased to 58.8% after additional injections with the modified formulation. Disability Assessment for Dementia scores showed less decline among active compared with control patients at week 84 (p = 0.002). No treatment differences were observed in three other efficacy measures.Conclusions: AN QS-21 elicited a positive antibody response to Aß42 in more than half of this elderly study population. Results: - One meningoencephalitis - Good immune response Source:

First human trial: AN1792 AN1792:phase IIa
Principal Objectif Patients Structure of immunisation Eligibility of inclusion Duration Randomized, multicenter, placebo controlled, double-blind IM Evaluation of safety and tolerance 300 patients : 225μg of AN μg of QS21 72 patients : NaCl Immunisation: 0, 1, 3, 6, 9 & 12 months -phase2a: criteres d’inclusion:personne entre 50 et 85 ans avec un mini mentale state examination entre 16 et 26 Injection plannifiées par mois:1er 3ième 6ième 9ième et 12ième Immunisation fut stopée:1 inj pr 2 patients; 2 inj pr 274 patients et 3 inj pr 24 patients Le double aveugle fut gardé pendant 12 mois et il n’y a pas de difference significative entre AN1792 / placebo. 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
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 People must know reading, writting (ethnic or cultural background) Not deafness or blindness MMSE Limite de sélectionner des patients dans les phases légères de la maladie Reading Where are we ? What is the date today?

Results of AN1792 13/59 of responders 6% of meningoencephalitis
IMMUNOGENIC RESULTS COGNITIVE EVALUATION OTHER EVALUATIONS 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 On a arrêté l’essai après avoir eu 18 personnes qui presentaient des meningoencephalites(13 personnes chez les repondeurs et 5 personnes chez les personnes qui avaient bcp moins bien répondus.On a arrrêté plus ot cependant on a mesuré tout de meme les effets au niveau cérébral et on a constaté qu’il n’y avait pas de difference significative entre les personnes qui avaient été traités et celle sous placebo parmi une batterie de test psychologique (seul le test NTF revele une difference favorable pour les personnes qui ont eu une reponse convenable) -CSF tau was decreased in antibody responders vs placebo subjects Source:- -Neurology.2005 May 10;64(9): Clinical effects of Abeta immunization (AN1792) in patients with AD in an interrupted trial

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 9 kinds of tests evaluatin L'empan mnésique désigne le nombre d'éléments (en général des chiffres) que l'on peut restituer immédiatement après les avoir entendus. Une expérience classique consiste à lire une liste de chiffres, à une vitesse donnée (par exemple un par seconde) puis à demander au sujet de les restituer dans l'ordre. Quand la liste contient moins de 5 éléments, le rappel ne pose normalement pas de problème. Au-dessus de 7 éléments il devient beaucoup plus difficile. Sensibilité supérieur a l’adas cog surtout chez patients faiblement atteint Mais échelle récente pas encore encré comme examen de référence mais en devenir Réf:maladie d’alzheimer et déclin cognitif Vol 13 Aout 2008 p 336 à 340 Acquisition test

Follow of AN1792 Obj: assess
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 Source:lancet 2008;372:216-23 En 2002 on a fini la phase1 et un an après on a decidé de suivre l’évolution des gens qui avaient été enrollé dans cet essai. Simplifier l’organigramme Le but l’objectif de cet prolongation est d’observer la reponse immune au long terme chez les gens traités ainsi que le degré d’elimination des plaques et les effets a long terms sur l’esperance de vie d’une part et l’evolution congitive d’autre part. En juin 2003 sur les 80 personnes du départ -20 sont mort avant le commencement de la prolongation -24 ont refusés de poursuivre -seulemetn 36 ont été suivis (10 sont morts et 26 en vie (20 AN1792 et 6 plavebo) -9 personnes parmi les décédés ont autorisées les analyses post mortem ( 1 a été exclus car elle n’avait pas la maladie d’alzheimer) 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

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) Comme on peut le voir sur le schema, l’immunisation permet d’avoir un Abeta load qui diminue chez les personnes avec un taux d’ac qui monte.Ce taux d’ac est egalement correlé avec la suppression des plaques amyloides Ces schemas nous montrent que l’immunisation est une methode efficace pour se debarasser des plaques amyloides au niveau cerebral etant donné que chez les personnes qui ont un haut taux d’anticorps on a une suppression importante des plaques amyloides ex:7-8 cependant on remarque que le temps de survi chez ces gens ne varie pas proportionnellement avec ce taux de suppression ex 7 8 et de plus on a aucune amelioration au niveau cerebral comme le montre le taux au MMSE This test show that immunotherapy is a good method to decrease Aβ load and to remove Aβ plaques but can’t improve survival time and cognitive performance!

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. Dans tout le groupe il n’y a pas de preuve de l’amélioration du temps de survie et d’amelioration des capacités cognitives par rapport au groupe placebo. Ajouter légende des courbes

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?

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) ABeta1-7 CRM197 Conjugate Schema du diapo de wyeth QS21 est un adjuvant qui stimule la voie th1et permet la production de cytokines pro inflammatoires comme l’IFN gamma. QS21 est un extrait d’ecorce d’arbre soap.(quillaja saponins)

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.

Story continus with ACC-001
Scheme of phase II Objectif Criteria of inclusion Evaluating Safety, Tolerability, and Immunogenicity of ACC-001 in Subjects With Alzheimer's Disease Age: 50 – 85 years MMSE 16 to 26 Arm Assigned Interventions 1: Active Comparator arm 1: ACC QS-21 2: Active Comparator arm 2: ACC-001 3: Placebo Comparator arm 3: QS-21 4: Placebo Comparator arm 4: Phosphate Buffered Saline ACC QS21 QS-21 is fixed at 50 micrograms. IM injection, dose 3-30micrograms, frequency: Day 1, month 1, 3, 6, &12. Etude commence en may 2007 et finira en may 2012 ACC-001 IM injection, dose 3-30micrograms frequency: Day 1, month 1, 3, 6, &12. QS-21: IM injection 50μg Drug: Phosphate buffered saline

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

IV/ Passive Immunisation

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 G 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

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 1°) because direct injection of antibody into the brain causes a decrease in amyloid β and only antibodies against the N term causes this effect 2°)consistent with this following peripheral administration of amyloid β specific antibody, activated microglial cells are found surrounding the amyloid β plaques, there is a less clearance of amyloid β following injections of amyloid β specific antibody 3°)Into animals studies: intravenous injection of antibodies  improvement in cognition and increased plasma concentrations of amyloid β The peripheral sink hypothesis : Administration of amyloid β specific antibodies Efflux of Amyloid β from brain to blood Neurology 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

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 Multiple ascending dose Safety and tolerability on a long term Serum Cerebral Spinal Fluid

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

Alzheimer’s tests Depression ? Ischemia start Ischemia evolution
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 Hygiène:bain? Habillage:choix des habits? Continence:décision de se rendre aux wc? Alimentation:besoin de manger?

Objectives: linear decline and compared treatment differences within dose cohorts Scr J1 W6 W12 W18 W24 W30 W36 W42 W48 W52 W54 W60 W66 W72 W78 Adas cog X DAD NTB Mmse CDR sb CSF MRI Safety Vol. Hachnski pour ne pas screener des patients avec dégénersecence vascumaire Insister sur la fait que test peu etre trop tard sur le niveau de a maladie Neurology december,2009

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 this picture? 11 advance sheets Elocution : Can you read us this word list? Movements : Can you send a letter? Scale fuller than MMSE No differences between kind of memory Faible sensibilité de l’adas cog pour l’évaluation du changement pour les patients à un stade léger de la maladie d’alzheimer caract par des scores élevés en MMSE Bad evaluation of attention fonctions & executive fonctions

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 Hygiène:bain? Habillage:choix des habits? Continence:décision de se rendre aux wc? Alimentation:besoin de manger? The clothing ? The lunches ? Daily wash ?

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 Hygiène:bain? Habillage:choix des habits? Continence:décision de se rendre aux wc? Alimentation:besoin de manger? The higher the score The lower evolution Alzheimer’s disease

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 9 kinds of tests evaluatin L'empan mnésique désigne le nombre d'éléments (en général des chiffres) que l'on peut restituer immédiatement après les avoir entendus. Une expérience classique consiste à lire une liste de chiffres, à une vitesse donnée (par exemple un par seconde) puis à demander au sujet de les restituer dans l'ordre. Quand la liste contient moins de 5 éléments, le rappel ne pose normalement pas de problème. Au-dessus de 7 éléments il devient beaucoup plus difficile. Sensibilité supérieur a l’adas cog surtout chez patients faiblement atteint Mais échelle récente pas encore encré comme examen de référence mais en devenir Réf:maladie d’alzheimer et déclin cognitif Vol 13 Aout 2008 p 336 à 340 Sensibility NTB > Sensibility ADAS- Cog for dimly affected

? 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 03: Home and Hobbies: Life at home No significant functions at home Memory:No memory losssevere memory loss Orientation:Fully orientedOriented to person only Personal care:Fully capable of self careRequires much help;frequent incontinence Community:Independent function in job, shoppingOnly functions in family home J and PS:Solves every problemsunable to make jugmenet or solve problems Community Judgment and Problem Solving

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 Mitt at least 1 infusion Completer  6 infusions In the Completer population: treatment differences were observed on the ADAS-Cog the DAD the NTB & only a trend on the MMSE Neurology december,2009

Pharmacokinetic Results Maximum concentrations 1 hour after each infusion Small volume of distribution = ml/Kg Slow clearance 0,07-0,09 mL/h/Kg Long t ½ = days One infusion every 13 weeks A dosage every 6 weeks No anti-bapineuzumab antibodies Bapineuzumab dosage CSF Bapineuzumab Maximum concentrations after 1 hour & a bioavailability of 100 %  forme IV 2 ‰ – 3 ‰ Bapineuzumab serum brain Bapineuzumab’s activity blotter mecanism Bioavailability = 100 % Neurology december,2009

Efficacy Results Exploratory analyses suggest to split population between ApoE4 Non ApoE4 Subjects Bapineuzumab group Placebo group mITT ApoE4 Non ApoE4 35 % 42 % 23 % 29 % Completer 65 % 58 % 77 % 71 % Neurology 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

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

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 ApoE4 non carriers Completer analyses showed greater treatment differences on all measures (36B/21P) ApoE4 carriers: although larger differences were present, a trend was not observed on ADAS-Cog & DAD (42B/57P) 74 Placebo No treatment differences were observed on any endpoint including the ADAS-Cog the DAD Neurology december,2009

ApoE 4 non carriers Mitt population
The development of the Bapineuzumab Efficacy Results Rouge évolution normale de la maladie sur 78 semaines Chaque courbe est statistiquement significative avec NTB le + car l’écart entre les courbes > Bapi ralentit l’évolution de la maladie mais n’engendre pas de bénéfices que ce soit sur les echelles cognitives ou évaluant l’impact de la maldie sur les tâches quotidiennes & même auhmentation du score dans les premières semaines Décrochage entre courbe rouge et bleu entre la 37 ème semaine pour adas cog & NTB, 50 ème semaine DAD ET CDR sb ApoE 4 non carriers Mitt population

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

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 No significant change in brain volume Significant increase in ventricular volume Clinical relevance is unclear Bapineuzumab patients Carriers Mean:2,5cc;95% CI:0,1 to 5,1 cc; p=0,037 Non carriers Mean:10,7 cc;95% CI:3,4 to 18,0; p=0,004 Neurology 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 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 Brain volume measured by brain boundary shift integral (BBSI) Mitt analyses using RM model without assumption of linearity, adjusted for whole brain volume at baseline, MMSE at baseline and ApoE4 status Ici, aussi on constate que le Bapi ne fait que ralentir la diminution du volume du cerveau traduisant une progression de la maladie avec un cerveau qui s’atrophie faut de stimulation Slowing brain atrophy

90 % mild to moderate in severity
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 Back pain ,1% vs 5,5% Weight loss ,5% vs 1,8% Anxiety ,3% vs 3,6% Paranoia ,5% vs 0,9% Vomiting ,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 ,1% vs 3,6% Muscle spasms 5,6 % vs 0,9% Neurology december,2009

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 december,2009

Bapineuzumab dose cohort
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 december,2009

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

Conlusion on Phase 2 study Positive benchmarks Negative Benchmarks 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 december,2009

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 ) 1 US 2 UE 800 ApoE4 carrier 2 cohorts well identified 1250 1 000 Avril 2009 ApoE4 non carrier

The phase 3 stugy design: Multiple dose, double-blind, placebo controlled, randomized, outpatient study The development of the Bapineuzumab 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 1 US 2 UE Non ApoE4 1,0 mg/kg of Bapineuzumab 2,0 mg/kg of Bapineuzumab

The phase 3 stugy design: Multiple dose, double-blind, placebo controlled, randomized, outpatient study The development of the Bapineuzumab 0,5 mg/kg of Bapineuzumab ApoE4 To decrease VE risk 1,0 mg/kg of Bapineuzumab 0,5 mg/kg of Bapineuzumab 1 US 2 UE Non ApoE4 1,0 mg/kg of Bapineuzumab To decrease VE risk 2,0 mg/kg of Bapineuzumab

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 Non ApoE4 Marketing for Non ApoE4 carriers diagnosis test 1,0 mg/kg

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

Critical reappraisal of amyloid hypothesis
22/01/10 Critical reappraisal of amyloid hypothesis Hypothesis Status Comments Other causes of AD would relate to Aβ production and clearance: PS I&II mutations γ secretase Aβ 42 ApoE Aβ deposition increased 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 Link unknown Reducing Aβ & plaques would ameliorate AD symptoms Non validated Not seen in clinical trials Need to consider the other mechanisms involved in AD JOURNAL OF NEUROCHEMISTRY | 2009 | 110 | 1129–1134 82

SWOT Opportunities Threats 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 Early diagnostic is a problem BSP:forbetaben (phase III) Bien qu’il soit résorbable

Our opinion about this deal !!

Thanks for your attention!

Any questions?

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)

Summary I/ The deal II/ Mechanism of Alzheimer’s disease

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Summary I/ The deal II/ Mechanism of Alzheimer’s disease

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